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Clin Exp Immunol. 2003 Jul;133(1):78-90.

HIV-1 infection is facilitated in T cells by decreasing p56lck protein tyrosine kinase activity.

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  • 1Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Abstract

Several studies have suggested an important role for the protein tyrosine kinase p56lck (Lck) in HIV infection; however, the exact nature of this role remains unclear. Using a series of well characterized Jurkat-derived cell lines having a wide range of Lck kinase activity, our results showed that, while the entry of HIV-1 into these cell lines was similar, the kinetics of virus production by these cells were very different. Cells expressing a kinase-inactive Lck showed accelerated viral replication, whereas, cells expressing Lck with normal or elevated enzymatic activity showed a delay in virus replication that was proportional to the initial level of endogenous Lck activity. The cell line having the highest initial Lck kinase activity showed the slowest rate of productive HIV-1 infection. Analysis of 2-LTR circles revealed that this inhibitory effect of Lck was not due to inhibition of reverse transcription of HIV-1 genome or migration of the proviral DNA into the nuclei. This affect of Lck was confirmed in additional studies that used either the S1T cell line lacking completely Lck or where the Lck activity was altered in Jurkat cells prior to infection. S1T cells showed a 3- to 12-fold increase in the level of infection compared to Jurkat cells despite similar CD4 and chemokine coreceptor expression and cell doubling times. Pretreatment of Jurkat with an antisense lck oligodeoxynucleotide inhibited the synthesis of functional Lck and facilitated the viral replication by the cells as did expressing a dominant-negative mutant Lck which increased the productive infection>3-fold. Conversely, whereas IL-16 had no affect on productive infection in S1T cells that lack Lck, IL-16 pretreatment of Jurkat cells resulted in an immediate (within 5 min) and sustained and gradual (over 5 h) increase in Lck activity that resulted in a reduction of HIV-1 replication that paralleled the increasing Lck kinase activity. These results show that the enzymatic activity of Lck kinase can affect viral replication, that a lack of, or decreased Lck activity facilitates viral replication. Conversely, Lck can mediate a delay in HIV-1 infection that is proportional to the initial endogenous Lck enzyme activity.

PMID:
12823281
[PubMed - indexed for MEDLINE]
PMCID:
PMC1808751
Free PMC Article
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