Cell-associated HIV mucosal transmission: The neglected pathway

Dr. Deborah Anderson from Boston University School of Medicine (BUSM) and her colleagues are challenging dogma about the transmission of the human immunodeficiency virus type 1 (HIV-1). Most research has focused on infection by free viral particles, while this group proposes that HIV is also transmitted by infected cells. While inside cells, HIV is protected from antibodies and other antiviral factors, and cell-to-cell virus transmission occurs very efficiently through intercellular synapses. The Journal of Infectious Diseases (JID) has devoted their December supplement to this important and understudied topic.

The 10 articles, four from researchers at BUSM, present the case for cell-associated HIV transmission as an important element contributing to the HIV epidemic. Anderson chides fellow researchers for not using cell-associated HIV in their transmission models: "The failure of several recent vaccine and microbicide clinical trials to prevent HIV transmission may be due in part to this oversight."

Approximately 75 million people in the world have been infected with HIV-1 since the epidemic started over 30 years ago, mostly through sexual contact and maternal-to-child transmission. A series of vaccine and microbicide clinical trials to prevent HIV transmission have been unsuccessful, and scientists are returning to the drawing board to devise new approaches. The JID supplement advocates for new strategies that target HIV-infected cells in mucosal secretions.

The publication presents evidence that HIV-infected cells populate genital secretions from HIV-infected men and women as well as breast milk, and genetic evidence suggesting that cell-associated HIV transmission occurs in people. Various models for studying cell-associated HIV transmission and molecular targets for intervention are also presented. Finally, the efficacy of current HIV prevention strategies against cell-associated HIV transmission and opportunities for further development are described.

Bone metastases in prostate cancer blocked by HIV drug

The receptor CCR5, targeted by HIV drugs, is also key in driving prostate cancer metastases, suggesting that blocking this molecule could slow prostate cancer spread

Although prostate cancer can be successfully treated in many men, when the disease metastasizes to the bone, it is eventually lethal. In a study researchers show that the receptor CCR5 best known for its role in HIV therapy, may also be involved in driving the spread of prostate cancer to the bone.

"Because this work shows we can dramatically reduce metastasis in pre-clinical models, and because the drug is already FDA approved for HIV treatment- we may be able to test soon whether this drug can block metastasis in patients with prostate cancer," says Richard Pestell, M.D., Ph.D., MBA, Director of the Sidney Kimmel Cancer Center at Thomas Jefferson University and senior author on the study.

The work builds on previous research from Dr. Pestell's lab that showed in 2012 that CCR5 signaling was key in the spread of aggressive forms of breast cancer to the lungs. Their prior paper demonstrated that breast cancer cells that carried the CCR5 receptor on their surface were drawn to the lung. Given that prostate cancer cells were attracted to the bone and brain, Pestell's team investigated whether CCR5 could play a role in prostate cancer metastases as well.

The research was complicated by the fact that there was no immune competent mouse model of prostate cancer that reliably developed bone and brain metastases. So the researchers developed a prostate cancer cell line, driven by an upregulated Src gene, that regularly caused bone metastases in immune-competent mouse models. Because the immune system is so important in human prostate cancer it was important to develop a model that reflected human disease.

The researchers analyzed the genes of the metastasized bone and brain tumors and found genes driving the cancer were also involved in the CCR5 signaling pathway. To investigate further, the researchers administered the CCR5-blocking drug maraviroc to the new prostate cancer mouse model. In comparison to control animals, maraviroc dramatically reduced the overall metastatic load by 60 percent in the bone, brain and other organs.

Finally, in order to determine whether a similar mechanism might be at play in human prostate cancer, the researchers mined the genomic data of patients with prostate cancer and found that CCR5 was more highly expressed in prostate cancer tissue compared with normal tissue, and even more highly expressed in metastases compared with primary tumors. "In fact, we noticed that patients who had a lower expression of the CCR5-pathway genes had a longer survival times, whereas high expression of these CCR5 genes was associated with a shorter overall survival," said co-first author Xuanmao Jiao, Ph.D., and an instructor in the department of Cancer Biology at Jefferson.

Hepatitis C ruled out as cause of mental impairment in HIV patients

To stop these changes, scientists have to learn what is causing them. One possibility researchers are considering is that long-term infections with other pathogens, common in HIV-positive patients, are affecting the brain. But a new study has eliminated one of their prime suspects: the hepatitis C virus, which infects about one in every three HIV-positive patients in the United States.

The research, conducted by a team that includes scientists at Washington University School of Medicine in St. Louis, appeared Dec. 10 in Neurology.
"Hepatitis C infection has serious long-term side effects, such as damage to the liver, but our research indicates that it does not affect the brain," said lead author David Clifford, MD, of Washington University.

The research was conducted as part of the CNS HIV Anti-retroviral Therapy Effects (CHARTER) study, a multicenter collaborative that is examining the long-term neurological effects of HIV infection.

Hepatitis C most commonly infects illicit-drug users who share needles used to inject the drugs. Drug abuse can harm the brain, making it difficult to determine whether hepatitis C or problems caused by drug use contribute to brain impairment in patients with both HIV and hepatitis C.

To answer this question, Clifford and his colleagues studied 1,582 HIV patients, 408 of whom were also infected with hepatitis C. Each patient received a detailed neuropsychological exam devised by Clifford and other CHARTER researchers to detect signs of HIV-associated mental deficits.

The exam takes two to 2 1/2 hours, and includes written examinations taken by the patient and physical exams given by medical professionals. Patients are tested for their ability to express themselves, to make decisions, to learn and retain new information using multiple types of memory, and to move the body and control muscles.

"In all, we looked at seven domains of mental function," said Clifford, who is the Melba and Forest Seay Professor of Clinical Neuropharmacology in Neurology. "We studied their overall performance and looked at each domain individually and found no evidence that the group with hepatitis C performed worse."

According to Clifford, this was particularly impressive because the participants in the group with hepatitis C were older, had less education and had lower scores on tests of reading, comprehension, spelling and math.

With hepatitis C eliminated, Clifford and his colleagues are turning their attention to the immune responses triggered by HIV in the brain and the bowel during the initial stages of infection. He and others believe these early responses, which include bursts of inflammation, lead to chronic inflammation that adversely affects the brain.

"If a hepatitis C infection gets to the point where it damages liver function, the resulting inflammation might well contribute to mental impairment," Clifford said. "Beyond that, though, it doesn't seem to be an active collaborator in the harm HIV does to the brain."

People with mental illness more likely to be tested for HIV

People with mental illness are more likely to have been tested for HIV than those without mental illness, according to a new study. The researchers also found that the most seriously ill – those with schizophrenia and bipolar disease – had the highest rate of HIV testing

The study assessed nationally representative data from 21,785 adult respondents from the 2007 National Health Interview Survey (NHIS) and provides an update of prior research using 1999 and 2002 NHIS data. The 2007 version is the most recent cycle of the survey that included information both on mental health diagnoses and HIV testing.

The current Penn-led study adds precision to earlier research by reporting on HIV-testing rates according to specific mental health diagnoses; previous studies did not differentiate persons with, for example, depression, bipolar disorder, and schizophrenia spectrum disorder.

The researchers found that 15 percent of respondents reported a psychiatric disorder. Of these, 89 percent had symptoms of depression and/or anxiety, 8.5 percent had bipolar disorder, and 2.6 percent had schizophrenia spectrum disorder. Among persons reporting at least one mental illness, 48.5 percent had been tested for HIV. The 48.5 percent rate compares to a testing rate of 35 percent among those without mental illness. More specifically, 64 percent of persons with schizophrenia, 63 percent of persons with bipolar disorder, and 47 percent of persons with depression and/or anxiety reported ever being tested for HIV.

"Our study shows that persons with mental illness and/or their care providers recognize that they are at higher risk and should be tested," said senior author Michael B. Blank, PhD, associate professor in Psychiatry at Penn and co-director of the Penn Mental Health AIDS Research Center. "However, by no means we should be complacent since these results may in large part be due to individual vigilance. The fact is there are few formal prevention and screening efforts targeted at this at-risk population. In light of the fact that mentally ill people are more likely to engage in risky behavior, mental health providers should consider routinely offering HIV/AIDS testing, something that does not typically occur now."

HIV infection and mental illness are often co-occurring health conditions, with nearly half of persons living with HIV having a psychiatric disorder while between 5-23 percent of those with mental illness are infected with HIV.

