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Interactions between alcohol and the HIV entry inhibitor Maraviroc.

ABSTRACT: Alcohol use is common among people with HIV, and beliefs about alcohol interactions with medications predict decreased medication adherence, risking drug-resistant mutations. Maraviroc is an HIV entry inhibitor approved for treatment of both drug-sensitive and drug-resistant HIV strains. The present study evaluated the effects of alcohol on maraviroc pharmacokinetics and the effects of maraviroc on alcohol pharmacokinetics.Ten healthy adults completed alcohol (1 g/kg) and placebo alcohol pharmacokinetics sessions before and after 7 days of maraviroc administration.Alcohol concentrations increased 12% following maraviroc. Maraviroc pharmacokinetics were unaffected by alcohol.Maraviroc treatment should not be interrupted if alcohol is consumed.

SUBMITTER: Gruber VA

PROVIDER: S-EPMC4100473 | biostudies-literature | 2013 Nov-Dec

REPOSITORIES: biostudies-literature

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Interactions between alcohol and the HIV entry inhibitor Maraviroc.

Gruber Valerie A VA Rainey Petrie M PM Lum Paula J PJ Beatty George W GW Aweeka Francesca T FT McCance-Katz Elinore F EF

Journal of the International Association of Providers of AIDS Care 20130723 6

<h4>Background</h4>Alcohol use is common among people with HIV, and beliefs about alcohol interactions with medications predict decreased medication adherence, risking drug-resistant mutations. Maraviroc is an HIV entry inhibitor approved for treatment of both drug-sensitive and drug-resistant HIV strains. The present study evaluated the effects of alcohol on maraviroc pharmacokinetics and the effects of maraviroc on alcohol pharmacokinetics.<h4>Methods</h4>Ten healthy adults completed alcohol ( ...[more]

PMID: 23881910

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Project description:Long-acting antiretrovirals could provide a useful alternative to daily oral therapy for HIV-1-infected individuals. Building on a bi-specific molecule with adnectins targeting CD4 and gp41, a potential long-acting biologic, GSK3732394, was developed with three independent and synergistic modes of HIV entry inhibition that potentially could be self-administered as a long-acting subcutaneous injection. Starting with the bi-specific inhibitor, an α-helical peptide inhibitor was optimized as a linked molecule to the anti-gp41 adnectin, with each separate inhibitor exhibiting at least single-digit nanomolar (or lower) potency and a broad spectrum. Combination of the two adnectins and peptide activities into a single molecule was shown to have synergistic advantages in potency, the resistance barrier, and the ability to inhibit HIV-1 infections at low levels of CD4 receptor occupancy, showing that GSK3732394 can work in trans on a CD4+ T cell. Addition of a human serum albumin molecule prolongs the half-life in a human CD4 transgenic mouse, suggesting that it may have potential as a long-acting agent. GSK3732394 was shown to be highly effective in a humanized mouse model of infection. GSK3732394 is currently in clinical trials.IMPORTANCE There continue to be significant unmet medical needs for patients with HIV-1 infection. One way to improve adherence and decrease the likelihood of drug-drug interactions in HIV-1-infected patients is through the development of long-acting biologic inhibitors. Building on a bi-specific inhibitor approach targeting CD4 and gp41, a tri-specific molecule was generated with three distinct antiviral activities. The linkage of these three biologic inhibitors creates synergy that offers a series of advantages to the molecule. The addition of human serum albumin to the tri-specific inhibitor could allow it to function as a long-acting self-administered treatment for patients with HIV infection. This molecule is currently in early clinical trials.

Project description:BackgroundTransportin-SR2 (TRN-SR2, TNPO3, transportin 3) was previously identified as an interaction partner of human immunodeficiency virus type 1 (HIV-1) integrase and functions as a nuclear import factor of HIV-1. A possible role of capsid in transportin-SR2-mediated nuclear import was recently suggested by the findings that a chimeric HIV virus, carrying the murine leukemia virus (MLV) capsid and matrix proteins, displayed a transportin-SR2 independent phenotype, and that the HIV-1 N74D capsid mutant proved insensitive to transportin-SR2 knockdown.ResultsOur present analysis of viral specificity reveals that TRN-SR2 is not used to the same extent by all lentiviruses. The DNA flap does not determine the TRN-SR2 requirement of HIV-1. We corroborate the TRN-SR2 independent phenotype of the chimeric HIV virus carrying the MLV capsid and matrix proteins. We reanalyzed the HIV-1 N74D capsid mutant in cells transiently or stably depleted of transportin-SR2 and confirm that the N74D capsid mutant is independent of TRN-SR2 when pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G). Remarkably, although somewhat less dependent on TRN-SR2 than wild type virus, the N74D capsid mutant carrying the wild type HIV-1 envelope required TRN-SR2 for efficient replication. By pseudotyping with envelopes that mediate pH-independent viral uptake including HIV-1, measles virus and amphotropic MLV envelopes, we demonstrate that HIV-1 N74D capsid mutant viruses retain partial dependency on TRN-SR2. However, this dependency on TRN-SR2 is lost when the HIV N74D capsid mutant is pseudotyped with envelopes mediating pH-dependent endocytosis, such as the VSV-G and Ebola virus envelopes.ConclusionHere we discover a link between the viral entry of HIV and its interaction with TRN-SR2. Our data confirm the importance of TRN-SR2 in HIV-1 replication and argue for careful interpretation of experiments performed with VSV-G pseudotyped viruses in studies on early steps of HIV replication including the role of capsid therein.

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Interactions between alcohol and the HIV entry inhibitor Maraviroc.

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Interactions between alcohol and the HIV entry inhibitor Maraviroc.

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