Medicine, Dentistry & Health Sciences Collected Works - Research Publications

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Author: Lewin, Sharon × Start date: 1999 × End date: 1999 ×

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    Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy
    Zhang, LQ ; Lewin, SR ; Markowitz, M ; Lin, HH ; Skulsky, E ; Karanicolas, R ; He, YX ; Jin, X ; Tuttleton, S ; Vesanen, M ; Spiegel, H ; Kost, R ; van Lunzen, J ; Stellbrink, HJ ; Wolinsky, S ; Borkowsky, W ; Palumbo, P ; Kostrikis, LG ; Ho, DD (ROCKEFELLER UNIV PRESS, 1999-09-06)
    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.
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    Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques
    Jin, X ; Bauer, DE ; Tuttleton, SE ; Lewin, S ; Gettie, A ; Blanchard, J ; Irwin, CE ; Safrit, JT ; Mittler, J ; Weinberger, L ; Kostrikis, LG ; Zhang, LQ ; Perelson, AS ; Ho, DD (ROCKEFELLER UNIV PRESS, 1999-03-15)
    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.