In addition, the study found that persons aged 25-44, women, racial and ethnic minorities, individuals who are windowed/divorced/separated, those reporting excessive use of alcohol or tobacco, and persons with HIV risk factors were significantly more likely to be tested for HIV than their counterparts.
Separate research has found that mentally ill individuals are more likely than others to engage in high-risk behaviors associated with HIV transmission, including unprotected sexual intercourse, injection drug use, and sex with multiple partners.

"Our finding that persons with mental illness were tested for HIV at a higher rate than those without mental illness is encouraging and consistent with previous analyses," said lead author Baligh R. Yehia, MD, MPP, MSHP, assistant professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and director of the Penn Medicine Program for LGBT Health. "However, the large number of people with mental illness who still have not been tested necessitates increased public health prevention efforts, particularly in light of the increased HIV risk in this population."

The CDC recommends that all persons aged 13-64 be tested for HIV in healthcare settings and that persons with increased risk such as injecting drug users and their sex partners, sex workers, men who have sex with men, and heterosexuals with multiple sex partners be tested at least annually.

HIV/AIDS drugs could be repurposed to treat AMD, researchers suggest

Drugs that have been used for the past 30 years to treat HIV/AIDS, could be repurposed to treat the dry form of age-related macular degeneration (AMD), a new study suggests. Age-related macular degeneration is a progressive condition that is untreatable in up to 90 percent of patients and is a leading cause of blindness in the elderly worldwide. The two forms of age-related macular degeneration, wet and dry, are classified based on the presence or absence of blood vessels that have invaded the retina.

Age-related macular degeneration is a progressive condition that is untreatable in up to 90 percent of patients and is a leading cause of blindness in the elderly worldwide. The two forms of age-related macular degeneration, wet and dry, are classified based on the presence or absence of blood vessels that have invaded the retina. A detailed understanding of the molecular mechanisms underlying wet age-related macular degeneration has led to several robust FDA-approved therapies. In contrast, there are no approved treatments for dry age-related macular degeneration thus far.

Nucleoside reverse transcriptase inhibitors (NRTIs) are the most widely used class of anti-HIV drugs. NRTIs are thought to be therapeutic in HIV/AIDS patients because they target the enzyme reverse transcriptase, which is critical for replication of HIV. Previous work from the Ambati lab found that a type of toxic molecule called Alu RNA accumulate in the retina to cause dry age-related macular degeneration; interestingly, Alu RNA and HIV are similar in that they both require reverse transcriptase to fulfill their life cycle.

In their Science publication, Fowler et al. report that multiple FDA-approved NRTIs prevented retinal degeneration in a mouse model of dry age-related macular degeneration. Surprisingly, this effect of NRTIs in the eye was not due to the well-known function of these drugs to inhibit reverse transcriptase. Instead, NRTIs blocked an innate immune pathway called the "inflammasome," even in experimental systems in which the NRTIs were not capable of blocking reverse transcriptase. In their report, they also showed that NRTIs were effective in other disease models that share common signaling pathways with the dry age-related macular degeneration model, including the "wet" form of age-related macular degeneration -- a disease that when treated still does not lead to substantial vision improvement in two-thirds of patients -- and graft-versus-host disease which is the major obstacle preventing successful allogeneic hematopoietic stem cell transplantation.

"Repurposing of NRTIs could be advantageous, for one, because they are very inexpensive. Moreover, through decades of clinical experience, we know that some of the drugs we tested are incredibly safe. Since these NRTIs are already FDA-approved, they could be rapidly and inexpensively translated into therapies for a variety of untreatable or poorly treatable conditions," said Benjamin Fowler, the lead author and a postdoctoral fellow in the Ambati lab. Ambati added, "We are excited at the prospect of testing whether NRTIs could be effective in halting the progression of age-related macular degeneration in patients."

NRTIs were originally designed to treat cancer in the 1960s. They re-emerged in the late 1980s and became the first drugs the FDA-approved to treat HIV/AIDS.

Semen directly impairs effectiveness of microbicides that target HIV

Researchers have discovered why microbicides developed to prevent HIV succeed in the lab but fail in clinical trials: Semen. Semen enhances the infectiousness of HIV by causing the virus to cluster together, increasing its ability to attach to and infect cells. This effect is then sufficient to override the antiviral properties of the microbicides.

In the fight against HIV, microbicides -- chemical compounds that can be applied topically to the female genital tract to protect against sexually transmitted infections -- have been touted as an effective alternative to condoms. However, while these compounds are successful at preventing transmission of the virus in a petri dish, clinical trials using microbicides have largely failed. A new study from the Gladstone Institutes and the University of Ulm now reveals that this discrepancy may be due to the primary mode of transportation of the virus during sexual transmission, semen.

"We think this may be one of the factors explaining why so many drugs that efficiently blocked HIV infection in laboratory experiments did not work in a real world setting," explains co-first author Nadia Roan, PhD, a visiting scientist at Gladstone and an assistant professor-in-residence in the Department of Urology at the University of California, San Francisco. "We've shown previously that semen enhances HIV infection, but this is the first time we've shown that this activity markedly reduces the antiviral efficacy of microbicides."

Semen markedly enhances the infectiousness of HIV through the presence of protein aggregates called amyloid fibrils. HIV binds to these fibrils, causing the virus to cluster together and increasing its ability to attach to and infect cells in the host -- in this case the sexual partner of the infected individual. This effect is then sufficient to increase the infectiousness of the HIV virus, thereby diminishing the antiviral properties of the microbicides.

In the study researchers tested the effectiveness of several different types of microbicides targeting the HIV virus on cells that had been exposed to HIV alone compared with cells that were treated with both HIV and semen. Across the board, they saw that not only did the cells with semen have rates of HIV infection approximately ten-fold higher than normal, these microbicides were up to twenty times less effective at blocking the virus in these cells than in those not exposed to semen.

Senior author Jan Munch, PhD, from the University of Ulm says, "Our findings suggest that targeting amyloids in semen is an alternative strategy to improve drug efficacy. The next step is to create a compound or cocktail of drugs that targets both the HIV virus and these amyloid fragments and to test its effectiveness. Also, given that semen is the main means of transmission of HIV, future testing of microbicides in the lab should be performed in the presence of semen to better predict antiretroviral efficacy in real life."

To test that it was the HIV-enhancing ability of semen that was having this effect on the microbicides and not some other substance, the researchers repeated the experiments using semen from men whose semen does not enhance HIV infection due to a disorder called ejaculatory duct obstruction. In the presence of these samples, there was no decrease in effectiveness of the anti-viral microbicides, confirming the importance of the HIV-promoting effects of semen in counteracting the effectiveness of these drugs.

Most microbicides work by targeting the virus itself, attempting to break it down or blocking its ability to infect a cell. However, the heightened infectiousness of HIV in the presence of semen appears to over-power any anti-viral effects the microbicides possess. The one exception to this finding is a different type of microbicide that acts on the host cells' receptors, stopping the virus from latching on from within. In the current study, this microbicide, called Maraviroc, was equally effective in preventing infection both with and without the presence of semen.

"There are important potential clinical implications for this study," says Warner Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology and a senior author on the paper. "Microbicides were originally developed as a way to empower and protect women in sub-Saharan Africa who often don't have a way to negotiate safe sex or condom use. However, the first generation of microbicides were largely ineffective or worse, some even leading to increased transmission of the virus. This study sheds light on why these microbicides did not work, and it provides us with a way to fix this problem by creating a new compound drug combining antivirals and amyloid inhibitors."

Altered milk protein can deliver aids drug to infants

A novel method of altering a protein in milk to bind with an antiretroviral drug promises to greatly improve treatment for infants and young children suffering from HIV/AIDS, according to a researcher.

That's critical because an estimated 3.4 million children are living with HIV/AIDS, the World Health Organization reports, and nine out of 10 of them live in resource-limited countries in sub-Saharan Africa, where effective antiretroviral treatments still are not widely accessible or available. International medical experts believe less than a third of affected children worldwide receive an antiretroviral drug.

Complicating treatment is that most antiretroviral drugs are not well tolerated by very young children. One of the most commonly prescribed antiretroviral drugs for treating and preventing HIV infection, Ritonavir, has undesirable side effects and important oral-delivery problems. Its physicochemical properties challenge its administration to infants, explained Federico Harte, associate professor of food science.

