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Mol Cell Biochem 2019 Dec;462(1-2):41-50

The effects of MAPK p38alpha on AZT resistance against reactivating HIV-1 replication in ACH2 cells.

Wang X, Zhao J, Ragupathy V, Hewlett I


Antiretroviral therapy (ART) has remarkably decreased HIV-related mortality. However, drug-resistant HIV variants pose a potential threat to the long-term success of ART. Both HIV mutants and host factors can cause HIV drug resistance. Using susceptible ACH2 cells chronically infected with HIV-1, we examined the effects of MAPK p38alpha on AZT resistance against reactivating HIV-1 replication that can be activated by HIV-1 superinfection. We found that HIV-1 superinfection induced more viral production, which was diminished by p38 inhibitor, SB203580, and by AZT in cells infected with non-AZT-resistant HIV-1 strain MN. p38alpha expression can resist action of AZT in inhibition of HIV-1 replication with increased expression of transcription factor, NF-kBp65, SP1, and c-Fos through activation of TCR-related pathways with upregulation of CD3, TCRalpha, TCRbeta, Zap-70, PKC, PLCgamma1, GRB2, and PI3K/Akt expression. In HIV-1 MN superinfection under AZT treatment, expression of p38alpha led to HIV vif expression and inhibited APOBEC3G expression. We also investigated effects of p38alpha on gp130/JAK-STAT pathways, in which p38alpha increased expression of protein, gp130, EGFR, Jak2, STAT1, STAT3, STAT5, ras, and TF. p38alpha could induce apoptotic pathways with upregulation of Fas, FADD, Caspase-8, p53, and Bax, and downregulation of Bcl2 expression. These results indicate that p38alpha plays a positive role in reactivation of viral replication from HIV-1 latent infection and leads to HIV-1 AZT resistance. In conclusion, MAPKp38alpha can activate HIV-1 replication inhibited by AZT from HIV-1 latent infection and may be used as a latency reversal agent. The activation involves induction of several cell signaling pathways that are required for HIV-1 replication, which may be integrated into future viral remission strategies.

Category: Journal Article
PubMed ID: #31432386 DOI: 10.1007/s11010-019-03608-6
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2019-03-24 Entry Last Modified: 2019-11-24