Abstract
Cocaine is a commonly used illicit drug among HIV-1 infected individuals and is known to increase HIV-1 replication in permissive cells including PBMCs, CD4+ T cells, and macrophages. Cocaine’s potentiating effects on HIV-1 replication in macrophages- the primary targets of the virus in the central nervous system, has been suggested to play an important role in HIV-1 neuro-pathogenesis. However, the mechanism by which cocaine enhances HIV-1 replication in macrophages remain poorly understood. Here, we report the identification of cocaine-induced signaling events that lead to enhanced HIV-1 transcription in macrophages. Treatment of physiologically relevant concentrations of cocaine enhanced HIV-1 transcription in a dose-dependent manner in infected THP-1 monocyte-derived macrophages (THP-1macs) and primary monocyte-derived macrophages (MDMs). Toward decoding the underlying mechanism, results presented in this report demonstrate that cocaine induces the phosphorylation of p38 mitogen activated protein kinase (p38 MAPK), a known activator of HIV-1 transcription. We also present data suggesting that the p38 MAPK-driven HIV-1 transcription is dependent on the induction of mitogen- and stress-activated protein kinase 1 (MSK1). Consequently, MSK1 mediates the phosphorylation of serine 10 residue of histone 3 (H3 Ser10), which is known to activate transcription of genes including that of HIV-1 in macrophages. Importantly, our results show that inhibition of p38 MAPK/MSK1 signaling by specific pharmacological inhibitors abrogated the positive effect of cocaine on HIV-1 transcription. These results validate the functional link between cocaine and p38 MAPK/MSK1 pathways. Together, our results demonstrate for the first time that the p38 MAPK/MSK1 signaling pathway plays a critical role in the cocaine-induced potentiating effects on HIV-1 infection, thus providing new insights into the interplay between cocaine abuse and HIV-1 neuro-pathogenesis.
Highlights
The Central Nervous System (CNS) is a major target of Human Immunodeficiency Virus type 1 (HIV-1; McArthur et al, 2010)
Using THP-1macs and primary monocytederived macrophages (MDMs), we show that cocaine induces the phosphorylation of p38 mitogen activated protein kinases (MAPK), which activates the mitogen- and stress-activated protein kinase 1 (MSK1) pathway that subsequently promotes the phosphorylation of serine 10 residue of histone 3 (H3 Ser10)
Because HIV1 entry into macrophages is mediated by the cellular receptor CD4 and the co-receptors-CCR5 (Grivel et al, 2011), it has been suggested that cocaine’s potentiating effect on HIV-1 in macrophages may depend on increased viral entry
Summary
The Central Nervous System (CNS) is a major target of Human Immunodeficiency Virus type 1 (HIV-1; McArthur et al, 2010). A commonly abused drug among HIV-1 positive individuals, has been associated with worsening of HAND pathogenesis (Pakesch et al, 1992; Larrat and Zierler, 1993; Goodwin et al, 1996; Nath et al, 2001; Ferris et al, 2008; Norman et al, 2009). Several mechanisms have been proposed for the potentiating effects of cocaine on HAND including enhanced neuro-invasion of HIV1, increased viral replication in the CNS, and elevated toxic effects of HIV-1 viral proteins (Pakesch et al, 1992; Larrat and Zierler, 1993; Goodwin et al, 1996; Nath et al, 2001; Ferris et al, 2008; Norman et al, 2009). The exact mechanism(s) by which cocaine potentiates HIV-1 replication in macrophages is poorly understood
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