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Session 77 Poster Abstracts
NK Cells in HIV Infection
Thursday, 1:30 - 3:30 pm
Hall D


414    
Innate Immunity in HIV Infection: Enhanced Natural Killer Cell-death and Turnover Mediated by Altered Expression of Interferon-stimulated Genes (ISG)s
Shyam Kottilil*1, J Jackson1, T W Chun1, M O'Shea1, M McLaughlin1, J Yang2, R Lempicki2, and A Fauci1
1NIAID, Bethesda, MD, USA and 2SAIC-NCI, Frederick, MD, USA

Background:  We have previously described a number of natural killer (NK) cell dysfunctions in HIV-viremic individuals, including abnormal surface receptor expression, reduced cytotoxicity, and lower levels of CC-chemokine secretion. In the present study, we performed DNA microarray followed by phenotypic and functional analyses in an effort to elucidate the mechanisms by which ongoing HIV replication affects the physiologic functions of NK cells.

Methods:  Genetic profiles (DNA microarray) and phenotypic and functional characteristics of NK cells isolated from HIV-viremic, HIV-aviremic, and HIV-seronegative individuals were compared.

Results:  More than 100 genes were shown to be up-regulated in NK cells from HIV-viremic individuals when compared to those from HIV-aviremic and HIV-negative individuals. Several of those genes belong to the interferon-stimulated gene family, including those associated with Fas-mediated apoptosis (FMA). Flow cytometry analyses confirmed the above observation at the protein level. Furthermore, increased expression of CD95 on NK cells of HIV-viremic individuals was associated with increased susceptibility to undergo FMA but not CD16- or NKG2D-mediated apoptosis. Among various subsets of NK cells, the CD56+ CD16+ population was the most susceptible to FMA. Serum levels of sFasL, NK-associated FMA, and expression of CD95 and Ki67 on NK cells were markedly elevated in HIV-viremic individuals when compared to those of HIV-aviremic and HIV-negative individuals.

Conclusion:  Our data demonstrate that ongoing HIV replication results in profound NK cell abnormalities that are likely to be due to the effects of virus-induced immune activation and increased susceptibility to cell death. Most noteworthy was the increased expression of CD95 and Ki67 correlating with susceptibility of NK cells from HIV-viremic individuals to undergo FMA and increased NK cell turnover. These data are consistent with our previous observations that ongoing HIV replication results in profound NK cell dysfunction and increased susceptibility to cell death.

Keywords: NK cell; apoptosis; ki67