Assessment of longitudinal changes in HIV-specific effector activity in subjects undergoing untreated primary HIV infection.

BACKGROUND: Despite the failure of HIV-specific cell-mediated immune responses to clear the virus, these cells play a critical role in the control of viral replication throughout HIV infection. OBJECTIVE: To characterize the natural evolution of the HIV-specific immune response in HIV primary infection (PI). METHODS: Untreated individuals, recruited in HIV PI, were monitored for the evolution of HIV-specific immune responses starting in early HIV disease. Longitudinal analysis of changes in the magnitude and breadth of HIV-specific responses to a panel of MHC class I-restricted peptides was performed using the quantitative interferon-gamma ELISPOT assay. RESULTS: Although immune responses were detected in all individuals at all times tested, the pattern of the immune responses differed significantly from that seen in subjects treated in PI. Untreated PI subjects exhibited dramatic changes with time in the frequency of individual HIV peptide-specific T-cell responses. In contrast HIV-specific immunity was stable in subjects treated in early PI or decreased in intensity and breadth in individuals treated later in PI. In untreated subjects the overall magnitude of HIV-specific reactivity persisted over at least 12 months whereas the number of peptides recognized declined. CONCLUSION: Given that a significant relationship existed between the magnitude of the HIV-specific response and viral load, it is likely that these effector cell expansions and contractions are driven by changes in antigen load.

HIV-specific CD8 T-cell activity in uninfected injection drug users is associated with maintenance of seronegativity.

OBJECTIVES: To determine whether HIV-exposed, uninfected subjects (EUs) having HIV-specific effector activity are at a reduced risk for seroconverting compared with EUs with no HIV-specific effector responses. DESIGN: Twenty-eight intravenous drug users (IVDU) with documented risk for HIV infection over a 1-year period were screened for the presence of HIV-specific CD8+ effector cell activity. Group I included 18 IVDUs who remained seronegative despite exposure to HIV through needle sharing with partner(s) known to be HIV infected. Group II included 10 IVDUs who seroconverted after similar HIV exposure. METHODS: The enzyme-linked immunospot (ELIspot; Mabtech AB, Nacka, Sweden) assay was used to measure the frequency of HIV-specific interferon-gamma secreting cells. Peripheral blood mononuclear cells (PBMC) were stimulated with a panel of synthetic HIV peptides in a major histocompatibility complex class I antigen-restricted fashion. PBMC from group II were obtained from timepoints 7 months or less before seroconversion. RESULTS: Twelve of 18 (66.7%) persistently seronegative subjects versus none of 10 seroconverters exhibited detectable HIV-specific effector responses at the sampling date (P < 0.001; Fisher's exact test). This represents an odds ratio of 40.38 (95% confidence intervals 2.95 to > 3000). CONCLUSION: EUs who have developed HIV-specific effector responses are at a reduced risk for seroconversion compared with EUs who do not develop this type of immunity. This observation supports the hypothesis that HIV-specific effector responses are a correlate of immune protection from HIV infection.

Human immunodeficiency virus (HIV)-specific effector CD8 T cell activity in patients with primary HIV infection.

The interferon-gamma ELISPOT assay was used to assess and compare the magnitude and breadth of human immunodeficiency virus (HIV)-specific CD8 T cell responses in treatment-naive subjects during the first year of HIV primary infection and during the chronic phase of infection. Twenty-five subjects tested within a year of exposure to HIV resulting in seroconversion and 20 subjects with chronic infection were screened for HIV peptide-specific activity by stimulating peripheral blood mononuclear cells with a panel of 5-21 HLA class I-restricted HIV peptides (mean, 11.2 +/- 3.5 HIV peptides). There was a significant correlation between the magnitude and breadth of HIV-specific effector responses and time elapsed from exposure (r=0.63 for magnitude vs. time and r=0.64 for breadth vs. time; P<.02, paired t test). Maximal breadth of the HIV gene product reactivity was achieved within 2 months of exposure for Nef-specific responses and by 4 months of exposure for responses directed to Env, Gag, and reverse transcriptase.