"Ritonavir has a high hydrophobicity and low solubility in water, which lead to a low dissolution rate in the gastrointestinal fluid and, hence, to insufficient bioavailability. The liquid formulation used to treat infants over one month of age contains 43 percent ethanol and has an awful flavor that has been described as bitter-metallic, medicinal, astringent, sour and burning," he said.

"Moreover, when coming into contact with the stomach mucosa, Ritonavir causes nausea, vomiting and diarrhea. Therefore, we need to develop alternative pediatric formulations of Ritonavir and overcome its poor water solubility to improve its oral administration to infants and children."

To solve that problem, Harte looked to a group of proteins in cow's milk celled caseins. Casein proteins form spherical aggregates called casein micelles, which are responsible, incidentally, for the white color of milk. The casein micelles in mammals' milk are natural delivery systems for amino acids and calcium from mother to young, and Harte reasoned, might deliver Ritonavir molecules as well.

"I have been working with bovine casein micelles for a few years now, and we have investigated the structure and functionality of these proteins," he said. "What we found is these micelles are able to carry molecules that have very little solubility in water, that have low molecular weight and that are very hydrophobic -- such as Ritonavir."

Significantly, Harte discovered in his research that subjecting milk to ultrahigh-pressure homogenization enhances the binding properties of the casein micelles. In previous studies, he learned that casein micelles could be bound to triclosan -- an antimicrobial used in deodorants -- and vitamin D, which is added regularly to skim milk.

Normal milk is homogenized at 10 to 15 megapascals, he pointed out. Milk in this research was homogenized at between 400 and 500 megapascals, disassociating the casein micelles and improving the protein's binding qualities to attach to drug molecules.

"As a result of this enhanced binding of molecules, we believe a milk powder containing Ritonavir can be used as baby formula, providing a transport system for a drug that is not very soluble in water. Right now we are running tests, and we are in the final stages of an experiment in which we gave three different formulations to piglets," Harte said.

"We are taking blood serum samples every three hours to study the kinetics of the drug in the piglets," he said. "The hope is that -- and we don't have the data yet -- we find that the Ritonavir is being adequately delivered by the protein in milk. So if that works, I think we are pretty close to having a formulation that can be used with hydrophobic drugs."

Harte noted that with his proposal for research funding he included a letter from a pediatrician at St. Jude Children's Research Hospital describing the challenge of orally administering Ritonavir to infants and young children.

"She has been treating patients with AIDS, and the awful flavor and ethanol content of Ritonavir were big issues for her," he said. "I am hopeful that this may lead to an application that works against AIDS. We have not done any clinical trials yet, so we will need to get data from those trials to say for sure."

First Immature form of HIV seen at high resolution surprises researchers

The first structure of the immature form of HIV at a high enough resolution has been obtained by researchers, allowing them to pinpoint exactly where each building block sits in the virus. The study reveals that the building blocks of the immature form of HIV are arranged in a surprising way.

Sientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany and collaborators from Heidelberg University, in the joint Molecular Medicine Partnership Unit, have obtained the first structure of the immature form of HIV at a high enough resolution to pinpoint exactly where each building block sits in the virus. The study reveals that the building blocks of the immature form of HIV are arranged in a surprising way.

"The structure is definitely different from what we'd expected," says John Briggs from EMBL, who led the work. "We assumed that retroviruses like HIV and Mason-Pfizer Monkey Virus would have similar structures, because they use such similar building blocks, but it turns out that their immature forms are surprisingly different from each other. At this point, we don't really know why."

Briggs and colleagues used cryo-electron microscopy to study the protein lattice that surrounds the virus' genetic material. After infecting one of the cells in our immune system, HIV replicates, producing more copies of itself, each of which has to be assembled from a medley of viral and cellular components into an immature virus. This is the form that leaves the cell. The protein building blocks that make up the virus are then rearranged into the virus' mature form, which can infect other cells.

The first cryo-electron microscopy images of immature HIV, obtained at EMBL in the 1990s, surprised researchers by showing that the virus did not have a regular symmetrical structure, as had been assumed. That meant it was going to be difficult to get a detailed picture of the structure of its protein lattice. Two decades on, by optimising both how data is collected at the microscope and how it is analysed, Florian Schur, a PhD student in Briggs' lab, has now achieved an unprecedentedly detailed structure.

With this structure in hand, scientists have a basis to probe further. They can use it to decide where to focus efforts for achieving the even greater detail needed to explore potential drug targets, for instance. It will also enable researchers to understand how mutations might influence how the virus assembles. And the techniques themselves can be applied to a variety of questions.

"This approach offers so many possibilities," says Schur. "You can look at other viruses, of course, but also at complexes and proteins inside cells, with a whole new level of detail."

In future, the EMBL scientists will use the approach to look at other viruses and at the vesicles that transport material inside cells. They also aim to push the techniques even further, to allow them to see other parts of the viral proteins that are currently beyond their reach, but which they suspect play an important role in HIV maturation.

"In the long term, we'd also like to investigate how drugs which are known to inhibit virus assembly and maturation actually work," Briggs concludes.

Can social media help stop the spread of HIV?

In addition to providing other potential benefits to public health, all of those tweets and Facebook posts could help curb the spread of HIV. Although public health researchers have focused early applications of social media on reliably monitoring the spread of diseases such as the flu, a new article tells of a future in which social media might predict and even change biomedical outcomes.

Although public health researchers have focused early applications of social media on reliably monitoring the spread of diseases such as the flu, Sean Young of the Center for Digital Behavior at the University of California, Los Angeles.

"We know that mining social media will have huge potential benefits for many areas of medicine in the future, but we're still in the early stages of testing how powerful these technologies will be," Young said.

With the right tools in place, he says, social media offers a rich source of psychological and health-related data generated in an environment in which people are often willing to share freely.

His recent work on Behavioral Insights on Big Data (BIBD) for HIV offers the tantalizing possibility that insights gleaned from social media could be used to help governments, public health departments, hospitals, and caretakers monitor people's health behaviors "to know where, when, and how we might be able to prevent HIV transmission."

Young details a social-media-based intervention in which African American and Latino men who have sex with men shared a tremendous amount of personal information through social media, including when or whether they had 'come out,' as well as experiences of homelessness and stigmatization. What's more, they found that people who discussed HIV prevention topics on social media were more than twice as likely to later request an HIV test.
In the context of HIV prevention, tweets have also been shown to identify people who are currently or soon to engage in sexual- or drug-related risk behaviors. Those tweets can be mapped to particular locations and related to actual HIV trends.

What's needed now is the updated infrastructure and sophisticated toolkits to handle all of those data, Young said, noting that there are about 500 million communications sent every day on Twitter alone. He and a team of University of California computer scientists are working to meet that challenge now.
Although privacy concerns about such uses of social media shouldn't be ignored, Young says there is evidence that people have already begun to accept such uses of social media, even by corporations looking to boost profits.

"Since people are already getting used to the fact that corporations are doing this, we should at least support public health researchers in using these same methods to try and improve our health and well being," he said. "We're already seeing increased support from patients and public health departments."

Real-life social networking prompts people to get tested for HIV

Old-school face-to-face social networking is a more effective way to identify people with HIV than the traditional referral method, suggests research. The study shows that social networking strategies - enlisting people in high-risk groups to recruit their peers to get tested – is more efficient and targeted than traditional testing and referral programs, resulting in 2-and-a-half times more positive test results.

As many as 20 percent of HIV-positive people are unaware of being infected with the virus, and therefore do not receive vital treatment. In addition to missing out on medications that can improve their prognosis and quality of life, these patients also are more likely to spread the disease to others. Therefore, encouraging people at risk for HIV to get tested is critical.

SNS programs likely are more effective because they are more proactive than traditional counseling, testing and referral (CTR) programs, which are available to anyone who wishes to be tested but do not offer the same motivation as encouragement by peers.

"A limitation of the traditional approach is that many people who are at high risk of HIV never take the initiative to get tested on their own," said Ryan Westergaard, MD, PhD, MPH, lead author of the study and assistant professor of medicine at the University of Wisconsin School of Medicine and Public Health, Madison. "Our study found that using social network strategies, in which we enlist people at high risk to encourage peers in their social networks to get tested, results in a higher proportion of positive HIV tests - making our efforts more effective and allowing us to reach the people who need it most."

