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BACKGROUND: To assess the risk factors associated with genotypic resistance to protease inhibitors (PI) in HIV-infected subjects with virologic failure despite highly active antiretroviral treatment (HAART). PATIENTS AND METHOD: Retrospective chart review including 47 consecutive patients with virologic failure despite PI-based HAART who had undergone a genotypic HIV-1 testing. The prevalence of genotypic resistance to PI was determined and several demographic, clinical and laboratory variables were compared between patients with and without genotypic resistance to those drugs. RESULTS: The entire nucleotide sequence of the protease gene was obtained in 43 of the 47 patients; 18 of them had genotypic resistance to PI. Genotypic resistance to PI was associated with a previous therapy with suboptimal antiretroviral regimens (OR = 10.2; 95% CI, 1.05-245.1; P = 0.02), duration of antiretroviral therapy longer than 18 months (OR = 13.3; 95% CI, 1.23-340.85; P = 0.01), greater number of antiretroviral regimens and drugs before the virologic failure (p < 0.01) and presence of the 184V mutation in the reverse transcriptase gene (OR = 5.6; 95% CI, 1.2-29.2; P = 0.02). There was no relationship between PI resistance and the risk group, viral load or CD4 cell count. In the multivariate analysis, previous therapy with suboptimal antiretroviral regimens was the better predictor of PI resistance (OR = 11.1; 95% CI, 1.04-117.47; P = 0.046). CONCLUSIONS: Patients treated with suboptimal antiretroviral activity regimens before starting HAART can be at greater risk of developing genotypic resistance to protease inhibitors.

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The zinc finger structure that is found in the nucleocapsid protein of nearly all retroviruses has been proposed as a target for antiviral therapy. Since compounds that chemically attack the cysteines of the finger have been shown to inactivate both human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus (MuLV) in vitro, 14 of these compounds were tested in an MuLV-induced Friend disease model to assess their ability to inhibit retroviral replication in vivo. Of the 14 compounds tested, only Aldrithiol-2 clearly exhibited anti-retroviral activity as measured indirectly by the delay of Friend disease onset (P < 0.05). These results were confirmed by quantitative competitive polymerase chain reaction studies which monitored viral spread by measuring the level of viral DNA in the peripheral blood mononuclear cells of treated mice. Comparison of treated mice with untreated mice revealed that Aldrithiol-2 produced a greater than 2-log reduction in virus levels. These results functionally demonstrate that a zinc finger-attacking compound can inhibit viral replication in vivo. Since only 1 of the 14 compounds studied was effective, this study also shows the importance of in vivo testing of these types of antiviral compounds in an animal model. Given the strict conservation of the metal-coordinating cysteine structure within HIV-1 and MuLV zinc fingers, our results support the proposal that anti-retroviral drugs which target the nucleocapsid zinc finger may be clinically useful against HIV-1.

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Several aurintricarboxylic acid (ATA) monomers, monomer analogs, and polymer fractions have been tested as inhibitors of HIV-1 integration protein (IN). Both of the ATA monomers and all of the ATA polymer fractions inhibited a selective DNA cleavage reaction catalyzed by IN. The ATA monomer analogs were inactive or had low activity. The activities of the substances as inhibitors of HIV IN correlated in a positive way with their activities as inhibitors of the cytopathic effect of HIV-1 in CEM and HIV-2 in MT4 cells. These results suggest that inhibition of HIV IN may contribute to the antiviral activity of the ATA monomers and monomer analogs in cell culture.

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The dipyridodiazepinone human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitor BI-RG-587 was tested for its ability to inhibit HIV-1 replication in both acutely and chronically infected cell lines. The ability of BI-RG-587 to inhibit steps in the virus replicative cycle other than reverse transcription was also assessed. BI-RG-587 was found to be a potent inhibitor of HIV-1 replication in acutely infected cells (50% inhibitory concentration [IC50] = 37.2 nM), and the sensitivity and kinetics of that inhibition was similar to the known RT inhibitor zidovudine (AZT). Even at 100x IC50, BI-RG-587 had no effect on gp120/CD4 interaction, syncytia formation, or envelope glycoprotein processing. In addition, no inhibition of viral replication or protein production was noted in a chronically infected cell line that produces viral products in an RT-independent manner. Finally, no inhibition of acute HIV-2 replication was noted, even with very high (2500x IC50 for HIV-1) concentrations of BI-RG-587. These results demonstrate that BI-RG-587 is a potent inhibitor of HIV-1 replication and that this inhibition occurs at the point of reverse transcription.

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