Human Immunodeficiency Virus Types 1 and 2 (HIV) are estimated to have infected 33.4 million persons by the end of 1998 and Acquired Immune Deficiency Syndrome (AIDS) has become the leading cause of death worldwide. Although recently developed antiretroviral therapy can decrease mortality due to HIV infection, these therapies are limited by the development of drug resistant HIV, which can be sexually transmitted to previously uninfected persons. The virulence of drug resistant HIV-1 in individual humans and human populations remains unclear. The capacity of drug resistant HIV-l to cause immunological injury within individual humans and transmission between humans will determine the long-term clinical and epidemiological outcomes of currently available therapy, which is associated with relatively high rates of drug resistance. The capacity of drug resistant HIV-1 to be transmitted is partly determined by the penetration of these viruses into genital secretions from which transmission may occur. The studies proposed here aim to understand the frequency that drug resistant HIV-1 appears in the genital secretions of women under treatment with combination therapy. Phylogenetic analysis of multiple viral sequences from envelope, reverse transcriptase, and protease reading frames will be used to assess the extent of viral compartmentalization and exchange between blood-associated virus populations and virus populations contributing to genital secretions. This analysis will be performed at different stages of treatment, including subjects who are not treated, subjects who experience early virological failure of therapy, and subjects who have been viremic on therapy for extended periods of time. Decreased penetration of drug resistant HIV-1 into genital secretions could be due to decreased tropism for macrophages, which are infected in the female genital tract and appear to be important for establishing infection in new human hosts. Preliminary reports indicate that drug resistant HIV-1 may have decreased capacity to replicate cell lines measured in single-cycle assays and in thymus tissue cultured as explants or after implantation into SCID mice. The studies proposed here will confirm our own preliminary observations suggesting that protease inhibitor resistant HIV-1 also has decreased tropism for macrophages and will develop cell culture models that will be used for studies to elucidate the mechanism of decreased tropism. Decreased tropism for macrophages of drug resistant HIV-1, if confirmed, could account for prolonged clinical benefit after virological failure in treated persons and would provide a basis for decreased transmissibility between hosts. This information is essential for predicting clinical and epidemiological outcomes of therapy and for development of novel therapy.
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