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.