In the study, researchers collected data from 45 HIV testing sites in Wisconsin over four years. Through SNS, 54 of 2,169 (2.49 percent) people tested were HIV-positive vs. 440 of 48,318 (.91 percent) of those tested through CTR.

In SNS - which is growing in large cities - people at high risk for HIV are paid an incentive (typically $10 to $20) for every person they refer who gets tested. Some experts are concerned that these programs are costly, but the new research suggests that SNS is worthwhile, because it results in a higher percentage of positive tests.

"Some SNS programs limit the numbers of people a recruiter can refer for testing, based on the assumption that that they're just signing up everyone they know to make more money, even if they're unlikely to be HIV-positive," said Dr. Westergaard. "Our study showed that, on average, the 30th or 40th person referred for testing through SNS had just as high if not a higher probability of having a positive HIV test than the first five or 10 people referred.This suggests SNS can be a cost-effective tool to increase testing in specific high risk pools, such as men who have sex with men and transgender people."

Antiretroviral therapy benefits HIV-infected stimulant users

New clinical research from UC San Francisco shows that 341 HIV-infected men who reported using stimulants such as methamphetamine or cocaine derived life-saving benefits from being on antiretroviral therapy that were comparable to those of HIV-infected men who do not use stimulants.

That said, those who reported using stimulants at more than half of at least two study visits did have modestly increased chances of progressing to AIDS or dying after starting antiretroviral therapy compared to non-users. The data was collected between 1996 and 2012.

"Patients with HIV who use stimulants and other substances often experience difficulties with accessing antiretroviral therapy, partially due to the concerns of healthcare providers that they will not be able take their medications as directed. Findings from this study demonstrate that many stimulant users take their antiretroviral therapy at levels sufficient to avoid negative clinical outcomes. When we look at overall mortality, antiretroviral therapy leads to similar clinical benefits for both stimulant users and non-users, notwithstanding stimulant use," said the study's primary investigator, Adam W. Carrico, PhD., UCSF assistant professor of nursing.

The study included 1,313 HIV-infected men who have sex with men within the Multicenter AIDS Cohort Study, an ongoing nationwide prospective study of HIV infection among men who have sex with men in the U.S.

"If we are to achieve the goals of the President's National HIV/AIDS Strategy and UNAIDS to end the HIV/AIDS epidemic, we will need to treat HIV-positive active substance users for their HIV while encouraging them to stop or reduce their substance use. Programs integrating substance abuse services with HIV clinical care may both improve health outcomes for patients and reduce new infections," said Carrico.

The UCSF Division of HIV/AIDS at San Francisco General Hospital has created an integrated care delivery system that could serve as a model for other clinics, added Carrico. The HIV primary care clinic utilizes a patient centered team care approach that includes substance abuse services for stimulant and opioid users, along with mental health services, all located onsite. STOP, the "stimulant treatment outpatient program," within the clinic provides outpatient substance abuse and mental health treatment integrated with patients' primary medical care.

"The pattern of use varies and the real issue is whether patients can take their antiretrovirals as prescribed. We find that some patients are able to start taking antiretrovirals very reliably before they are able to decrease or stop their stimulant use, which often requires more complex behavioral, emotional, interpersonal and environmental changes. Being in an HIV primary care setting allows us to engage stimulant users even if they are not ready to go to specialty substance abuse programs or support groups," said Valerie Gruber, PhD, STOP director and UCSF professor of psychiatry.

Could there be an end in sight for AIDS?

South Africa is the epicentre of the HIV and AIDS epidemic with a staggering 6.4 million HIV infected citizens. In 1990 the WHO reported just 386 cases in South Africa. Over the next 15 years, despite warnings from scientists and policy makers, a tidal wave of infections ensued.  How can policy and health provision cope to improve the outlook?  A new article strategically examines the whole epidemic and identifies economic, epidemiological, and programmatic points for transition and future improvement.

Until 2001, HIV infection in the developing world amounted to certain death for all but the wealthiest. Development of Antiretroviral (ART) drugs now gives an infected young adult a life expectancy of 60. A massive break through, but each patient needs drugs for up to 30 years, representing a huge burden of cost and an enduring challenge for government and health providers to manage. The high cost of drugs may over reach the South African national health budget in a very few years. New infections outnumber AIDS deaths, increasing the number of people living with AIDS; patients requiring treatment increase faster than funding and the scenario escalates. Can the epidemic ever be managed out of an emergency into a more controlled state?

Prevention is central; only by reducing the rate of new infections can an eventual decline in HIV sufferers be achieved; an economic transition. After this tipping point those newly receiving treatment can outpace new infections; an epidemiological transition. In 2006 programmatic transition took place when newly initiated ART patients exceeded numbers of new patients needing ART. Sustained commitment to prevention and treatment has undoubtedly resulted in attrition of untreated HIV/AIDS patients. In future ART is proposed for a wider group of HIV patients, which the WHO believes will prevent 3 million deaths and 3.5 million new infections. It is clear though that despite this, AIDS and the financial load of ART will be here for many more generations, even if infection rates are brought under control.

The authors note "Although significant progress has been made in combating HIV and AIDS, the end of the epidemic may still be a long way off. However, sustained efforts to expand prevention and treatment programmes, as well as health systems strengthening and innovative financing, will ensure the long-term impact of these transitions."

Stem cell transplant does not cure SHIV/AIDS after irradiation of infected rhesus macaques

A new study reports a new primate model to test treatments that might cure HIV/AIDS and suggests answers to questions raised by the "Berlin patient," the only human thought to have been cured so far.

Being HIV-positive and having developed leukemia, the Berlin patient underwent irradiation followed by a bone-marrow transplant from a donor with a mutation that abolishes the function of the CCR5 gene. The gene codes for a protein that facilitates HIV entry into human cells, and the mutation - in homozygous carriers who, like the donor, have two defective copies - protects against HIV infection.

Several factors could have contributed to the cure of HIV/AIDS in the patient:

1. the ablation of blood and immune cells following irradiation killed all or many of the viral reservoir cells that are not eliminated by antiretroviral treatment (ART);
2. the CCR5 deletion mutation in the donor cells protected them and their progeny from HIV infection;
3. a "graft versus host" reaction occurred, where the transplanted cells and their progeny recognize the host cells as foreign and attacked and eliminated HIV-positive reservoir cells that survived the irradiation.

Guido Silvestri, from Emory University in Atlanta, USA, and colleagues investigated the relative contribution of the irradiation to eliminate the reservoir of HIV-infected cells. The scientists worked with the animal model of Simian Immunodeficiency Virus (SIV, a close relative of HIV that infects primates and causes a disease similar to AIDS) infection in rhesus macaques. Using a total of six monkeys (three of which served as controls and did not receive transplants) they performed, for the first time, hematopoietic stem cell transplantation in rhesus macaques infected with a chimeric simian/human immunodeficiency virus (SHIV) and treated with ART.

The researchers harvested hematopoetic stem cells from three macaques prior to infection (of all six animals) with SHIV. They also treated the macaques with ART to reduce viral load and mimic the situation in human HIV-infected patients on ART. They then exposed the three monkeys from which they had collected hematopietic stem cells to a high dose of radiation. This killed most of their existing blood and immune cells, including between 94 and 99% of their CD4-T cells -- the main target of HIV infection -- in the blood. The irradiation was followed by transplantation of each monkey's own virus-free hematopoietic stem cells. The latter can regenerate the blood and immune cells, and did so in all three monkeys within 3 to 6 weeks. Because the transplanted cells are not from a different donor, no graft versus host disease would be expected, and none was observed.

After that time, the scientists stopped ART in all six monkeys. As expected, the virus rebounded rapidly in the control animals. Of the three transplanted animals, two also showed a rapid rebound. The third monkey developed kidney failure two weeks after ART was stopped and was euthanized. It still had undetectable levels of virus in the blood at that time, but post-mortem analysis showed low levels of viral DNA in a number of tissues, arguing that none of the three transplanted monkeys was cured.

The researchers acknowledge a number of limitations of the study, including the small number of monkeys, and the relatively short period of ART prior to irradiation and transplantation. Nonetheless, they say their study "supports the hypothesis that myeloablative total body irradiation can cause a significant decrease in the viral reservoir in blood cells, even though it was not sufficient to eliminate all reservoirs." Their results, they say, suggest that in the cure of the Berlin patient, "the use of the CCR5 mutant donor and/or the presence of graft versus host disease played a significant role."

