Research has 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 Dr Douglas Nixon, and colleagues at UCSF, USP in Brazil, and the Gladstone Institutes, looked at data from the Pre-exposure Prophylaxis Initiative (iPrEx) trial, the first randomised 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 Nixon, chair of the department of microbiology, immunology & 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 rigour 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 US) 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.
HIV-1–specific T-cell responses in exposed seronegative subjects suggest that a viral breach of the exposure site is more common than current transmission rates would suggest and that host immunity can extinguish subsequent infection foci. The Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial provided an opportunity to rigorously investigate these responses in a case–control immunology study; 84 preinfection peripheral blood mononuclear cell samples from individuals enrolled in the iPrEx trial who later seroconverted were matched with 480 samples from enrolled subjects who remained seronegative from both the placebo and active treatment arms. T-cell responses to HIV-1 Gag, Protease, Integrase, Reverse Transcriptase, Vif, and Nef antigens were quantified for all subjects in an IFN-γ enzyme-linked immunospot (ELISpot) assay. IFN-γ responses varied in magnitude and frequency across subjects. A positive response was more prevalent in those who remained persistently HIV-1–negative for Gag (P = 0.007), Integrase (P < 0.001), Vif (P < 0.001), and Nef (P < 0.001). When correlated with outcomes in the iPrEx trial, Vif- and Integrase-specific T-cell responses were associated with reduced HIV-1 infection risk [hazard ratio (HR) = 0.36, 95% confidence interval (95% CI) = 0.19–0.66 and HR = 0.52, 95% CI = 0.28–0.96, respectively]. Antigen-specific responses were independent of emtricitabine/tenofovir disoproxil fumarate use. IFN-γ secretion in the ELISpot was confirmed using multiparametric flow cytometry and largely attributed to effector memory CD4+ or CD8+ 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 demonstration and clinical relevance of HIV-1–specific immune responses in exposed but uninfected seronegative individuals have been controversial. Studies seeking to detect these responses have generally been small in size and have varied in study population, methods of detection, and control groups. We conducted a large case–control immunology study of participants in the Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial, selecting preinfection time points for those who became infected compared with persistently HIV-1–negative controls. We confirmed that HIV-1–specific responses are present in exposed uninfected individuals, sometimes at very high magnitude. HIV-1–specific responses also correlated with infection risk.