Infection with HIV results in an incremental loss of T helper cell (TH) function, which can occur years before CD4 cell numbers are critically reduced and AIDS is diagnosed. All TH function is not affected, however, because B cell activation and hypergammaglobulinema are also characteristic of this period. Recently, in a murine model of AIDS an early loss in production of the CD4 cytokines IL-2 and IFN-gamma was correlated with an increase in the B cell stimulatory cytokines IL-4, IL-5, and IL-10. We therefore assessed the production of IL-4 generated by PBL from HIV-seropositive (HIV+) individuals who did not have AIDS, yet who exhibited different TH functional categories based on their IL-2 production profiles. We observed that the decreases in recall antigen-stimulated IL-2 production were accompanied by an increase in IL-4 production. The loss of recall antigen-stimulated responses in HIV+ individuals could be reversed in vitro by anti-IL-4 antibody. Our results suggest that the TH functions assessed by IL-4 production replace the normally dominant TH function of antigen-stimulated IL-2 production in the progression toward AIDS, and raise the possibility of cytokine cross-regulation in AIDS therapy.

The loss of T helper cell (TH) function in asymptomatic HIV type 1-infected individuals occurs before the decline in CD4+ T cells. At least part of the loss in TH function results from changes in immunoregulatory cytokine profiles. To investigate the role of IL-10 in such dysregulation, we tested whether: (a) expression of IL-

Peripheral blood mononuclear cells (PBMCs) from many asymptomatic individuals infected with human immunodeficiency virus-type 1 (HIV) are unresponsive as measured by in vitro T cell proliferation and interleukin-2 (IL-2) production to influenza virus and synthetic peptides of HIV envelope (Env). Strong influenza virus- and Env-stimulated IL-2 responses and T cell proliferation were restored when cultures were stimulated in the presence of IL-12. Interferon-gamma production by PBMCs from HIV seropositive (HIV+) patients was also restored with IL-12. Furthermore, in vitro antigen-specific production of IL-2 and proliferation of PBMCs from HIV- donors were suppressed by antibody to IL-12, but were not enhanced by addition of exogenous IL-12. Thus, IL-12 may be limiting in PBMCs from HIV+ but not HIV- individuals. These findings demonstrate that IL-12 can restore HIV-specific cell-mediated immunity in vitro in HIV-infected individuals and suggest a potential use of IL-12 in augmenting the diminished immunologic functions associated with HIV infection.

In vitro T-cell receptor-induced programed cell death in both activated T cells from human immunodefciency virus-seronegative (HIV-) donors and resting T cells from HIV+ donors was substantially influenced by cytokines.

Human immunodeficiency virus type 1 (HIV-1)-infected patients (n = 335) in the US Air Force HIV Natural History Program were followed for 3 years (mean) after skin testing, immunophenotyping of CD4+ cell subsets, and measurement of in vitro interleukin-2 production after stimulation by phytohemagglutinin, alloantigens, tetanus toxoid, and influenza A virus. The T cell functional assay predicted survival time (P < .001) and time for progression to AIDS (P = .014). Skin testing for tetanus, mumps, and Candida antigen and the total number of positive tests (P < .001 for each) stratified patients for survival time. In a multivariable proportional hazards model, the T cell functional assay (P = .008), the absolute number of CD4+ T cells (P = .001), the percentage of CD4+ CD29+ cells (P = .06), and the number of reactive skin tests (P < .001) predicted survival time. Thus, cellular immune functional tests have significant predictive value for survival time in HIV-1-infected patients independent of CD4+ cell count.