This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.HIV infection produces sweeping effects on the immune system. These include a sustained release of acute inflammatory mediators (Breen et al. 1990), increased levels of immunosuppressive cytokines (Breen 2002; Clerici et al. 1997), a relative deficiency in the production of interferon-gamma (IFN-g)(Ma and Montaner 2000), the destruction and functional impairment of T-cells, dendritic cells (DC)(Steinman et al. 2003) and impaired immunity (Ruegg and Engleman 1990). The consequences of these changes include the permissive expansion and replication of HIV, inflammatory injury and a profound immunodeficiency that facilitates the development of opportunistic infections. Based on the rationale that agents that promote a similar pattern of immune dysfunction could enhance HIV pathogenesis we have been investigating the impact of non-injection drugs of abuse on HIV pathogenesis. Using a mouse/human chimera model, we published the first direct evidence that cocaine enhances HIV replication and alters the expression and function of human immune cells in vivo (Roth et al. 2002; Roth et al. 2005; Roth MD 2005). Although the impact of cocaine abuse on disease progression in HIV-positive individuals continues to be a major public health concern, increases in the use and abuse of another stimulant, methamphetamine (MA), has recently reached crisis proportions in both the HIV-seronegative and the HIV-seropositive population. Among drugs of abuse, the use of methamphetamine continues to increase among HIV-infected individuals, and the rate of stimulant use is four times higher in men who have sex with men, an HIV-at-risk population, compared to heterosexual men (Woody et al. 2001). In effect, HIV and the use of methamphetamine have become a 'double epidemic' over the past decade (Halkitis et al. 2001). Based on our previous work and what may be viewed as public health imperative in the HIV-seropositve community, we have hypothesized that the immune modulating effects of methamphetamine will increase susceptibility to HIV infection and disease progression. In vivo and in vitro studies have shown that high levels of activity in the sympathetic division of the autonomic nervous system, and concomitant release of norepinephrine, increase HIV replication. We have hypothesized that this may be one mechanism by which methamphetamine affects immune function and HIV replication. Therefore to test our hypothesis we will determine whether pharmacologic suppression of sympathetic nervous activity through the administration of beta-adrenergic antagonist (such as the well-tolerated pharmacologic agent, propranolol) abrogates the effects of methamphetamine on parameters of immunity pertinent to HIV infection. To test this hypothesis, we will investigate and define the immunologic impact of experimentally administered methamphetamine in non-treatment seeking methamphetamine-dependent volunteers, who are either HIV-seropositive (N=20) or HIV-seronegative (N=20) using a within subjects study design.
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