Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques.

To determine the role of CD8(+) T cells in controlling simian immunodeficiency virus (SIV) replication in vivo, we examined the effect of depleting this cell population using an anti-CD8 monoclonal antibody, OKT8F. There was on average a 99.9% reduction of CD8 cells in peripheral blood in six infected Macaca mulatta treated with OKT8F. The apparent CD8 depletion started 1 h after antibody administration, and low CD8 levels were maintained until day 8. An increase in plasma viremia of one to three orders of magnitude was observed in five of the six macaques. The injection of a control antibody to an infected macaque did not induce a sustained viral load increase, nor did it significantly reduce the number of CD8(+) T cells. These results demonstrate that CD8 cells play a crucial role in suppressing SIV replication in vivo.

Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy.

The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed alpha1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.

Genetic characterization of vif, vpr, and vpu sequences from long-term survivors of human immunodeficiency virus type 1 infection.

The identification of HIV-1-infected individuals who remain asymptomatic despite prolonged infection presents a unique opportunity to understand virologic and host factors involved in the pathogenesis of AIDS. We have previously identified 10 long-term survivors (LTS) who are clinically healthy and immunologically normal despite 13 to 15 years of HIV-1 infection. In this study, we examined three accessory genes of HIV-1, vif, vpr, and vpu, in these LTS. A total of 52 vif, 54 vpr, and 55 vpu nucleotide sequences were obtained from the peripheral blood mononuclear cells of these patients. Analysis of these sequences revealed no gross deletions or insertions. Most of the clones were full-length with an intact open reading frame. Phylogenetic analyses of the vif, vpr, and vpu sequences from the LTS suggested that the HIV-1 strains found in the study subjects are not significantly different from those found in patients with AIDS and that the viruses in the LTS are unlikely to share a common genetic origin. Furthermore, a similar degree of overall genetic diversity between viruses from the LTS and AIDS patients suggests that there is unlikely a significant correlation between the degree of genetic diversity and the rate of disease development. Factors other than genetic divergence, such as viral load and phenotype, are likely to impact more on disease status.