Acquired immunodeficiency syndrome (AIDS) was first reported in 1981. Today, an estimated > 33 million people globally are infected and living with the etiological agent of AIDS, Human immunodeficiency virus type 1 (HIV-1), a member of the Retroviridae family of viruses, Lentivirus genu; and approximately 25 million individuals have died from AIDS . Although there are now more than 30 anti-HIV drugs developed, none can eliminate the virus completely and no prophylactic vaccines are currently available. Therefore, HIV continues to represent a significant public health problem that mandates intensified efforts and investment in both clinical management and research.
Mitogen-activated protein kinase (MAPK) pathways consist of a group of serine-threonine kinases and link extracellular signals to the machinery that controls fundamental cellular processes such as growth, pro-liferation, differentiation, migration, and apoptosis . MAPK pathways contain a three-tier kinase module, in which a MAPK is activated upon phosphorylation by a mitogen-activated protein kinase kinase (MAPKK), which in turn is activated when phosphorylated by a mitogen-activated protein kinase kinase kinase (MAPKKK).
To date, the MAPK pathways are mainly composed of extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38 MAPK signal pathways . The ERK pathway is the best studied of the mammalian MAPK pathways. In the ERK pathway, ERK (ERK1 and ERK2) is activated upon phosphorylation by MEK (MEK1 and MEK2), which is itself activated by Raf (Raf-1, B-Raf, and A-Raf). The ERK pathway is activated by numerous extracellular signals and responsible for the activation of a number of transcription factors participating in cell growth, proliferation, and differentiation [7, 21]. PD98059  is an effective ERK pathway-specific inhibitor. The c-Jun N-terminal kinase (JNK) cascade represents the other MAPK signaling pathway that is activated primarily by cytokines and exposure to environmental stress [6, 23]. The general substrate of JNKs is c-Jun but can also activate the transcription factors ATF-2, Elk-1, MEF-2c, p53, c-Myc and other factors such as Bcl-2, Bcl-xL [24, 25]. The JNK signaling pathway is mainly responsible for cell proliferation, apoptosis, and survival under stress and SP600125 is a JNK signaling pathway-specific inhibitor . The cellular p38 cascade is another MAPK signaling pathway and contributes to cell apoptosis and cell cycle regulation. The mammalian p38 pathway can be activated by a wide range of cellular stresses, such as inflammatory cytokines, pathogens, osmotic pressure, heat shock, ultraviolet radiation, oxidative stress, and mitogens, and can also be specifically inhibited by the p38 pathway inhibitor, SB203580 .
Previous studies have shown that HIV-1 infection can activate the host cellular MAPK signaling pathway by the viral proteins, gp120 [9, 18], Tat , and Nef . Conversely, activation of the MAPK signaling pathway can enhance HIV-1 gene expression level, viral genome replication level, and virus infection activity [3, 11, 26]. These studies have provided a new insight in the prevention and control of HIV-1 infection. In the current study, we further studied the contribution of each MAPK signal pathway com-ponent among the ERK, JNK, and p38 pathways to HIV-1 infection using pathway-specific inhibitors alone and in combination.
Down-regulation of HIV-1 Infection by Inhibition of the MAPK Signaling Pathway*
- Received Date: 20 January 2011
- Accepted Date: 15 February 2011
Abstract: The human immunodeficiency virus type 1 (HIV-1) can interact with and exploit the host cellular machinery to replicate and propagate itself. Numerous studies have shown that the Mitogen-activated protein kinase (MAPK) signal pathway can positively regulate the replication of HIV-1, but exactly how each MAPK pathway affects HIV-1 infection and replication is not understood. In this study, we used the Extracellular signal-regulated kinase (ERK) pathway inhibitor, PD98059, the Jun N-terminal kinase (JNK) pathway inhibitor, SP600125, and the p38 pathway inhibitor, SB203580, to investigate the roles of these pathways in HIV-1 replication. We found that application of PD98059 results in a strong VSV-G pseudotyped HIV-1NL4-3 luciferase reporter virus and HIV-1NL4-3 virus inhibition activity. In addition, SB203580 and SP600125 also elicited marked VSV-G pseudotyped HIV-1NL4-3 luciferase reporter virus inhibition activity but no HIV-1NL4-3 virus inhibition activity. We also found that SB203580 and SP600125 can enhance the HIV-1 inhibition activity of PD98059 when cells were treated with all three MAPK pathway inhibitors in combination. Finally, we show that HIV-1 virus inhibition activity of the MAPK pathway inhibitors was the result of the negative regulation of HIV-1 LTR promoter activity.