Abstract
The main objective of this study was to examine effects of cocaine on HIV-1 replication in primary CD4+ T cells. Cocaine a commonly used drug among HIV-1 positive individuals serves as a cofactor for HIV-1 infection and progression to acquired immunodeficiency syndrome (AIDS). Accumulating evidence suggest that cocaine increases HIV-1 replication in cell cultures, peripheral blood mononuclear cells (PBMCs) and animal models. Intriguingly, there are no studies on cocaine-induced alterations in HIV-1 replication in primary CD4+ T cells that serve as the main targets for HIV-1 replication in vivo. In this report, we demonstrate cocaine-induced enhancement of HIV-1 replication in primary CD4+ T cells isolated from human PBMCs. To decipher a potential mechanism, we examined whether cocaine targets the innate antiviral immunity of CD4+ T cells mediated by cellular microRNAs (miRNAs). This is because recently a network of anti-HIV miRNAs in CD4+ T cells is highlighted to suppress viral replication. Our genome wide miRNA expression analysis indicated downregulation of several anti-HIV miRNAs (miR-28, miR-125b, miR-150, miR-223, and miR-382) in cocaine treated CD4+ T cells. However, our real-time quantitative PCR analysis revealed significant downregulation of miR-125b only. Our results illustrated that miR-125b knockdown enhances HIV-1 replication, whereas overexpression of miR-125b decreases HIV-1 replication in these cells. Therefore, we believe miR-125b is a key player for the cocaine induced enhancement of HIV-1 replication in CD4+ T cells. Since, miR-125b targets the 3′ UTR regions of HIV-1 transcripts and inhibits viral protein translation, our data suggest modulation of post entry steps of HIV-1 by cocaine. Given that a plethora of studies suggest that cocaine regulates HIV entry, our results implicate a potentially novel mechanism by which cocaine can increase viral replication in CD4+ T cells.
Highlights
Illicit drug use remains the second most frequent mode of acquisition of HIV and drugs such as amphetamines, cocaine, marijuana, and opiates serve as cofactors for susceptibility to HIV infection and disease progression [1,2,3,4,5,6,7,8]
Members of the b-chemokine family that bind to CCR5 such as regulated upon-activation T expressed and secreted (RANTES), macrophage inflammatory protein 1a (MIP-1a), and MIP-1b have been demonstrated to inhibit entry of certain HIV-1 strains [22]
It has been described that cocaine enhances HIV-1 replication in peripheral blood mononuclear cells (PBMCs) and animal models [14,15,16]
Summary
Illicit drug use remains the second most frequent mode of acquisition of HIV and drugs such as amphetamines, cocaine, marijuana, and opiates serve as cofactors for susceptibility to HIV infection and disease progression [1,2,3,4,5,6,7,8]. Epidemiological studies suggest that HIV positive cocaine users have lower CD4+ T cell counts, increased risk of diseases progression and AIDS-related death [11,12,13]. Proteomics analysis of cocaine treated PBMCs isolated from HIV-positive donors suggests that cocaine differentially regulates expression of several key host proteins that may influence HIV-1 replication [23]. Since these studies were conducted using cell culture models or the mixed cell populations of PBMCs, there are no reports on primary CD4+ T cells. Given that CD4+ T cells are the main targets for HIV-1 infection and replication in vivo [24], it is critical to evaluate whether cocaine enhances HIV-1 replication in primary CD4+ T cells
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