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A S Fauci
NIAID, NIH, Bethesda, MD
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Background: Replication of HIV leading to viremia and aberrant activation of the immune system results in a number of phenotypic and functional abnormalities of immune-competent cells that contribute substantively to the pathogenesis of HIV disease. In order to assess directly the multifaceted effects of virus replication on the host, we studied HIV-infected individuals during viremic and aviremic stages of disease. We examined the effects of virus replication on: a) the physiologic state of the resting CD4+ T cell reservoir; and b) the phenotype and function of B cells and NK cells.
Methods: Highly enriched resting CD4+ T cells, NK cells and B cells were obtained from normal controls, and from viremic or aviremic HIV-infected individuals at comparable stages of immune system compromise. Cells were characterized by gene expression using microarray analysis and were assayed for a variety of functional capabilities.
Results: Profound differences were found between immune-competent cell subsets in HIV-infected individuals with viremia (whether or not they were receiving HAART) versus those who were aviremic as a result of HAART. Cell-free HIV virions were spontaneously released ex vivo from the viral reservoir of viremic, but not aviremic patients despite the fact that the resting CD4+ T-cells from viremic and aviremic individuals were phenotypically identical. Furthermore, DNA microarray analysis demonstrated that the resting CD4+ T-cells from viremic patients expressed a variety of genes that would favor virus replication compared to those of aviremic patients. Striking differences were also seen in gene expression in B-cells from viremic versus aviremic patients. In addition, B-cells from viremic patients manifested marked abnormalities in the ability to respond to CD4+ T-cell help due to low induction of CD25 expression on responder B-cells, as well as a low B-cell co-stimulatory function with CD4+ T-cells due to defective induction of CD80/CD86 on effector B-cells. Finally, NK-cells from viremic versus aviremic patients showed marked abnormalities of a variety of functions; in addition, viremic patients showed an increased expression of certain inhibitory receptors and a decreased expression of all major activating receptors examined.
Conclusions: Active virus replication has profound and multi-faceted effects on resting CD4+ T-cells, B-cells, and NK-cells in HIV-infected individuals involving aberrant gene expression, phenotypic abnormalities, and functional defects that likely play an important role in the pathogenic mechanisms of HIV disease.
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