HIV-1-specific cytotoxic T cell (CTL) activity has been suggested to correlate with protection from progression to AIDS. We have examined the relationship between HIV-specific CTL activity and maintenance of peripheral blood CD4+ T lymphocyte counts and control of viral load in 17 long-term survivors (LTSs) of HIV-1 infection. Longitudinal analysis indicated that the LTS cohort demonstrated a decreased rate of CD4+ T cell loss (18 cells/mm3/year) compared with typical normal progressors (approximately 60 cells/mm3/year). The majority of the LTSs had detectable, variable, and in some individuals, quite high (>10(4) RNA copies/ml) plasma viral load during the study period. In a cross-sectional analysis, HIV-specific CTL activity to HIV Gag, Pol, and Env proteins was detectable in all 17 LTSs. Simultaneous analysis of HIV-1 Gag-Pol, and Env-specific CTLs and virus load in protease inhibitor-naive individuals showed a significant inverse correlation between Pol-specific CTL activity and plasma HIV-1 RNA levels (p = 0.001). Furthermore, using a mixed linear effects model the combined effects of HIV-1 Pol- and Env-specific CTL activity on the viral load were significantly stronger than the effects of HIV-1 Pol-specific CTL activity alone on predicted virus load. These data suggest that the presence of HIV-1-specific CTL activity in HIV-1-infected long-term survivors is an important component in the effective control of HIV-1 replication.
A flow cytometric assay based on expression of the activation antigen CD69 was developed to analyze immunological responses of T cells from human immunodeficiency virus (HIV)-infected (HIV+) or HIV-seronegative (HIV-) donors after in vitro simulation by antigens and polyclonal activators. The levels of CD69 on freshly-isolated or unstimulated, cultured CD3+, CD4+, or CD8+ peripheral blood lymphocyte (PBL) subsets were low and did not differ greatly between HIV+ and HIV- donors. The frequencies of CD3+, CD4+, and CD8+ lymphocytes from HIV+ donors that expressed CD69 after culture with antigenic or mitogenic stimuli were significantly lower than in HIV- donors. Comparison of CD69 expression with [3H]thymidine incorporation revealed that both assays could detect lymphocyte responses to antigenic or mitogenic stimuli. The CD3+ PBL from HIV+ or HIV- donors did not show increased CD69 expression after culture with soluble or cross-linked recombinant envelope glycoprotein, gp120. The gp120, however, significantly inhibited CD69 expression in phytohemagglutinin-stimulated T cells in vitro and may also affect T-cell activation in vivo. These studies demonstrate the usefulness of this CD69 expression assay for the rapid assessment of defects in immune responses of phenotypically defined lymphocyte subsets in HIV+ patients and for testing the effects of agents that modulate immune activation.
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