Science Spotlight

Oral pre-exposure prophylaxis as a possible two-fold attack

Comparison of the exposure risk score and percent IgA neutralization of women on PrEP. A 1-unit increase in exposure was associated with a 5% increase in neutralization.
Provided by Dr. Lund

Over the years, treatment and prevention of HIV has been a major focus of the public health community. With the advancements in the field we now have antiviral treatments that have greatly prolonged the life of those living with HIV. However, prevention strategies are still being studied and developed. WHO has recently recommended the use of a daily oral antiretroviral for HIV-1 uninfected high risk individuals as a pre-exposure prophylaxis (PrEP).  The daily oral antiretroviral is made up of either tenofovir (TDF) alone or TDF with emtricitabine (TDF/FTC).  Both drugs inhibit viral reverse transcriptase. Since the use of PrEP is increasing, studies to understand the effects of treatment on the host’s immune system are needed. Currently PrEP is thought to be effective due to its effect as a general antiviral. However it is hypothesized that this effect may also elicit further downstream immune recognition of HIV-1.

In a Journal of Virology paper Dr. Jennifer Lund (Vaccine and infectious Disease Division) and colleagues looked at the effect of PrEP on IgA levels in genital mucosa, which is the site of HIV-1 entry after sexual transmission. A protective response at the site of acquisition could prevent a productive infection. The authors collected cervical and vaginal swabs from a cohort of women from the Partners PrEP Study who were seronegative for HIV-1, but whose partners are HIV-1 positive. The study consisted of three groups; women currently taking PrEP, women who ended PrEP treatment two months prior to sample collection, and placebo samples. Upon collection of the samples, an HIV-1 exposure score was collected. IgA antibodies were isolated from the swabs and used to test neutralization of an HIV-1 clade C virus.

Overall the researchers found that women on PrEP had statistically higher percent IgA neutralization (33%) of HIV-1 compared to those on placebo (7%), and that this level dropped to 26% after discontinuing PrEP. This reduction could suggest a short half-life of the mucosal antibodies, indicating a weak local memory B cell response. When IgA antibody levels were compared to HIV-1 exposure scores, there was a trend towards higher percent IgA neutralization associating with increased score. When put together, PrEP usage and increased HIV-1 score correlated with slightly higher IgA neutralization however this was not statically significant.

This study is the first of its kind to report an increase in human genital HIV-1 IgA neutralizing response with oral PrEP. The study also looked at the effects of stopping PrEP on the IgA response. Another unique characteristic of the study is the use of longitudinal HIV-1 risk scores. This enabled linking of HIV-1 score with IgA host responses. The study supports the hypothesis that PrEP use may enhance IgA HIV-1 neutralization response but there is still work to be done. "We next plan to investigate if PrEP has effects on other mucosal immune responses such as T cell responses, as well as unravel the mechanism by which PrEP and HIV-1 exposure can enhance local antibody responses", commented Dr. Lund. The authors hypothesize that non-productive HIV-1 exposure during PrEP use allows enhanced immune priming, potentially leading to better T cell help and/or B cell priming. Previous studies looking at T cell responses in peripheral blood did not show much change between placebo and PrEP treated, but it is possible that the differences would only be seen in HIV-1 tissue-resident cells.

Due to low sample volumes, the neutralization of only one viral isolate, HIV-1 subtype C, could be tested. Because subtype A and D are dominant at the sample site location, measuring neutralization of subtype C only, likely underestimates the neutralization capacity of IgAs elicited by PrEP.  Sample size also limited the amount of tests able to be performed and leaves room for further studies to add to our knowledge of the mucosal immune response in the presence of PrEP. This study provides baseline evidence that oral PrEP use is associated with increased mucosal IgA antibodies in addition to its known antiviral effect.

Lund JM, Broliden K, Pyra MN, Thomas KK, Donnell D, Irungu E, Muwonge TR, Mugo N, Manohar M, Jansson M, Mackelprang R, Marzinke MA, Baeten JM, Lingappa JR, Partners PrEP Study. 2016. HIV-1-neutralizing IgA is detected in genital secretions of highly HIV-1 exposed seronegative women on oral pre-exposure prophylaxis. J Virol. Epub ahead of print.

Funding for this study was provided by the National Institutes of Health and by the Swedish Research Council.