HIV-SPECIFIC CYTOTOXIC T-LYMPHOCYTE ACTIVITY IN IMMUNOLOGICALLY NORMAL HIV-INFECTED PERSONS

Background: CD8+ T-cell counts usually increase soon after infection w ith HIV, whereas CD4+ cell counts decrease. The result of these change s in T-cell subpopulation subsets in most HIV-infected subjects is inv ersion of the CD4 : CD8 ratio from greater than 1.0 typical of uninfec ted persons to less than 1.0 after infection. Subjects: Six HIV-infect ed individuals were identified in whom the CD4 : CD8 ratio remained no rmal throughout follow up (4.0-11.25 years). They all maintained level s of CD4+ cells above 500 x 10(6)/l and had never received antiretrovi ral therapy. Because HIV-specific cytotoxic T lymphocytes (CTL) have b een implicated in control of HIV during the asymptomatic phase of dise ase, we screened these individuals for the presence of HIV-specific CT L activity. Methods: CTL activity was assessed in freshly isolated per ipheral blood mononuclear cells (PBMC) and in phytohaemagglutinin stim ulated interleukin-2 expanded cell lines established from PBMC. Cytoto xicity to HIV-1 env, gag, pol and nef gene products was surveyed in a 4 h Cr-release assay using autologous Epstein-Barr virus (EBV) transfo rmed B cells infected with vaccinia constructs expressing each of thes e HIV genes. The immunodominant CTL epitope and MHC class I antigen re striction specificity of HIV specific CTL was mapped when present. Pla sma viral load was assessed by branched DNA assay. Attempts were made to isolate virus from these individuals by the PBMC coculture assay. R esults: None of the six immunologically normal HIV-infected (INHI) sub jects exhibited direct HIV-specific CTL activity in their freshly isol ated PBMC compared with 16 (47%) out of 34 HIV disease progressors (P = 0.03, chi(2) test) and one out of 10 seronegative subjects. Three of the six INHI subjects had detectable memory HIV-specific precursor CT L (pCTL) activity in in vitro-activated T-cell lines compared with 25 (73.5%) out of 34 HIV-1 disease progressors and in none out of 10 sero negative individuals. All three INHI subjects had Gag-specific pCTL, a nd none had reverse transcriptase-specific pCTL. Plasma HIV viraemia i n all six INHI subjects was below the level of detection by branched D NA assay (< 500 copies/ml). Virus could not be isolated from four of t hese individuals despite multiple attempts to do so by PBMC coculture assays. Conclusions: Direct HIV-specific CTL activity mediated by acti vated circulating PBMC was undetectable in six INHI individuals under conditions where it is Frequently observed in HIV disease progressors. Despite the absence of cells activated for killing HIV-infected targe ts in the circulation of these individuals, they appeared able to cont rol their HIV infection by maintaining normal levels of CD4 and CD8 ce lls and low viral load. (C) 1998 Lippincott Williams & Wilkins