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Herpesvirus saimiri (HVS), strain 488-77, was used to derive continuously growing transformed human CD8+ T cell lines that can suppress HIV replication in CD4+ cells via the production of an antiviral factor(s). Transformed CD8+ cell lines were obtained by HVS infection of peripheral blood mononuclear cells or purified CD8- T cells from HIV-infected or uninfected individuals. Suppression of primary or laboratory isolates of HIV was mediated by factor permeation of a transwell membrane or by cell-free culture supernatants. Suppressing and nonsuppressing cell lines were IL-2-dependent for good growth and showed a similar activated cell surface phenotype. The cell lines produced varying amounts of the cytokines IL-8, IL-10, TNF-alpha, TNF-beta, RANTES, MIP-1 alpha, and MIP-1 beta, but not IFN-alpha. No correlation was observed between the level of any of these cytokines and the presence or absence of antiviral activity in cell line culture supernatants. These cell lines have become an important resource for studying antiviral factors produced by CD8+ T cells from HIV-infected individuals.

CD8+ T cell suppression of HIV replication in vitro was evaluated over 1-2 years in 12 HIV-infected individuals receiving daily dosages of Zidovudine (AZT) and in 9 untreated subjects. In the 12 AZT-treated patients, the level of CD8+ cell antiviral activity increased an average of 6.6-fold above pretreatment levels. These increases in antiviral activity observed were only transient in 6 of the subjects, returning to pretreatment levels, or lower, over the study period. In the other 4 subjects, the CD8+ cell antiviral response remained elevated at the end of the study period. The changes in CD8+ cell responses did not correlate with observed alterations in the absolute number or the percentage of CD4+ or CD8+ peripheral blood lymphocytes. Untreated HIV-infected subjects generally showed a gradual decrease in the CD8+ cell response over time to as much as 16-fold below baseline and in contrast to the treated group, these changes correlated with similar changes in CD4+ cell counts (P = 0.02). The average level of CD8+ cell antiviral activity observed over the entire study period was more than 2-fold above baseline in the 12 AZT-treated subjects, whereas it was more than 3-fold below baseline in the untreated subjects (P = 0.0001). Culturing CD8+ cells in the continued presence of AZT (1 microM) showed no effect on the ability of the cells to inhibit replication of an AZT-resistant HIV-1 strain. The results suggest that AZT therapy can have a beneficial effect, albeit often of limited duration, on CD8+ T cell function in HIV-infected individuals.

We have examined the relation of cell surface marker phenotype to the anti-human immunodeficiency virus (HIV) function of CD8+ cells from individuals at various clinical stages of HIV infection. Multiparametric flow cytometry analysis demonstrated that the most significant changes in cell surface phenotype was found within the CD8+ cell subset expressing HLA-DR and CD28. These changes in the levels of CD28 and HLA-DR expression on CD8+ cells were found to be related to antiviral activity and have clinical relevance based on three pieces of evidence: (1) strong CD8+ cell antiviral responses were associated in infected individuals with high levels of HLA-DR+ and CD28+ subsets; (2) CD8+ cell anti-HIV activity in vitro resides predominantly in the separated CD8+ cell subsets that express HLA-DR or CD28; and (3) in longitudinal studies, CD8+ cell anti-HIV activity decreased as an individual progressed from a healthy state to an AIDS condition. Taken together, the data suggest that the CD8+ cell subset identified phenotypically as a CD8+ CD28+ HLA-DR+ cell is responsible for natural anti-HIV activity. Longitudinal studies should determine if alterations in this subset can be used as a prognostic indicator for disease progression.