Antiretroviral Pre-Exposure Prophylaxis Does Not Enhance Immune Responses to HIV in Exposed but Uninfected Persons

Abstract

Background: Antiretroviral preexposure prophylaxis (PrEP), using daily oral combination tenofovir disoproxil fumarate plus emtricitabine, is an effective human immunodeficiency virus (HIV) prevention strategy for populations at high risk of HIV acquisition. Although the primary mode of action for the protective effect of PrEP is probably direct antiviral activity, nonhuman primate studies suggest that PrEP may also allow for development of HIV-specific immune responses, hypothesized to result from aborted HIV infections providing a source of immunologic priming. We sought to evaluate whether PrEP affects the development of HIV-specific immune response in humans.

Methods and results: Within a PrEP clinical trial among high-risk heterosexual African men and women, we detected HIV-specific CD4(+) and CD8(+) peripheral blood T-cell responses in 10%-20% of 247 subjects evaluated. The response rate and magnitude of T-cell responses did not vary significantly between those assigned PrEP versus placebo, and no significant difference between those assigned PrEP and placebo was observed in measures of innate immune function.

Conclusions: We found no evidence to support the hypothesis that PrEP alters either the frequency or magnitude of HIV-specific immune responses in HIV-1-exposed seronegative individuals. These results suggest that PrEP is unlikely to serve as an immunologic prime to aid protection by a putative HIV vaccine.

Keywords: HIV-1; T-lymphocyte; cellular immunity; prevention of sexual transmission.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Preexposure prophylaxis (PrEP) does not modify the magnitude of human immunodeficiency virus–specific CD8+ and CD4+ T-cell responses. A, Magnitude of CD8+ T-cell responses was measured as the frequency of interferon (IFN) γ and CD107a dually producing cells. B, Magnitude of CD4+ T-cell responses was measured as IFN-γ and tumor necrosis factor (TNF) α dually producing cells. Cell frequencies for PrEP and placebo groups are shown on stimulation with Env, Gag, and Tat PTE peptide pools.

Figure 2.

Preexposure prophylaxis (PrEP) does not affect the maturation of T cells. Frequencies of CD4+ and CD8+ T cells were calculated as fractions of CD3+ lymphocytes. CD45RA and CCR7 were used to distinguish naive (CD45RA+CCR7+), central memory (TCM; CD45RA−CCR7+), effector memory (TEM; CD45RA−CCR7−) and terminally differentiated effector memory (for CD8+ T cells only, TEMRA; CD45RA+CCR7−). A, B, Frequency and distribution in the maturation subsets are shown for CD4+ (A) and CD8+ (B) T cells. C, Frequency of regulatory T cells (Tregs; CD127loCD25+FoxP3+) was calculated as a percentage of either CD4+ or CD3+ T cells, and expression of activation markers was calculated as the percentage of the total Treg population.

Figure 3.

Innate and B-cell immune responses are not affected by preexposure prophylaxis (PrEP). A, Frequencies of total, cytotoxic (CD56dimCD16+), cytokine-secreting (CD56hiCD16−), and exhausted (CD56−CD16+) natural killer (NK) cells and B, B-cell (CD19+), myeloid dendritic cell (mDC; CD11c+), and plasmacytoid dendritic cell (pDC; CD123+) frequencies for PrEP and placebo recipients.