Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients.
Substance abuse is a major barrier in eradication of the HIV epidemic because it serves as a powerful cofactor for viral transmission, disease progression, and AIDS-related mortality. Cocaine, one of the commonly abused drugs among HIV-1 patients, has been suggested to accelerate HIV disease progression. However, the underlying mechanism remains largely unknown. Therefore, we tested whether cocaine augments HIV-1-associated CD4(+) T-cell decline, a predictor of HIV disease progression. We examined apoptosis of resting CD4(+) T cells from HIV-1-negative and HIV-1-positive donors in our study, because decline of uninfected cells plays a major role in HIV-1 disease progression. Treatment of resting CD4(+) T cells with cocaine (up to 100 μmol/L concentrations) did not induce apoptosis, but 200 to 1000 μmol/L cocaine induced apoptosis in a dose-dependent manner. Notably, treatment of CD4(+) T cells isolated from healthy donors with both HIV-1 virions and cocaine significantly increased apoptosis compared with the apoptosis induced by cocaine or virions alone. Most important, our biochemical data suggest that cocaine induces CD4(+) T-cell apoptosis by increasing intracellular reactive oxygen species levels and inducing mitochondrial depolarization. Collectively, our results provide evidence of a synergy between cocaine and HIV-1 on CD4(+) T-cell apoptosis that may, in part, explain the accelerated disease observed in HIV-1-infected drug abusers.
Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, Tennessee; Department of Graduate Studies, Meharry Medical College, Nashville, Tennessee.
Jui
J
Pandhare
Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, Tennessee; Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee.
Amma B
AB
Addai
Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, Tennessee.
Chinmay K
CK
Mantri
Infectious Disease Division, Vanderbilt University School of Medicine, Nashville, Tennessee.
Cynthia
C
Hager
Infectious Disease Division, Vanderbilt University School of Medicine, Nashville, Tennessee.
Rita M
RM
Smith
Infectious Disease Division, Vanderbilt University School of Medicine, Nashville, Tennessee.
Louis
L
Barnett
Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee.
Fernando
F
Villalta
Infectious Disease Division, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Spyros A
SA
Kalams
Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, Tennessee; Department of Graduate Studies, Meharry Medical College, Nashville, Tennessee; Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee; Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee. Electronic address: cdash@mmc.edu.
Chandravanu
C
Dash
D017209:Apoptosis / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D002469:Cell Separation; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000150:complications* / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D015658:HIV Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology; D015497:HIV-1; D006801:Humans; D014771:Virion / Q000187:drug effects
D018765:Dopamine Uptake Inhibitors; D003042:Cocaine