750    

Background:   The capacity to mount broad and potent adaptive immune responses develops progressively in infancy and early childhood. Many children who acquired HIV-1 infection before 1990 are now reaching adulthood, despite the unavailability of potent ART during this key period of immunological ontogeny. Because chronic infection drives vigorous and broad CTL responses, we hypothesized that clonal exhaustion might lead to a skewed or narrowed CTL response to HIV.

Methods:  We studied 15 perinatally infected subjects averaging age 18 years (range 14 to 22). All were treated with combination drug therapy at the time of study; 9 of 15 had undetectable plasma viremia (< 50 or < 400 RNA copies/mL), 4 of 15 had detectable viremia < 1000, and 2 of 15 had viremia of 1000 to 5000. Of 15 subjects, 9 had been categorized as CDC disease stage C, 5 stage B, and 1 stage A. HIV-1-specific CTL responses were examined by IFN-γ ELISpot assay using 53 pools of consecutive peptides (15 mers overlapping by 11, NIH AIDS Repository) based on clade B consensus sequences of all 9 viral proteins, with polyclonally expanded CD8⁺ peripheral blood mononuclear cells (PBMC). In addition, T-cell receptor recombination excision circle (TREC) PCR quantitation and flow cytometric analysis of lymphocyte markers were performed using unexpanded PBMC.

Results:  The mean total HIV-1-specific spot forming cells (SFC) per 10⁶ CD8⁺ T cells was 2975 (range 230 to 12920). Each subject recognized an average of 5.3 of the 53 peptide pools (range 0 to 17). The most highly targeted proteins overall were Gag (mean 2.19 SFC/10⁶ CD8⁺ cells/amino acid), Pol (mean 1.37), and Nef (mean 1.13). The magnitude and breadth of the CTL response were highly correlated, but did not correlate to measures of PBMC TREC (which were similar to those of uninfected seronegative controls) or percentages of naïve (CD45RA⁺/CD27⁺ CD4⁺ T cells. CTL responses correlated to markers of CD8⁺ T-lymphocytes activation (CD38 and DR).

Conclusions:  Many of these subjects demonstrated surprisingly vigorous CTL responses despite long-term infection as neonates, and recent suppressive antiretroviral therapy. Targeting of these responses was similar to that previously reported for adults. Combination antiretroviral therapy instituted years after perinatal infection and symptomatic disease may therefore preserve or reconstitute the CTL response against HIV-1.

Keywords: perinatal infection; HIV; cellular immunity