title: Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients.
abstract: Epidemiologic studies suggest that cocaine abuse worsens HIV-1 disease progression. Increased viral load has been suggested to play a key role for the accelerated HIV disease among cocaine-abusing patients. The goal of this study was to investigate whether cocaine enhances proviral DNA integration as a mechanism to increase viral load. We infected CD4(+) T cells that are the primary targets of HIV-1 in vivo and treated the cells with physiologically relevant concentrations of cocaine (1 µM-100 µM). Proviral DNA integration in the host genome was measured by nested qPCR. Our results illustrated that cocaine from 1 µM through 50 µM increased HIV-1 integration in CD4(+) T cells in a dose-dependent manner. As integration can be modulated by several early postentry steps of HIV-1 infection, we examined the direct effects of cocaine on viral integration by in vitro integration assays by use of HIV-1 PICs. Our data illustrated that cocaine directly increases viral DNA integration. Furthermore, our MS analysis showed that cocaine is able to enter CD4(+) T cells and localize to the nucleus-. In summary, our data provide strong evidence that cocaine can increase HIV-1 integration in CD4(+) T cells. Therefore, we hypothesize that increased HIV-1 integration is a novel mechanism by which cocaine enhances viral load and worsens disease progression in drug-abusing HIV-1 patients.
authors.affiliation: *The Laboratory of Retrovirology and Epigenetics, Center For AIDS Health Disparities Research, and Departments of Biochemistry and Cancer Biology and Graduate Studies, Genomics and Proteomics Core, Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA.
authors.forename: Amma B
authors.initials: AB
authors.lastname: Addai
authors.affiliation: *The Laboratory of Retrovirology and Epigenetics, Center For AIDS Health Disparities Research, and Departments of Biochemistry and Cancer Biology and Graduate Studies, Genomics and Proteomics Core, Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA.
authors.forename: Jui
authors.initials: J
authors.lastname: Pandhare
authors.affiliation: *The Laboratory of Retrovirology and Epigenetics, Center For AIDS Health Disparities Research, and Departments of Biochemistry and Cancer Biology and Graduate Studies, Genomics and Proteomics Core, Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Paromov
authors.affiliation: *The Laboratory of Retrovirology and Epigenetics, Center For AIDS Health Disparities Research, and Departments of Biochemistry and Cancer Biology and Graduate Studies, Genomics and Proteomics Core, Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA.
authors.forename: Chinmay K
authors.initials: CK
authors.lastname: Mantri
authors.affiliation: *The Laboratory of Retrovirology and Epigenetics, Center For AIDS Health Disparities Research, and Departments of Biochemistry and Cancer Biology and Graduate Studies, Genomics and Proteomics Core, Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Pratap
authors.affiliation: *The Laboratory of Retrovirology and Epigenetics, Center For AIDS Health Disparities Research, and Departments of Biochemistry and Cancer Biology and Graduate Studies, Genomics and Proteomics Core, Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA cdash@mmc.edu.
authors.forename: Chandravanu
authors.initials: C
authors.lastname: Dash
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology* / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000150:complications; D004279:DNA, Viral / Q000235:genetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D057809:HEK293 Cells; D015658:HIV Infections / Q000150:complications; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D010835:Phytohemagglutinins / Q000494:pharmacology; D011533:Proviruses / Q000187:drug effects; D018116:Vesiculovirus / Q000648:ultrastructure; D019562:Viral Load; D014771:Virion / Q000502:physiology; D016662:Virus Integration / Q000187:drug effects*
chemical_list: D004279:DNA, Viral; D010835:Phytohemagglutinins; D003042:Cocaine
keywords: Raltegravir; mass spectrometry; preintegration complex