Having demonstrated in this first test-of-concept study that total body irradiation and hematopoietic stem cell transplantation in ART-treated SIV-infected rhesus macaques is feasible, the researchers express hope that "further studies using this model will provide critical information for the requirements to cure HIV infection in humans."

HIV antibody discovered that binds to novel target on virus

An NIH-led team of scientists has discovered a new vulnerability in the armor of HIV that a vaccine, other preventive regimen or treatment could exploit. The site straddles two proteins, gp41 and gp120, that jut out of the virus and augments other known places where broadly neutralizing antibodies (bNAbs) bind to HIV. This newly identified site on the viral spike is where a new antibody found by the scientists in an HIV-infected person binds to the virus. Called 35O22, the antibody prevents 62 percent of known HIV strains from infecting cells in the laboratory and is extremely potent, meaning even a relatively small amount of it can neutralize the virus.

Following their discoveries, the scientists found that 35O22-like antibodies were common in a group of HIV-infected people whose blood contained antibodies that potently neutralized a broad array of HIV strains. According to the researchers, this suggests that it might be easier for a vaccine to elicit 35O22 than some other known bNAbs, which are less common.

Since 35O22 binds only to forms of the viral spike that closely resemble those that naturally appear on HIV, the scientists believe a vaccine that elicits 35O22-like antibodies would need to mimic the natural shape of the spike as closely as possible. This would require a different approach than that used in many previous experimental HIV vaccines, which have included just parts of the viral spike rather than a structure that looks like the entire native viral spike.

In addition, the researchers report, the HIV strains that 35O22 neutralizes complement strains neutralized by other bNAbs. This suggests that eliciting or combining 35O22 with a few other bNAbs in a vaccine or a prevention or treatment regimen could likely neutralize the vast majority of HIV strains found around the globe, according to the scientists.

Tolerating, not fighting, viruses a viable survival strategy

In ecology, disease tolerance is defined as a host strategy not to fight a pathogen tooth and nail, but rather tolerate it to live (and survive) better in the long term. One key feature of tolerance is that the disease only progresses very slowly - if at all - even if the host carries a high pathogen load.

Roland Regoes, a senior scientist at ETH Zurich's Institute of Theoretical Biology, has now transferred this approach to HIV. He set about investigating whether there are infected people who are more tolerant of the HI virus than others and if so which factors this tolerance depends upon.

Regoes came up with the idea for the study during his postdoctoral stay in Atlanta, where he was working with researchers from a large primate centre. They studied sooty mangabeys (Cercocebus atys) infected with SIV, an HIV-like virus that affects primates. Although a large amount of the SI virus was found in their blood, some of the monkeys did not become ill. "The infection in this primate species is one of the best examples of disease tolerance," says the researcher. He and his co-authors -- all medical doctors -- are now interested in whether the concept of tolerance can also be carried over to human diseases. In order to determine which factors are linked to tolerance, the scientists evaluated the data from the Swiss HIV Cohort Study statistically.

Their analyses revealed that certain patient groups are more tolerant of HIV than others. For instance, the twenty-year-old group is more tolerant than sixty-year-olds, with the disease developing 1.7 times more rapidly in older patients than in their younger counterparts.

The same goes for the group of patients whose HLA-B genes come in two different variants. HLA-B genes are a group of genes which facilitate immunity to the HI virus. Every person has two copies of every gene, which do not have to be identical. If they are not, this is referred to as heterozygosity. If both HLA-B variants are identical, i.e. homozygotes, the tolerance of the virus is considerably lower.

Certain HLA-B variants are known to facilitate an immune defence against the virus geared towards its destruction. These variants are not responsible for tolerance. Instead, tolerance is linked to combinations of other HLA-B variants.

Regoes and his co-authors did not find any difference in tolerance between genders. The ETH-Zurich researcher recorded roughly the same high values in women and men, although on average women exhibit lower initial viral loads than men.

For his analyses, Regoes used the number of particular immune cells, the CD4+ cells, on the one hand and the viral load during the asymptomatic phase on the other. The latter is a key quantity in HIV infection. As soon as the virus infects someone, it multiplies rapidly and heavily before the immune system reduces its number to a certain level. From then on, the immune system keeps the pathogen relatively well under control for a long time. However, the number of CD4+ cells drops continuously until it reaches a critical level. If the number of these immune cells falls below 200 per millionth of a litre of blood, AIDS breaks out. The researchers calculated the tolerance of HIV sufferers to the virus from the correlation between the rate at which the CD4+ cells decreased and the viral load during the asymptomatic phase.

Tolerance and resistance are alternative but complementary defence strategies deployed by a host to combat pathogens. In the case of tolerance, it is not the destruction of the adversary and thus the reduction of the viral load that is the priority, but rather the alleviation of the negative effects of the infection for the host. This is not tantamount to capitulation. Instead, the strategy ensures that the evolutionary race between the parties cools off. "It is heading in the direction of commensalism," says Regoes -- a kind of ceasefire between two disparate partners. However, the two strategies have different evolutionary consequences: while tolerance tends to suppress the emergence of adaptations, resistance challenges the adaptability of viruses, which results in an evolutionary arms race with the adversaries.

"In the long run, one could try to use this ceasefire therapeutically," says the ETH-Zurich researcher. Tolerance-based therapeutic strategies could constitute interesting alternatives as they are not expected to lead to treatment-resistant pathogens.

Complexities of reducing HIV rates in Russia

Decreasing HIV transmission among Russian HIV-infected drinkers will require creative and innovative approaches, results of a new study conducted in St. Petersburg, Russia, show. While new HIV infections globally have declined, HIV rates remain high in Russia. This is due in large part to injection drug use and spread via heterosexual sex transmission.Results of a new study conducted in St. Petersburg, Russia, show that decreasing HIV transmission among Russian HIV-infected drinkers will require creative and innovative approaches.

While new HIV infections globally have declined, HIV rates remain high in Russia. This is due in large part to injection drug use and spread via heterosexual sex transmission. Alcohol use also has been shown to be related to risky sexual behaviors and sexually transmitted infections (STIs).

The study showed that a behavioral intervention did not lead to a reduction of STIs and HIV risk behaviors in Russian HIV-infected heavy drinkers when compared to the control group. This study was led by researchers from Boston University School of Medicine (BUSM), Boston Medical Center (BMC) and First St. Petersburg Pavlov State Medical University, Russia.

In this study, the researchers adapted a Centers for Disease Control and Prevention-best evidence risk reduction intervention for a Russian clinical setting and assessed its ability to reduce STIs and HIV risk behaviors among 700 HIV-infected heavy drinkers. The intervention stressed disclosure of HIV serostatus and condom use in two individual sessions and three small group sessions. Participants had a laboratory test at a 12-month follow up appointment to determine if they had contracted STIs. They also answered questions about risky behaviors, including unprotected sex, drinking alcohol or injecting drugs.

At the 12-month follow-up assessment, STIs occurred in 20 subjects (8 percent) in the intervention group and 28 subjects (12 percent) in the control group. Both groups, however, reported having decreased their participation in risky behaviors.

"Addressing prevention of HIV transmission from HIV-infected Russian drinkers, a group at particularly high risk for disease transmission, requires creative approaches and aggressive uptake of antiretroviral therapy," said Jeffrey Samet, MD, MA, MPH, professor of medicine at BUSM and chief of the section of general internal medicine at Boston Medical Center. "This study shows that we need to explore other options to help stem the growing epidemic.".

Why HIV patients develop dementia

HIV-associated neurocognitive disorders" (HAND) include disorders of the cognitive functions, motor capacities as well as behavioural changes. How exactly HAND occur has not, as yet, been fully understood. "Scientists assume that HIV is harmful to cells directly and that is also triggers indirect mechanisms that lead to nerve cell damage," explains Dr Simon Faissner (RUB clinic for neurology, St. Josef-Hospital).

The researchers strongly suspect that, once activated in the brain and the spinal cord, immune cells keep up a chronic inflammation level which then results in the destruction of nerve cells. An immune activation in peripheral tissue as well as therapeutic consequences may likewise contribute to nerve cell damage in the brain.

