HIV-specific Immune Responses Linked to Reduced Infection Risk in PrEP Study

People who remained HIV-negative in the iPrEx pre-exposure prophylaxis (PrEP) trial were more likely to show evidence of HIV-specific T-cell responses, and certain responses were significantly associated with reduced risk of infection, according to research published in the June 22 advance edition of Proceedings of the National Academy of Sciences. These findings suggest that natural immunity may be giving Truvada PrEP a boost in preventing HIV infection.

Prior research has shown that some HIV-negative people show evidence of HIV-specific immune responses, indicating that they were likely exposed but their immune system successfully fought off the virus. But the clinical relevance of these responses is not well understood.

Peter Kuebler from the University of California at San Francisco and colleagues conducted a case-control study looking at immune responses among participants in the large iPrEx trial.

As previously reported, iPrEx was an international study in which 2499 men who have sex with men and a small number of transgender women were randomly assigned to receive oral Truvada (tenofovir/emtricitabine) or placebo once-daily. Participants taking Truvada had a 44% lower risk of HIV infection overall, rising to 92% among those with blood drug levels indicating good adherence.

This study analyzed 84 pre-infection samples of peripheral blood mononuclear cells from iPrEx participants who later seroconverted, matched with 480 samples from participants who remained HIV-negative in both the active treatment and placebo arms. The researchers measured T-cell interferon-gamma responses to HIV antigens including gag, vif, nef, integrase, protease, and reverse transcriptase.

HIV-specific responses to gag, nef, vif, and integrase were significantly more prevalent in participants who remained HIV-negative compared with seroconverters. Antigen-specific responses were independent of Truvada use. When correlated with iPrEx outcomes, vif- and integrase-specific T-cell responses were associated with reduced risk of HIV infection (hazard ratio 0.36 and 0.52, respectively). Each 10-fold increase in vif- and integrase-specific responses was associated with further reduction in infection risk. These responses were largely attributable to CD4 and CD8 effector memory T-cells.

"Our results show that HIV-1-specific T-cell immunity can be detected in exposed but uninfected individuals and that these T-cell responses can differentiate individuals according to infection outcomes," the study authors concluded.

However, given that these HIV-specific responses were seen among both Truvada and placebo recipients, iPrEx principle investigator Robert Grant noted that they could not explain the protective effect of PrEP.

Below is an edited excerpt from a George Washington University press release describing the study findings in more detail.

Prep Data Links Anti-HIV Immune Response to Reduce Chance of Infection

Washington, DC -- June 22, 2015 -- Research published in the Proceedings of the National Academy of Sciences found that some individuals exposed to HIV-1, but who remain uninfected, have a certain pattern of virus-specific immune responses that differentiated them from individuals who became infected. The findings build upon prior research by studying these responses in the context of a controlled clinical trial, examining a large number of subjects, and by having access to specimens saved before anyone was infected. In the future, this information could be used to assess HIV-1 infection risk or inform the design of a preventative HIV-1 vaccine.

This new research, co-authored by George Washington University (GW) researcher Douglas Nixon, MD, PhD, and colleagues at UCSF, University of Sao Paulo in Brazil, and the Gladstone Institutes, looked at data from the Pre-exposure Prophylaxis Initiative (iPrEx) trial, the first randomized controlled trial of pre-exposure chemoprophylaxis (PrEP) in humans. Remaining specimens from the trial were used to test for naturally acquired or induced immunity to HIV-1 infection. Those who became infected typically lacked responses to two HIV-1 proteins. The finding suggests that such immune responses may play a role in blocking systemic infection after exposure to the virus.   

"Research has shown that T-cell responses can be observed in virally exposed but uninfected persons," said Dr. Nixon, chair of the Department of Microbiology, Immunology and Tropical Medicine and Walter G. Ross Professor of Basic Science Research at the GW School of Medicine and Health Sciences. "The question that has remained unanswered is whether or not these T-cell responses could be protecting people from acquiring systemic HIV infection. The rigor of the placebo-controlled iPrEx trial gave us access to the necessary data and specimens to address that question. What we found was what people have been looking for, for a long time -- a correlation between future infection risk and a measureable immune response."

Using samples from the iPrEx trial, the research team compared immune responses mounted against an array of HIV-1 antigens by peripheral blood mononuclear cell samples: 84 samples were collected prior to infection from men who became HIV-positive and 480 samples from men who remained HIV-negative throughout the trial, including those who received the drug or placebo. T-cell responses against certain HIV-1 antigens were significantly higher and more frequent among those who remained uninfected compared with those who became HIV-positive, and these responses were associated with reduced risk of infection. 

"The iPrEX trial showed that pre-exposure prophylaxis (or PrEP) with emtricitabine and tenofovir disoproxil fumarate (brand name Truvada in the United States) was highly effective for HIV prevention when used," said Dr. Robert Grant, of the Gladstone Institutes, the protocol chair of iPrEx, which was sponsored by the National Institutes of Health. "Whether taking drug or placebo, the observed immune responses were still present, so the protective benefit we saw with PrEP was not due to these immune responses. The discovery that cellular immunity correlates with HIV infection risk is a distinct and very exciting one. I hope it will provide clues leading to an HIV vaccine."

"Demonstrating HIV protection associated with vaccine or, as in this case, exposure-induced immunity is a very high bar to achieve, and appropriately so. Our findings indicate that the host immune system interfaces with the virus or its proteins more commonly than previously thought, generating naturally induced immunity in the form of T-cell responses that contribute to a persistent HIV negative status in some exposed people. Only with additional research can we truly know if these immune responses can be induced by a vaccine candidate, and whether vaccine-induced responses provide protection," according to Dr. Esper Kallas of USP, co-senior author of the manuscript.

"A safe, effective, and easily administered preventative HIV vaccine is still needed and remains an important public health goal. HIV’s interaction with the human immune system is complex, therefore success with a vaccine is hard to predict. Nevertheless, the possibility that T-cell immunity, in addition to antibody-derived immunity, may contribute to protection is quite promising. The more 'shots on goal' we can take in a given vaccine, the more likely we are to succeed at preventing infection, and perhaps most importantly eventual eradication of HIV," said lead author Dr. Peter Kuebler.

7/3/15

Reference

PJ Kuebler, ML Mehrotra, JJ McConnell, et al. Cellular Immune Correlates Analysis of an HIV-1 Pre-exposure Prophylaxis Trial. Proceedings of the National Academy of Sciences USA. June 22, 2015 (Epub ahead of print).

Other Source

George Washington University.Prep Data Links Anti-HIV Immune Response to Reduce Chance of Infection. Press release. June 22, 2015.