Pathogenic Mechanisms In HIV Disease

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Abstract

The immune systems of patients with HIV infection are characterized by a decrease in the number of helper/inducer (CD4) T lymphocytes. In an effort to determine whether these decreases were secondary to decreased T cell production or increased T cell destruction a series of studies were carried out in which rates of T cell turnover were studied using labeling of DNA. These studies clearly demonstrated that the decreases in CD4 T cells seen in the setting of HIV infection are due to an increase in cell death and not due to a decrease in cell production. The CD4 T cell declines seen in the setting of progressive HIV infection were previously found to be associated with a progressive skewing of the T cell receptor (TCR). Follow-up of these observations has revealed that this skewing can be persistent despite more than 1-year of successful antiretroviral therapy. At this time it appears that this skewing is a combination of antigen driven clonal expansion in the setting of a decrease in the overall size of the CD4 T cell pool. Studies of patients receiving IL-2 as part of clinical trials on another project revealed that IL-2 directly induces cells to proliferate in the absence of other signals. The increases in cell production were associated with increased expression of the alpha chain of the IL-2 receptor. Complementary data were generated with in vitro systems in which IL-2 was shown to be capable of binding to and activating cells that did not express the high-affinity IL-2 receptor complex. Additional in vivo studies revealed that IL-2 also resulted in an increase in the rates of cell death. Taken together, these data suggest that the expansions of CD4 T cells seen in the setting of IL-2 therapy are likely secondary to an increase in CD4 T cell survival. Despite being able to suppress HIV replication, antiretroviral therapy is not able to eradicate HIV from patients with established infection. In studies designed to examine the dynamics of viral replication during periods of therapy it was discovered that HIV replication is an ongoing process despite levels of plasma HIV RNA <50 copies/ml. Similarly it was shown that viruses previously thought to be coming from latent reservoirs were actually the products of ongoing low-level replication. Careful analyses of the viruses obtained from patients with high levels of HIV replication in the presence of HAART identified a unique mutation involving the deletion of amino acid 67 of the HIV reverse transcriptase of HIV. This deletion in combination with a T69G mutation led to a novel pattern of drug-resistance that may indicate future difficulties in the control of HIV replication in patients with viruses in which these mutations are present.