The HIV virus overcomes the blood-brain barrier hitchhiking on infected immune cells, the monocytes and probably the T cells. The researchers from Bochum tested the hypothesis that HIV-infected monocytes activate specific immune cells in the brain, the so-called microglial cells. These cells, in turn, respond by releasing harmful substances, such as reactive oxygen metabolites and inflammatory signalling molecules, i.e. cytokines. To test this hypothesis, the researchers developed a cell culture system in which they initially examined the effect of HIV-infected monocytes on microglial cells. The researchers simulated the individual steps of HIV infection and measured the volume of the cytokines released at each stage. Thus, they were able to demonstrate that releasing the viral RNA in the monocytes was a sufficient trigger for maximal microglial activation. Subsequent infection phases -- reverse transcription into DNA and the resulting formation of HIV proteins -- did not augment activation any further.

In the second step, they analysed nerve cells from rat brains to determine if the substances released by the microglial cells could lead to cell death. Compared with the control group, the number of cell deaths was indeed twice as high. Studies of liquor cerebrospinalis received from HIV-infected patients have shown a positive correlation with marker of neuronal degeneration in patients who did not as yet present any neurocognitive disorders. Detailed understanding necessary for therapeutic strategies

"Thanks to our research, we have gained a better understanding of the mechanisms of HIV-associated neurodegeneration," concludes Prof Dr Andrew Chan. "These results are likely to contribute to HAND biomarkers becoming established. In the long term, these data will be used to develop therapeutic strategies aiming at retarding HAND progression in HIV-infected patients." Starting points may include activation of microglial cells -- a method that is applied in other autoimmune diseases of the central nervous system, for example in multiple sclerosis.

Gut flora influences HIV immune response

Normal microorganisms in the intestines appear to play a pivotal role in how the HIV virus foils a successful attack from the body's immune system, according to new research.

The study builds on previous work from researchers at the Duke Human Vaccine Institute that outlined a perplexing quality about HIV: The antibodies that originally arise to fight the virus are ineffective.

These initial, ineffective antibodies target regions of the virus's outer envelope called gp41 that quickly mutates, and the virus escapes being neutralized. It turns out that the virus has an accomplice in this feat -- the natural microbiome in the gut. "Gut flora keeps us all healthy by helping the immune system develop, and by stimulating a group of immune cells that keep bacteria in check," said senior author Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute. "But this research shows that antibodies that react to bacteria also cross-react to the HIV envelope."

Haynes said the body fights most new infections by deploying what are known as naïve B cells, which then imprint a memory of the pathogen so the next time it encounters the bug, it knows how to fight it.

But when the HIV virus invades and begins replicating in the gastrointestinal tract, no such naïve B cells are dispatched. Instead, a large, pre-existing pool of memory B cells respond -- the same memory B cells in the gut that fight bacterial infections such as E coli. This occurs because the region of the HIV virus that the immune system targets, the gp41 region on the virus's outer envelope, appears to be a molecular mimic of bacterial antigens that B cells are primed to target. "The B cells see the virus and take off -- they make all these antibodies, but they aren't protective, because they are targeted to non-protective regions of the virus envelope."

Haynes and colleagues said the findings were confirmed in tests of people who were not infected with HIV. Among non-infected people, the researchers isolated mutated gp41-gut flora antibodies that cross-react with intestinal bacteria.

"The hypothesis now is that the gp41 antibody response in HIV infection can be derived from a pre-infection memory B cell pool triggered by gut bacteria that cross-reacts with the HIV envelope," said lead author Ashley M. Trama. "This supports the notion that the dominant HIV antibody response is influenced by previously activated memory B cells that are present before HIV infection and are cross-reactive with intestinal bacteria."

Haynes said the finding provides compelling new information for HIV vaccine development, which is the next phase of research. "Not only can gut flora influence the development and function of the immune system, but perhaps also pre-determine our reaction to certain infections such as HIV," Haynes said.

AIDS and Seniors

HIV (short for human immunodeficiency virus) is a virus that kills cells in your immune system, the system that fights diseases. Once your immune system is weakened to the point where you get certain types of life-threatening diseases, infections, and cancers, you have what is called AIDS or acquired immunodeficiency syndrome. AIDS is the most advanced stage of HIV infection. If there's any chance that you might be infected with HIV, you should be tested because now there are drugs you can take to help your body keep the HIV in check and fight against AIDS.

Many people do not have any symptoms when they are first infected with HIV. It can take as little as a few weeks for minor flu-like symptoms to show up or as long as 10 years or more for more serious symptoms. Symptoms can include headache, chronic cough, diarrhea, swollen glands, lack of energy, loss of appetite and weight loss, frequent fevers and sweats, frequent yeast infections, skin rashes, pelvic and abdominal cramps, sores on certain parts of your body, and short-term memory loss. People age 50 and older may not recognize HIV symptoms in themselves because they think what they are feeling and experiencing is part of normal aging.

Anyone can get HIV and AIDS. Regardless of your age, and especially if you are 50 years old or older, you may be at risk for HIV if any of the following is true:

• If you are sexually active and don't use a male latex condom. You can get HIV/AIDS from having sex with someone who is infected with the HIV virus. The virus passes from the infected person to another through the exchange of body fluids such as blood, semen, and vaginal fluid. HIV can get into your body during sex through any opening, such as a tear or cut in the lining of the vagina, vulva, penis, rectum or mouth.
• If you don't know your partner's sexual and drug history. Has your partner been tested for HIV/AIDS? Has he or she had a number of different sex partners? Does your partner inject drugs?
• If you inject drugs and share needles or syringes with other people. Drug users are not the only people who might share needles. People with diabetes, for example, who inject insulin or draw blood to test glucose levels, might share needles. If you have shared needles for any reason or if you have had sex with someone who has, you should be tested for HIV/AIDS.
• If you had a blood transfusion between 1978 and 1985, or a blood transfusion or operation in a developing country at any time.
• If any one of the above is true, you should be tested for HIV/AIDS. Check your local phone directory for the number of a hospital or health center where you can get a list of test sites. In most states the tests can be confidential (you give your name) or anonymous (you don't give your name).

There are many myths about HIV/AIDS. The examples below are facts:

1. You cannot get HIV through casual contact such as shaking hands or hugging a person with HIV/AIDS.
2. You cannot get HIV from using a public telephone, drinking fountain, restroom, swimming pool, Jacuzzi, or hot tub.
3. You cannot get HIV from sharing a drink or being coughed or sneezed on by a person with HIV/AIDS.
4. You cannot get HIV from donating blood
5. You cannot get HIV from a mosquito bite.

What Are The Real Chances Of Finding Cure For HIV?

Human Immunodeficiency Virus (HIV) is behind the largest and deadliest pandemic in the recent human history. In 2011, 34 million people were living with HIV worldwide. In our age of advanced medicine, the situation when infectious disease spreads seemingly out of control is very rare. For the majority of common infectious diseases we have either medicine capable of curing them, or at least, medication making them manageable. Also, preventive measures such as vaccinations allow to put most infections under control. But effective therapeutic management is now available. HAART (Highly Active AntiRetroviral Therapy) helps to eliminate the most of virus from the body of infected person, thus reducing to the minimum his or her chances to develop AIDS and suffer any other infection-related health problems. In fact, people receiving the antiretroviral therapy can now expect to live almost normal life, and their average life expectancy is almost the same as in the healthy population.

Advantages And Problems Of Modern Antiretroviral Therapy

Modern drugs effectively reduce the level of virus in the blood (viral load) to almost undetectable level. The decrease in viral load not only improves the immune system of the patient but also decrease the risk of HIV transmission to healthy people. The price to pay - take a pill every day. Like any other chronic disease, HIV needs to be treated by drugs on a daily basis. And there is always a danger of developing drug resistance thus making the medicines ineffective. On top of this, drugs do have both short-term and long-term side effects that in some cases can be severe.

Finally, the newest and most efficient drugs are costly and often unaffordable. The price of unsubsidized drug bill can easily reach $30,000 per year.
The problems of living with HIV make the development of cure very desirable. Lots of research is being done worldwide in the pursuit of this goal. But how achievable is this target? Can we expect any real breakthrough that is so eagerly anticipated by millions of infected people? Although modern HAART therapy is hailed as a great success, the cure of HIV remains an elusive goal. There were, however, several reports of so-called functional cure of HIV infection in several individuals.

One HIV-positive patient received the bone marrow transplant from a donor with a rare natural genetically programmed resistance to HIV infection. The monitoring of this patient so far did not reveal any signs of disease return. He was declared completely free from HIV thus making him the first ever person to be cured of the disease.

