The HIVToolbox 2 web system integrates sequence, structure, function and mutation analysis.

There is enormous interest in studying HIV pathogenesis for improving the treatment of patients with HIV infection. HIV infection has become one of the best-studied systems for understanding how a virus can hijack a cell. To help facilitate discovery, we previously built HIVToolbox, a web system for visual data mining. The original HIVToolbox integrated information for HIV protein sequence, structure, functional sites, and sequence conservation. This web system has been used for almost 40,000 searches. We report improvements to HIVToolbox including new functions and workflows, data updates, and updates for ease of use. HIVToolbox2, is an improvement over HIVToolbox with new functions. HIVToolbox2 has new functionalities focused on HIV pathogenesis including drug-binding sites, drug-resistance mutations, and immune epitopes. The integrated, interactive view enables visual mining to generate hypotheses that are not readily revealed by other approaches. Most HIV proteins form multimers, and there are posttranslational modification and protein-protein interaction sites at many of these multimerization interfaces. Analysis of protease drug binding sites reveals an anatomy of drug resistance with different types of drug-resistance mutations regionally localized on the surface of protease. Some of these drug-resistance mutations have a high prevalence in specific HIV-1 M subtypes. Finally, consolidation of Tat functional sites reveals a hotspot region where there appear to be 30 interactions or posttranslational modifications. A cursory analysis with HIVToolbox2 has helped to identify several global patterns for HIV proteins. An initial analysis with this tool identifies homomultimerization of almost all HIV proteins, functional sites that overlap with multimerization sites, a global drug resistance anatomy for HIV protease, and specific distributions of some DRMs in specific HIV M subtypes. HIVToolbox2 is an open-access web application available at [http://hivtoolbox2.bio-toolkit.com].

Behavioral and molecular evidence for a feedback interaction between morphine and HIV-1 viral proteins.

Morphine use and addiction is common among HIV infected individuals. There is an abundance of research supporting the effects of morphine and other mu opioid receptor (MOR) ligands, on the function of HIV-1 viral proteins and progression of HIV-1 viral infection to AIDS. On the other hand, there is much less research that investigates the possible effects of the persistent presence of HIV-1 viral proteins on the expression of the MOR and the analgesic and rewarding effects of MOR ligands such as morphine. While researchers have made a great deal of progress in the past several years, the overall investigation of the interaction between opiates such as morphine and HIV-1 viral proteins is largely unilateral. It has become widely accepted that drugs of abuse interact with HIV-1 viral proteins, but the mechanisms by which this takes place are only recently being discovered. Molecular and behavioral research suggests a feedback interaction between morphine and HIV-1 viral proteins. This interaction is mediated largely by the MOR as well as interplay between MOR ligands and cytokines, chemokines and their receptors. Some of the mechanisms underlying the feedback interaction between morphine and HIV-1 viral proteins has been demonstrated using cell culture and the recently engineered HIV-1 transgenic (HIV-1Tg) rat models.

ADAR1 is a novel multi targeted anti-HIV-1 cellular protein.

We examined the antiviral activity of ADAR1 against HIV-1. Our results indicated that ADAR1 in a transfection system inhibited production of viral proteins and infectious HIV-1 in various cell lines including 293T, HeLa, Jurkat T and primary CD4+ T cells, and was active against a number of X4 and R5 HIV-1 of different clades. Further analysis showed that ADAR1 inhibited viral protein synthesis without any effect on viral RNA synthesis. Mutational analysis showed that ADAR1 introduced most of the A-to-G mutations in the rev RNA, in the region of RNA encoding for Rev Response Element (RRE) binding domain and in env RNA. These mutations inhibited the binding of rev to the RRE and inhibited transport of primary transcripts like gag, pol and env from nucleus to cytoplasm resulting in inhibition of viral protein synthesis without any effect on viral RNA synthesis. Furthermore, ADAR1 induced mutations in the env gene inhibited viral infectivity.

Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel.

Resistance to antiretroviral drugs remains an important limitation to successful human immunodeficiency virus type 1 (HIV-1) therapy. Resistance testing can improve treatment outcomes for infected individuals. The availability of new drugs from various classes, standardization of resistance assays, and the development of viral tropism tests necessitate new guidelines for resistance testing. The International AIDS Society-USA convened a panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care to review recently published data and presentations at scientific conferences and to provide updated recommendations. Whenever possible, resistance testing is recommended at the time of HIV infection diagnosis as part of the initial comprehensive patient assessment, as well as in all cases of virologic failure. Tropism testing is recommended whenever the use of chemokine receptor 5 antagonists is contemplated. As the roll out of antiretroviral therapy continues in developing countries, drug resistance monitoring for both subtype B and non-subtype B strains of HIV will become increasingly important.