Most Highly Exposed Seronegative Men Lack HIV-1-Specific, IFN-γ-Secreting T Cells

Abstract

Naturally acquired cellular immunity in individuals who have been exposed to HIV-1 but have remained uninfected may hold clues for the design of an effective HIV vaccine. To determine the presence and nature of such an HIV-1-specific immune response, we evaluated the quantity and fine specificity of HIV-1-reactive IFN-γ-secreting T cells in a group of highly exposed seronegative men having sex with men. All 46 ES reported frequent unprotected anal sex with known HIV-1-infected partners at enrollment, and high risk activities continued in at least one-half of the volunteers for up to >6 years of observation. Despite the high frequency of unprotected anal intercourse and potential HIV-1 exposure, the vast majority of individuals demonstrated no or very low numbers of HIV-1-specific, IFN-γ-secreting T cells. Even when HIV-1 epitopes were presented by peptide-pulsed autologous dendritic cells in 15 of the highest risk volunteers, HIV-1-specific T cells remained infrequent, and the proportion of responders was not significantly different from that in a lower risk seronegative control cohort. Only PBMC from two individuals who have remained uninfected to date exhibited distinctly positive responses. However, these responses rarely persisted over time, single epitope specificities were identified in only one volunteer, and HIV-1-specific memory T cell clones did not expand in vitro. HIV-1-specific, IFN-γ-secreting T cells are thus unlikely to substantially contribute to resistance against infection in most exposed seronegative men having sex with men.

Low-Level Exposure to HIV Induces Virus-Specific T Cell Responses and Immune Activation in Exposed HIV-Seronegative Individuals

“…High expression levels of b-chemokines, as well as HIV-specific IFN-g or IL-2-secreting T cells have been recognized in different cohorts of ESN individuals (16)(17)(18)(19)(20)(21). However, others have not confirmed these findings acknowledging a lack of HIV-specific immune responses in ESN individuals (3). Detection of HIV-specific cytotoxic T lymphocytes in these individuals may simply be the consequence of exposure to the virus and not necessarily be associated with resistance to infection (20,21).…”

“…Firstly, a panel of overlapping peptides spanning the whole HIV genome was used in the stimulation assays, in contrast to other studies which used only a few viral proteins (8,9,21) or peptide panels restricted to few HLA I alleles (3,27). Secondly, we measured two different cytokines to assess immune responses, thus increasing the probability of finding a positive response.…”

Epigenetic control of IRF1 responses in HIV-exposed seronegative versus HIV-susceptible individuals

“…[1][2][3][4] Some groups have identified HESN groups that can be epidemiologically defined as relatively resistant to HIV infection (HIV-R). 2,5 Understanding what protects these HIV-R individuals from acquiring HIV infection will help in developing preventative measures against infection.…”

Global human genetics of HIV-1 infection and China

“…There are also some individuals who remain seronegative despite high risk and/or multiple exposures to HIV-1. These exposed seronegatives (ES) include infants born to HIV-1 infected mothers [5][6][7], commercial sex workers in epidemic areas [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], hemophiliacs who received HIV contaminated factor VIII preparations [26,27], and sexual partners of known HIV-1 infected persons [28][29][30][31][32][33]. Understanding the mechanisms that account for slower disease progression in LTNP and the protection against HIV-1 infection observed with ES is important for the development of more potent therapeutic regimens and a vaccine.…”