Differences in HIV-specific T cell responses between HIV-exposed and -unexposed HIV-seronegative individuals

Abstract

HIV-1-specific T lymphocyte responses in individuals exposed to HIV-1 but who remain persistently seronegative (HESNs) have been reported in some but not all previous studies. This study was designed to resolve unequivocally the question of whether HESNs make HIV-1-specific T cell responses. We performed a blind investigation to measure HIV-1-specific T cell responses in both HIV-1-serodiscordant couples and HIV-1-unexposed seronegative controls (HUSNs). We found low-frequency HIV-1-specific T cells in both HESNs and HUSNs but show that the response rates were higher over time in the former (P = 0.01). Furthermore, the magnitudes of the HIV-1-specific T cell responses were significantly higher among responding HESNs than among HUSNs over time (P = 0.002). In both groups, responses were mediated by CD4 T cells. The responses were mapped to single peptides, which often corresponded to epitopes restricted by multiple HLA-DR types that have previously been detected in HIV-1-infected patients. HIV-1-specific T cell responses in HUSNs and some HESNs likely represent cross-reactivity to self or foreign non-HIV-1 antigens. The significantly greater T cell responses in HESNs, including in two who were homozygous for CCR5Δ32, demonstrates that HIV-1-specific T cell responses can be induced or augmented by exposure to HIV-1 without infection.

FIG. 1.

HESNs better maintain HIV-1 T cell responses than HUSNs. A participant was considered to have an HIV-1-specific T cell response at a visit if a positive ELISpot response to one or more HIV-1 proteins was observed. Data pertaining to the maintenance of responses against a single HIV-1 protein are contained in Table S1 in the supplemental material. Data represent the percentages of HUSNs (left panel) and HESNs (right panel) having detectable T cell responses against any HIV-1 protein during 0 to 4 of the 4 study visits.

FIG. 2.

HESNs have higher-magnitude HIV-1 T cell responses than HUSNs. PBMCs were cultured against 6 pools of HIV-1 and 1 pool of FEC (control) peptides for 10 days and responses quantified using the cultured IFN-γ ELISpot assay. (A) All HESNs and HUSNs with responses to HIV-1 peptides by the DFR(2×) method described in the text. Generalized estimating equations (GEE) were used to model the log₁₀-transformed total magnitudes over time of HIV-1 responders in the HESN and HUSN groups, revealing a higher magnitude of responses in the HESN group across time (Wald P = 0.002). (B) All visit 1 responses to the FEC peptide pool were quantified and found to be not significantly different across the 3 study groups (Kruskal-Wallis P = 0.12) or between the HESN and HUSN groups (Wilcoxon P = 0.08). Box plots are superimposed on the raw data for each individual, with a midline and box used to represent the median ± the 25th and 75th percentiles, respectively; whiskers extend to the extreme data points that are ≤1.5 times the interquartile range.