Another very recent report described the case of a newborn baby who got infection from mother. Therapeutic intervention with HAART has started almost immediately after the baby was born and seemed to be successful in completely elimination of virus.

Obviously, the above strategies are not viable for the overwhelming majority of patients. Something else has to be done.

Complete Cure For HIV Is Difficult But Not Impossible To Achieve - The problem lies with the mechanism of drug action: all modern drugs are active only against the actively replicating virus. The virus does become silenced in some situation. For example, the host cells of immune system can become dormant and shut down almost all replication mechanisms. In such cells virus can stay without showing any activity for very long time. As a result, this virus remains completely insensitive to all drugs. Once the cell wakes up, the virus starts to reproduce as well and easily replenish its population in the body if the drugs were discontinued.

There are also so-called anatomical reservoirs of the virus. HIV can hide at different anatomic locations such as gastrointestinal tract and brain of the patients receiving antiretroviral therapy. These sites have various kind of barriers limiting the ability of antiretroviral drugs to reach the infected cells. Again, when the treatment is stopped the virus from these places could cause re-infection. Some researchers hypothesize that HIV can infect certain non-immune cells and survive there in dormant stages for many years.

The logical answer to the problem of latent viruses lurking somewhere in the safe heavens around the body is to get them out of their hiding places. Two major strategies are currently being developed by researchers working in this field. First strategy aims to activate the latent cells of immune system. Activation would also turn on the replication process of the virus .With the virus replicating inside the cell, the cell will ultimately die, and the released viruses could be get rid of using the traditional and highly effective antiretroviral therapy. There are different agents which could potentially help in activating the latent T cells. One such agent, Interleukin-7 (IL7) is currently undergoing clinical trials. Prostratin is another compound that could do this but at present time only limited data is available for its safety profile and efficiency in humans. It will take several years to get enough data and see if these drugs serve the purpose.

The second strategy relies on turning on the HIV genes within the latent cells infected by virus. Histone deacetylase inhibitors (HDACI) seem to be able to do exactly this. These drugs could turn on the gene expression in the viruses present inside the silent T cells thus making them vulnerable for antiretroviral drugs. Further studies are needed to evaluate the efficiency of these drugs.

With the pace of developments in the HIV research, many scientists now believe that the cure for HIV is only few years away. The infection has already proven itself as a very difficult target to treat. Many drugs previously developed with curative intent have failed to their promises.

But this time the level of confidence among scientists and observers is higher than ever. Let’s hope that they are right.

Linking microbial, immune environment in semen to HIV viral load, transmission

While HIV is found in many body fluids, sexual transmission through semen is the most common route of infection. Consequently, the amount of virus in semen (the semen viral load) affects the likelihood of HIV transmission. Besides sperm, semen also contains immune factors and communities of bacteria, an environment that could influence the viral load. Research published on July 24th in PLOS Pathogens reports that HIV infection re-shapes the relationship between semen bacteria and immune factors which in turn affects viral load, suggesting that the semen microbiome plays a role in sexual transmission of HIV.

Researchers led by Lance Price, from the Translational Genomics Research Institute, USA, and Rupert Kaul, from the University of Toronto, Canada, studied the relationship of semen bacteria with HIV infection by analyzing semen samples from 49 men who have sex with men (MSM). They focused on MSM because of the high risk of sexual HIV transmission in this population. 27 of the men were HIV infected, and provided samples both before they started anti-retroviral therapy (ART) and one and six months after. Samples from 22 MSM not infected with HIV served as controls.

In HIV-infected men not on ART, overall numbers of bacteria in the samples -- the semen bacterial load -- was correlated with HIV viral load. Analyzing the bacterial DNA in the samples, the researchers detected a total of 248 unique types of bacteria in semen from the controls, on average 71 different ones per sample. In samples from HIV-infected untreated men, semen microbiome diversity was markedly reduced, and the relative abundance of the more common bacterial groups differed. ART for six months reduced semen viral load to undetectable levels, and restored bacterial diversity and composition to a situation similar to the controls.

There was no correlation in uninfected controls between levels of immune factors and semen bacterial load. In contrast, in HIV-infected men, several factors, and most strongly one called interleukin-1beta (IL-1b), a mediator of inflammation, showed a correlation with both semen bacterial load and semen viral load.

"While delineating the directionality and causality of the complex relationships they observed will require further studies," the researchers say, their data "suggest an interaction between semen microbiome, local immunology, and semen viral load. Higher bacterial load in semen could lead to higher IL-1b levels, which in turn could induce viral shedding, thereby increasing viral load." They conclude that the results "support the hypothesis that semen bacteria play a role in local inflammation and HIV shedding, and that they are a possible target for reducing HIV transmission."

Women living with HIV benefit from 'expressive therapy' intervention

New research from UC San Francisco shows that an "expressive therapy" group intervention conducted by The Medea Project helps women living with HIV disclose their health status and improves their social support, self-efficacy and the safety and quality of their relationships.

"Medication alone is totally insufficient," said the study's first author, Edward L. Machtinger, MD, director of the Women's HIV Program at UCSF. "Over 90 percent of our patients are on effective antiretroviral therapy but far too many are dying from suicide, addiction, and violence. Depression, addiction, and especially trauma are very common and often devastating for women living with HIV but are not being effectively addressed by most clinics. We believe that helping women develop the skills and confidence to tell their stories publicly will reduce their isolation and be the first step towards their becoming genuinely healthy. We partnered with The Medea Project to deliver an effective expressive therapy intervention that starts to address the primary causes of death in our patients."

The Medea Project was founded in 1989 by Rhodessa Jones as a group performance intervention to empower incarcerated women to improve their lives and reduce recidivism. Jones adapted the program to help women living with HIV. The process consists of a series of intensive workshops that culminate in a theatrical performance.

The Medea Project's method focuses on storytelling as a means of healing and empowerment. The storytelling includes talking about and processing other stigmatizing and traumatic experiences in a group setting with the support of other women. In the case of the study, the process included specific prompts given to the women asking how they found out they were HIV-positive and whom they had told about their HIV status. The burden of secrecy was relieved and self-identity could be recast in a more positive light. Then, through public performance, participants felt the power that their stories could have on others and gained both an appreciation for their lives and a desire to unleash their newly found "voices" to change the social conditions that create HIV risk, stigma and trauma.

In the study, eight HIV-positive women and seven HIV-negative women from Medea's core group formed the final performance group that culminated in a professional theatrical run of eight shows seen by more than 1,000 people. None of the HIV-positive participants had publically disclosed their HIV status prior to the study; all disclosed their status during the performances.

"Eddy Machtinger challenged me to take women living with HIV and apply the processes I had used for over two decades with incarcerated women to get them to open up and talk about living with HIV. Sharing is an important process in creating the play and violence is what they talked about the most," said study co-author Rhodessa Jones, director of The Medea Project. "Our data revealed five core themes that described the impact of the intervention on the participants' lives: sisterhood, catharsis, self-acceptance, safer and healthier relationships and gaining a voice.

Importantly, half of the participants reported leaving or avoiding unhealthy or unsafe relationships, a significant impact since we know women living with HIV experience high rates of intimate partner violence," said Machtinger. "Integrating this type of intervention into the primary care of women living with HIV is the first step towards transforming primary care from treatment to actual healing," he said.

The Use of Human Growth Hormone in the treatment of HIV / AIDS

HIV (human immunodeficiency virus) is the virus that causes AIDS (acquired immune deficiency syndrome). The HIV retrovirus may be passed from one person to another when infected blood, semen, vaginal secretions or other bodily fluids come in contact with an uninfected person's broken skin or mucous membranes. People with HIV have what is called HIV infection and are fit and well. Some of these people will develop AIDS as a result of their HIV infection.

Growth hormone is a popular bodybuilding and performance enhancing aid, and the use of recombinant human growth hormone (rHGH, or simply GH) to treat various conditions in HIV infection has been debated with excitement for years. Indeed it is licensed for the treatment of wasting syndrome in advanced stages of AIDS. GH is also a commonly used bodybuilding and performance enhancing drug, which can be purchased on the black market; used to help both muscle anabolism / strength and reduction in body fat levels. Both of these applications have possible significance in the treatment of HIV.

