The human immunodeficiency virus type 1 (HIV-1) has been identified as the causative agent of disorders of the immune and nervous systems referred to as the acquired immunodeficiency syndrome (AIDS) and HIV-associated dementia complex. A number of cell types have been shown to be susceptible to HIV-1 infection, with susceptibility to viral infection critically dependent on the interaction of the HIV-1-specific viral envelope proteins gp120 and gp41 with the primary cellular receptor molecule identified as CD4. This molecule is highly prevalent on the surface of lymphocytes but has also been identified on the surface of other cells of immune and nervous system origin. More recent in vitro studies have identified a number of CD4 negative cell types that are susceptible to HIV-1 during the course of disease and have complicated the development of broad antiviral strategies designed to block HIV-1 transmission and entry. Although HIV-1 has been shown to be transmitted by a variety of means, the most rapidly increasing mode of transmission is transmission during the act of heterosexual intercourse. Although mechanical barriers represent an effective means of preventing sexually transmitted diseases (STDs), their universal acceptance as the sole approach to disease prevention is unlikely due to a number of psychosocial considerations. As a result, a highly desirable alternative approach to preventing STDs centers on the development of nontoxic broad spectrum microbicide.
The Specific Aims of this portion of the Program Project are to: (1) utilize an in vitro cell culture system to examine the HIV-1 inactivation by microbicidal formulations (performed in conjunction with Dr. Malamud, (2) examine the cytotoxicity and anti-HIV-1 activity of microbicidal formulations using continuous vaginal epithelial cells and primary human vaginal keratinocytes (performed in conjunction with Dr. Heyner, establish and characterize conditions for HIV-1 infection of human vaginal xenografts (performed in conjunction with Dr. Kreider,; (4) identify cellular targets for HIV-1 infection within the human vaginal xenografts (performed in conjunction with Dr. Kreider, and (5) examine the cytotoxicity and anti-HIV-1 activity of microbicidal formulations (identified as effective anti-HIV compounds under Specific Aim 1) in human vaginal xenografts (performed in conjunction with Dr. Kreider, Project Number 1). The results of these investigations will be integrated into those of the complete Program Project, the goal of which is the development and characterization of an effective, nontoxic microbicidal approach to prevent or reduce the transmission of agents that cause painful and often life-threatening STDs, including retroviruses like HIV-1.
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