The critical role of p38 MAP kinase in T cell HIV-1 replication.
BACKGROUND
Replication of HIV-1 in human T lymphocytes requires the activation 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.


METHODS
Primary human T lymphocytes were infected with the LAI strain of HIV-1 and Jurkat cells were infected with the RF strain of HIV-1. HIV replication was measured by reverse transcriptase activity. Cellular expression of endogenous p38 MAPK protein was analyzed using immunoprecipitation. Blockade of p38 MAPK expression was achieved using antisense oligonucleotides to p38 MAPK and the guanylhydrazone compound CNI-1493, an inhibitor of p38 MAPK activation.


RESULTS
HIV-1 infection of both primary human T lymphocytes and a T cell line rapidly activated the cellular p38 MAPK pathway, which remained activated for the duration of the culture. Addition of phosphothioated antisense oligonucleotides to p38 MAPK specifically inhibited viral replication. Blockade of p38 MAPK activation by addition of CNI-1493 also inhibited HIV-1 viral replication of primary T lymphocytes in a dose- and time-dependent manner. Stimulation of p38 MAPK activation did not occur with the addition of heat-inactivated virus, suggesting that viral internalization, and not just membrane binding, is necessary for p38 MAPK activation.


CONCLUSIONS
These results indicate that activation of the p38 MAPK cascade is critical for HIV-1 replication in primary T lymphocytes, and that blockade of this signal transduction pathway may be a novel therapeutic approach to the treatment of HIV-1 infection.
Cohen
P S
PS
Picower Institute for Medical Research, Manhasset, New York 11030, USA.
Schmidtmayerova
H
H
Dennis
J
J
Dubrovsky
L
L
Sherry
B
B
Wang
H
H
Bukrinsky
M
M
Tracey
K J
KJ
D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases; D016376:Oligonucleotides, Antisense; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases; D000813:Anilides; D006146:Guanidines
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006835:Hydrazones; D020928:Mitogen-Activated Protein Kinases; D016376:Oligonucleotides, Antisense; D048051:p38 Mitogen-Activated Protein Kinases; C097256:semapimod; D000813:Anilides; D006146:Guanidines