Other than in the treatment of wasting disease, results from the studies using rHGH to treat body changes associated with HIV and/or drugs used to treat HIV have been very favourable. One which has been studied extensively is the use of rHGH in reducing HIV-associated adipose redistribution syndrome (HARS). However, the positive effects of HGH treatment in HIV may be more direct. Several studies have proposed that rHGH may bolster the immune system in ways that might improve clinical outcomes in HIV.

Wasting
Like cancer cachexia, advanced stages of AIDS are characterised by severe muscle wasting and weakness. The reasons for this are because the patient often has a very poor appetite and food intake, as well as there being direct wasting effects from the HIV and some associated diseases which the patient may have, e.g. pneumonia. The patient then enters a downward cycle with diminished strength, poor food intake and further wasting, and it's often this which leads to eventual death.

Both anabolic steroids and rHGH therapy are used clinically to both slow the effects of wasting and to help improve appetite. Both have been shown to prolong life significantly and improve quality of life in advanced stages of AIDS.

HIV-associated adipose redistribution syndrome (HARS)
HARS is a type of lipodystrophy (abnormal distribution of body fat), where there is accumulation of excess truncal fat and visceral adipose tissue, as opposed to regular gynoid (glutes and hips) or android (abdomen) deposition. This is observed in HIV infected people, moreso as virus load increases. Although not a debilitating condition in itself (indeed extra body fat can prolong life if followed by wasting), HARS is unpleasant for the individual, giving reduced confidence in body image; another negative aspect of the disease. rHGH therapy has been shown to significantly reduce HARS, leading to an improved body image, and significant improvement in psychological well-being. Numerous studies have demonstrated the benefits of this, leading to rHGH being licesenced for the treatment of HARS in some countries. It should also be noted that improvement in psychological well-being could also contribute to a positive clinical outcome, in that it reduces the effects of wasting.

Immune system
Of most interest in HIV therapy are the possible benefits of rHGH use on the immune system, since HIV's primary adverse effect is reduction in the immune system. It has been clearly demonstrated that rHGH does benefit the immune system, but the method by which it helps is still under debate. One theory is that rHGH may stimulate renewal of the thymus gland, an important organ in the immune system. This may, in turn, lead to improved immune health in people with HIV. Studies are now examining whether or not renewing thymus tissue leads to better health and longer survival.

The thymus is necessary for developing new T-lymphocytes, which are key immune cells in the defence against disease, and numbers of which steadily reduce in HIV as infection progresses. In particular the thymus gland is involved in the development of CD4+ and CD8+ cells, and it is the CD4+ level which is a very critical marker in HIV outcome. Without some thymus activity, immune reconstitution that produces a wide range of functional CD4+ cells is not believed to be possible. Thus, the state of the thymus in HIV disease and how therapies affect it are of great interest to those researching ways to restore the immune system.

Napolitano et al  researched rHGH and its impact on the thymus in HIV. Doses ranged from 1.5 (4.5IU) to 3.0mg (9IU) per day for 6–12 months in healthy HIV volunteers. After six months, marked increases in thymus mass were noted, beyond what has been seen using anti-HIV therapy alone. This increase was sustained during the course of rHGH therapy and correlated with a higher CD4+ count, suggesting that the thymus is functioning properly and helping make new T-cells, further suggesting a stronger immune system. When rHGH was stopped, there was a loss of thymus mass; however, CD4+ cell count increases seen over the course of therapy were sustained despite this loss of mass.

Napolitano later did a twenty-person study using 3mg (9IU) rHGH a day injected under the skin (subcutaneous injection). This was followed by 1.5mg (4.5IU) rHGH a day for another six months, for a total of one year of daily therapy. Of the 20 volunteers (all of whom stayed on anti-HIV therapy during the study), ten took one year of rHGH according to the schedule described above while the other ten were merely observed. After one year, the group on rHGH stopped therapy and were observed for a second year, while the group who hadn't taken rHGH therapy then started one year of it. The size of the thymus increased in those on rHGH during the first year, but not among the second group. Those on rHGH had a significant increase in thymus mass while those only on anti-HIV therapy actually had a slight decrease.

Also, these increases in thymus size (together with increases in both thymus density and volume) related to marked increases in naïve CD4+ cells (69% increase among those taking rHGH during the first year compared to only 9% increase for those only on anti-HIV therapy), but not naïve CD8+ cells. This was further associated with more pronounced increases in total CD4+ cell counts (19% increase among those on rHGH versus 1% increase among those only on anti-HIV therapy).

Interestingly the most pronounced increase in both naïve and total CD4+ cell counts were seen among those on rHGH with a rise in the hormone IGF-1 (insulin-like growth factor-1) which is also associated with immune function. In subjects with pronounced increase in IGF-1 levels due to rHGH use, naïve cells increased by 95% and CD4+ increased by 25%.

The AIDS Clinical Trials Group (ACTG) conducted a larger 60-person study. One group was given anti-HIV therapy and 1.5mg (4.5IU) rHGH a day for 48 weeks. A second group took anti-HIV therapy alone for 24 weeks, followed by 3mg (9IU) rHGH a day for 24 weeks. By the end of 48 weeks, both groups showed notable increases in naïve and total CD4+ cell counts. The first group took rHGH for a longer period of time but were on a lower dose that took longer to result in CD4+ cell increases. However, people in the lower dose group showed more pronounced increase by week 48 in another measure of recent thymic activity called TREC (T cell receptor excision circles). Seven out of 11 people in the lower dose rHGH group showed increased thymus mass after 24 weeks while seven out of nine showed the same effect after 24 weeks on the higher dose.

Researchers at Imperial and Chelsea and Westminster Hospital in London (2006) administered rHGH therapy in chronic HIV patients in an attempt to reconstitute HIV specific CD4+ and CD8+ T-cell responses. While viral load and CD4+ and CD8+ counts remained unchanged, T-cell maturation and differentiation were significantly enhanced.

In all of these studies, using rHGH related to increases in thymus size and CD4+ T cell counts. Taken together these studies are promising, but they are not studies of effectiveness. Many questions remain unanswered about using rHGH to treat immune suppression in HIV disease. It does seem that there may be little benefit in respect of the immune system when CD4+ level is still at a reasonable level, but when it goes below an acceptable reference range then rHGH therapy may be worth considering. Obviously a high percentage of newly diagnosed patients are already in more advanced stages of the disease as they only present to their doctor when they have symptoms, so these may already have reduced CD4+.

Acute Infections
HIV patients are often more prone to acute infections which may take longer to clear up than in non-HIV individuals. Sometimes these can be associated with poor appetite and weight loss. rHGH therapy may curb rapid weight loss often associated with acute infections in HIV positive people and may also reduce length of infection. Far more research is needed here though.

Fasting lipid profile
HIV patients have been shown to have elevated serum lipids, and dyslipidaemia, i.e. high LDL (bad) cholesterol and low HDL (good) cholesterol with raised total cholesterol and triglycerides. This is associated with anti-HIV drug treatment especially later on in infection. This does increase risk of cardiovascular diseases, and rHGH treatment may improve lipid profiles.

Bone Building
HIV patients may have loss of bone density associated with wasting. Both treatment with rHGH and growth hormone releasing factor (GHRF) have indicated improved bone mass in HIV patients.

Side effects of rHGH treatment
Although we have focused on the promising benefits for rHGH treatment in HIV infection, consideration of possible side effects is important in ensuring an informed decision can be made. Side effects of rHGH therapy include possible joint pain (arthralgia), abnormal growth of the body's extremities and impaired glucose intolerance, increasing the risk of type 2 diabetes.

Caution is also advised against using over-the-counter or faddy internet products that claim to contain human growth hormone. Some of them claim to contain plant-derived growth hormone, others claim to contain cow or goat growth hormone, and still others claim to contain substances that increase the body's production of GH. There is no evidence that any of these products contain either a relevant product or a dose needed to induce the types of effects seen in studies. Over-the-counter and internet sales of these 'growth hormone' products are a major source of health fraud.

Certainly rHGH has shown benefits in treating wasting syndrome in advanced stages of HIV disease or AIDS, and its approval as a treatment for body lipodystrophy is encouraging. However, it's important that larger studies confirm these early findings. They can tell us whether or not increases in thymus size and CD4+ cell numbers, associated with rHGH use, ultimately benefit people living with HIV and result in better quality of life and longer life. Treatment with GH in HIV is encouraging and exciting, but far more research is still required.