Stimulant use such as cocaine has been shown to impact the human immune system. In regards to the human immunodeficiency virus (HIV) infection, a number of studies have indicated that cocaine users are at an increased risk for infection and display more rapid disease progression and morbidity. However due to many variables such as adherence to antiretroviral therapy, use of multiple classes of drugs and co-infections among others, it is difficult to fully appreciate the impact drug abuse has on HIV disease. In this proposal, we aim to develop an in vitro and in vivo system to examine the impact of cocaine on HIV infection.
In Specific Aim #1, we propose to examine the effects of cocaine on quiescent CD4 T cell (G0) permissiveness to HIV and the kinetics of infection. This will be assessed by comparing the HIV infection kinetics of G0 cells in the presence or absence of cocaine (in vivo and in vitro). The mechanisms of cocaine effects will be determined by the use of neutralizing antibodies and receptor agonists and antagonists.
In Specific Aim #2, we will investigate in vivo the effect of cocaine on HIV replication using the humanized BLT mouse model. These mice have a fully reconstituted human immune system that allows for the study of HIV infection. Mice will be infected with HIV prior or post-drug exposure and disease progression will be assessed compared to non-infected and/or untreated mice. In addition, we will examine the reactivation of viral reservoir from latently infected cells isolated from these mice. The proposed studies will expand our knowledge on HIV infection in quiescent cells in drug abusers, will shed light on the mechanisms which may activate provirus expression in this long-lived stable reservoir, and ultimately lead to the development of effective therapies tailored to individuals, both HIV seropositives and seronegatives, suffering from drug abuse.

Public Health Relevance

Drugs of abuse have been shown to promote immune dysfunction and influence human immunodeficiency virus (HIV) disease progression. Resting T cells make up the majority of the stable viral reservoir. In this proposal, which focuses on the effects of cocaine on HIV infection of quiescent T cells, the goals are to examine in vivo and in vitro how stimulants (1) affect HIV infectivity in quiescent T cells and (2) influence the activation of the HIV reservoir.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA031036-02
Application #
8288071
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Purohit, Vishnudutt
Project Start
2011-07-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$231,000
Indirect Cost
$81,000
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Nixon, Christopher C; Vatakis, Dimitrios N; Reichelderfer, Scott N et al. (2013) HIV-1 infection of hematopoietic progenitor cells in vivo in humanized mice. Blood 122:2195-204
Zack, Jerome A; Kim, Sohn G; Vatakis, Dimitrios N (2013) HIV restriction in quiescent CD4? T cells. Retrovirology 10:37
Kim, Sohn G; Jung, James B; Dixit, Dhaval et al. (2013) Cocaine exposure enhances permissiveness of quiescent T cells to HIV infection. J Leukoc Biol 94:835-43