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To directly examine the role of CD8+ T cells in controlling viremia and disease during chronic, low-level primate immunodeficiency virus infection in DNA prime/protein boost-vaccinated macaques.A cohort of macaques, vaccinated with either a DNA prime/HIV-1 gp160 boost regimen or with gp160 alone was previously protected partially from sequential challenges with non-pathogenic and pathogenic strains of chimeric simian/human immunodeficiency virus (SHIV). In this study, the effect of temporary ablation of CD8+ T cells in these animals was examined.Animals were treated with an anti-CD8 antibody and CD8+ T-cell levels in peripheral blood, plasma viral loads, peripheral blood mononuclear cell-associated virus levels, neutralizing antibody (nAb) titers and simian immunodeficiency virus Gag-specific CD8+ T-cell numbers were followed.Plasma viremia rose sharply in direct synchrony with a rapid but transient drop in CD8+ T cells. However, although levels of cell-associated virus also rose concomitantly, peak levels were much lower than those in virus-challenged, naive animals. In addition, despite a rise of pathogenic SHIV89.6P RNA levels in three animals, CD4+ T-cell counts remained unchanged. In each of these animals, neutralizing antibody titers against the pathogenic SHIV89.6P strain were high.The results indicate that CD8+ T cells play a key role in suppressing viremia in a chronically infected host. In addition, the results suggest that in the absence of CD8+ T cells, nAb may act as an effective second line of defense by limiting both the spread of infectious virus to new target cells and CD4+ T-cell loss.