THE CRITICAL ROLE OF P38 MAP KINASE IN T-CELL HIV-I REPLICATION

Background: Replication of HIV-1 in human T lymphocytes requires the a ctivation of host cellular proteins. This study identifies p38 mitogen -activated protein kinase (MAPK) as one such kinase necessary for HIV- 1 replication in T cells. Materials and Methods: Primary human T lymph ocytes were infected with the LAI strain of HIV-1 and Jurkat cells wer e infected with the RF strain of HIV-1. HIV replication was measured b y reverse transcriptase activity. Cellular expression of endogenous p3 8 MAPK protein was analyzed using immunoprecipitation. Blockade of p38 MAPK expression was achieved using anti-sense oligonucleotides to p38 MAPK and the guanylhydrazone compound CNI-1493, an inhibitor of p38 M APK activation. Results: HIV-1 infection of both primary human T lymph ocytes and a T cell line rapidly activated the cellular p38 MAPK pathw ay, which remained activated for the duration of the culture. Addition of phosphothioated antisense oligonucleotides to p38 MAPK specificall y inhibited viral replication. Blockade of p38 MAPK activation by addi tion of CNI-1493 also inhibited HIV-1 viral replication of primary T l ymphocytes in a dose- and time-dependent manner. Stimulation of p38 MA PK activation did not occur with the addition of heat-inactivated viru s, suggesting that viral internalization, and not just membrane bindin g, is necessary for p38 MAPK activation. Conclusions: These results in dicate that activation of the p38 MAPK cascade is critical for HIV-1 r eplication in primary T lymphocytes, and that blockade of this signal transduction pathway may be a novel therapeutic approach to the treatm ent of HIV-1 infection.