The mechanism of CD4+ T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1–infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death. In CD4+ T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls. In CD8+ T cells, the mean proliferation rate was 7.7-fold higher in HIV-1 infection, but the mean death rate was not significantly increased. Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy. The lymphocyte proliferation and death rates in both CD4+ and CD8+ cell populations were substantially reduced by 5–11 weeks and nearly normal by one year. Taken together, these new findings strongly indicate that CD4+ lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.

Peripheral blood leukocytes (PBL) from male homosexual and heterosexual volunteers who did not have evidence of acquired immunodeficiency syndrome (AIDS) were studied for their ability to generate cytotoxic T lymphocyte (CTL) responses in vitro to allogeneic stimulator PBL from a single individual or from a pool of donors (allo-pool). Seventeen of 39 homosexual donors generated strong primary CTL activity to a single randomly selected stimulator donor, whereas only two of 16 heterosexual donors generated a strong CTL response to the same stimulators. A more detailed study was performed by using PBL from 11 of the homosexual and five of the heterosexual donors, in which CTL responses to the allo-pool were repeatedly tested over a 14-mo period. The response status of the donors that were strong and weak or moderate responders did not change during this period. No correlation of strength of CTL activity was observed with the following: HLA mismatching between responder and stimulator; proportion of OKT4+ and OKT8+ subsets in peripheral blood; antibodies to HTLV-III; antibody titers to hepatitis B, Epstein Barr virus, cytomegalovirus, or HLA alloantigens; homosexual practices; or circulating immune complex levels, although a statistical correlation by multivariate analysis was observed between elevated allogeneic CTL and a combination of other factors. The findings are discussed with respect to possible relevance to AIDS susceptibility and development.