Suppression of HIV-1 viral replication and cellular pathogenesis by a novel p38/JNK kinase inhibitor.
OBJECTIVE
To analyze a novel compound, which inhibits serine-threonine protein kinase p38, for its possible bioactivity against HIV-1 infection.


METHODS
Proteins involved in cellular signal transduction pathways represent a novel class of host therapeutic targets for infectious diseases. In this regard the serine/threonine kinase p38 MAPK, a member of the mitogen-activated protein (MAP) kinase superfamily of signal transduction molecules may play an important role in HIV-1 infection. We analyzed the ability of this compound (RWJ67657) to inhibit HIV replication in primary T cells and monocytes. Cellular expression of phospho-p38MAPK was studied by Western blot analysis. Blockade of HIV infection induced apoptosis was measured by Annexin V staining.


RESULTS
p38 inhibitor RWJ67657 was effective in inhibiting HIV-1 replication in both T-cell and monocyte cell lines, irrespective of the coreceptor used by the virus for entry into the cell. Importantly, both reverse transcriptase and protease resistant escape mutant viruses were effectively suppressed by RWJ67657. In addition, the tested compounds block HIV-induced T-cell apoptosis, a critical means of T-cell depletion linked to AIDS progression.


CONCLUSIONS
Several steps in the HIV-1 virus life cycle appear to depend on cellular activation, including activation of the p38 pathway. Without activation virus replication is thought to be blocked due to incomplete reverse transcription and a lack of proviral DNA integration. The data collectively illustrate that inhibition of the p38 pathway can affect HIV-1 replication. Interruption of HIV infection by p38 inhibitors underscores the value of exploring antiviral drugs that target host cellular proteins.
Muthumani
Karuppiah
K
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Wadsworth
Scott A
SA
Dayes
Nathanael S
NS
Hwang
Daniel S
DS
Choo
Andrew Y
AY
Abeysinghe
Harindra R
HR
Siekierka
John J
JJ
Weiner
David B
DB
D000704:Analysis of Variance; D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000473:pathology / Q000821:virology; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D020298:U937 Cells; D014779:Virus Replication / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases
D017304:Annexin A5; D015415:Biomarkers; D007093:Imidazoles; D011725:Pyridines; C400277:RWJ 67657; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases