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 p38α 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. p38α expression can resist action of AZT in inhibition of HIV-1 replication with increased expression of transcription factor, NF-ĸBp65, SP1, and c-Fos through activation of TCR-related pathways with upregulation of CD3, TCRα, TCRβ, Zap-70, PKC, PLCγ1, GRB2, and PI3K/Akt expression. In HIV-1 MN superinfection under AZT treatment, expression of p38α led to HIV vif expression and inhibited APOBEC3G expression. We also investigated effects of p38α on gp130/JAK-STAT pathways, in which p38α increased expression of protein, gp130, EGFR, Jak2, STAT1, STAT3, STAT5, ras, and TF. p38α could induce apoptotic pathways with upregulation of Fas, FADD, Caspase-8, p53, and Bax, and downregulation of Bcl2 expression. These results indicate that p38α plays a positive role in reactivation of viral replication from HIV-1 latent infection and leads to HIV-1 AZT resistance. In conclusion, MAPKp38α 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.

中文翻译：

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MAPK p38α 对 AZT 对 ACH2 细胞中重新激活 HIV-1 复制的抗性的影响。

抗逆转录病毒疗法 (ART) 显着降低了与 HIV 相关的死亡率。然而，耐药性 HIV 变体对 ART 的长期成功构成潜在威胁。HIV 突变体和宿主因素均可引起 HIV 耐药性。使用长期感染 HIV-1 的易感 ACH2 细胞，我们检查了 MAPK p38α 对 AZT 抵抗重新激活 HIV-1 复制的影响，这种复制可以被 HIV-1 重复感染激活。我们发现 HIV-1 重复感染诱导了更多的病毒产生，而 p38 抑制剂 SB203580 和 AZT 在感染非 AZT 抗性 HIV-1 株 MN 的细胞中减少了这种产生。p38α 表达可以抵抗 AZT 抑制 HIV-1 复制的作用，通过激活 TCR 相关通路，上调 CD3、TCRα、TCRβ、Zap-70、PKC、PLCγ1、GRB2 和 PI3K/Akt 表达。在 AZT 治疗下的 HIV-1 MN 重复感染中，p38α 的表达导致 HIV vif 表达并抑制 APOBEC3G 表达。我们还研究了 p38α 对 gp130/JAK-STAT 通路的影响，其中 p38α 增加了蛋白质、gp130、EGFR、Jak2、STAT1、STAT3、STAT5、ras 和 TF 的表达。p38α 可诱导凋亡途径，上调 Fas、FADD、Caspase-8、p53 和 Bax，下调 Bcl2 表达。这些结果表明 p38α 在 HIV-1 潜伏感染的病毒复制再激活中起积极作用，并导致 HIV-1 AZT 耐药。总之，MAPKp38α 可以激活 AZT 抑制 HIV-1 潜伏感染的 HIV-1 复制，并可用作潜伏期逆转剂。