The rapid evaluation of new antiretroviral agents will be markedly changed by the development of accurate virologic markers. We have developed the concept of plasma HIV viremia as a marker for antiretroviral studies. However, cultur methods are slow and virion detection by HIV-RNA PCR methods may afford a more rapid, sensitive and quantitative assessment of antiviral response to therapy. We feel that a systematic evaluation of plasma viremia and HIV RNA virus detection is warranted and are proposing a series of investigations with the following aims:
AIM 1, to further develop plasma viremia as a marker of antiretroviral therapy by assessing the relationship between infectivity of cell-free plasma virus and presence of both cell-associated HIV proviral DNA and cell-free HIV RNA;
AIM 2, to develop further a direct ex vivo assay that will measure the in vivo response of HIV infection to antiretrovirals an provide a method for targeting subsequent in vivo levels for further phase I study;
AIM 3, determine if the blocking of HIV infectivity by immune-based viral neutralization therapies, such as sCD4 and antiretrovirals such as the glycosylation inhibitor deoxynorjirimycin and protease inhibitors, will decrease cell-associated and cell-free infectious titers of HIV and quantity of HIV nucleic acid. We anticipate that these methods will prove to be a particularly useful in vitro guide for he more rapid assessment of antiretrovirals in general; particularly those with either a narrow therapeutic index or poor bioavailability following oral dosing. In conjunction with other quantitative virologic methods such as cell-dilution infectivity assays, HIV-DNA distribution of HIV among the various cell- associated and cell-free reservoirs during antiretroviral therapy, and will thus expedite the overall early phase I and II development of these drugs.
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