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.