This proposal responds to RFA-MH-05-010 - "HIV and Psychiatric Comorbidity Research Project." The RFA is "directed at determining the genetic and biological underpinnings of comorbid HIV-infection and psychiatric illness" and to look at gene x environment interactions using samples from well-characterized patients such as those in the Women's Interagency HIV Study (WIHS)." In response to this RFA, investigators from WIHS have begun collaboration with Mary Jeanne Kreek and her colleagues at Rockefeller University who, over last 10 years, have studied the genetics of substance abuse finding significant associations between drug abuse and polymorphisms in opioid, stress response, and serotonin genes. The WIHS cohort includes 3700 women, 75% are HIV positive. The participants have been followed every 6 months for up to 12 years; 2400 women are still being followed, and cryopreserved peripheral blood mononuclear cells (PBMCs) are available for DNA extraction on all participants. Clinical, virologic, immunologic and social history data, including detailed information on drug use are collected at every visit. We have found that continuous substance abuse is associated with more rapid progression of HIV. Opiates have been postulated to increase the rate HIV infection, the progression to AIDS, and the severity of HIV encephalitis. Drug abuse is prevalent in WIHS; most women stop using drugs consistently after they contract HIV, but many do not. Because single nucleotide polymorphisms (SNPs) in opiate receptor gene are associated with changes in opiate-induced physiology, we hypothesize: (1) genetic factors account for more of the substance-abuse risk in persistent users than in inconsistent users, and (2): SNPs in opiate and stress response genes influence HIV progression and HIV-induced cognitive impairment. Finally, depression is very prevalent in women with HIV. Emerging evidence suggests that an interaction between genetic predisposition and stressful life events may lead to depression. We hypothesize: (3) specific SNPs in stress response and serotonergic genes interact with life stressors and HIV to increase the risk of depression. Our specific aims are to determine whether SNPs in opioid, stress response, and serotonergic genes are associated: (1) with particular patterns of drug abuse; (2a) the rate of progression of HIV infection; and (2b) cognitive impairment in HIV; and (3) with the risk for major depression for women in WIHS. At a single follow-up, we will use validated instruments to diagnose major depression and substance abuse on all WIHS participants. Previously obtained frozen PBMCs will be genotyped for multiple variants in several genes of the opioid, stress response, and serotonergic systems. Using all relevant longitudinal data, we will evaluate the effects of gene polymorphisms on the risk of persistent substance abuse, on progression to AIDS and to death, and on the risk of depression.