enfuvirtide and vicriviroc

To provide an update on viral entry inhibitors focusing on recently published clinical trials, the routine clinical use of these medications, and future drug candidates.. Clinical trials and cohort studies support the efficacy of both enfuvirtide and maraviroc in the management of treatment-experienced patients. In clinical practice, tolerability issues, particularly injection site reactions, have limited the clinical use of enfuvirtide. Providers should be aware of the need for tropism determination and dosing requirements for maraviroc. The novel chemokine (C-C motif) receptor 5-blocking agent, vicriviroc, has shown promise and is currently in phase III clinical development.. The rapid pace of scientific discovery and pharmaceutical development has led to the release of several novel and well tolerated antiretroviral agents, with activity against resistant isolates. Entry inhibitors remain a critical therapeutic option for treatment-experienced patients. Providers need to be familiar with these agents, and future drug development should be encouraged.

Topics: CCR5 Receptor Antagonists; Cyclohexanes; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Maraviroc; Peptide Fragments; Piperazines; Pyrimidines; Salvage Therapy; Triazoles; Virus Internalization

Human immunodeficiency virus (HIV) is a retrovirus that is the causative agent of acquired immunodeficiency syndrome (AIDS). Current HIV therapy is based on targeting two critical enzymes in the viral replication machinery: reverse transcriptase and a virally encoded protease. Although mortality rates due to HIV infection have been dramatically reduced, AIDS remains a major health problem throughout the world. The emergence of HIV variants that are resistant to current therapies and potential toxicity associated with their chronic use has highlighted the need for new approaches to HIV inhibition. Identification of the mechanisms underlying viral entry into the host cell has provided a number of novel therapeutic targets and the first of these HIV fusion inhibitors (enfuvirtide [pentafuside, T-20, Fuzeon; Roche Laboratories and Trimeris]) has recently been approved in the US and Europe. This review will focus on recent progress in the development of therapeutics that target the HIV entry process.

Topics: Amino Acid Motifs; Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Antigens; Clinical Trials as Topic; Cyclic N-Oxides; Dogs; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Haplorhini; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Membrane Fusion; Membrane Glycoproteins; Organic Chemicals; Oximes; Peptide Fragments; Piperazines; Piperidines; Protein Binding; Pyridines; Pyrimidines; Rabbits; Receptors, CCR5; Receptors, CXCR4; Reverse Transcriptase Inhibitors; Spiro Compounds

We previously described an HIV-1-infected individual who developed resistance to vicriviroc (VCV), an investigational CCR5 antagonist, during 28 weeks of therapy (Tsibris AM et al., J. Virol. 82:8210-8214, 2008). To investigate the decay of VCV resistance mutations, a standard clonal analysis of full-length env (gp160) was performed on plasma HIV-1 samples obtained at week 28 (the time of VCV discontinuation) and at three subsequent time points (weeks 30, 42, and 48). During 132 days, VCV-resistant HIV-1 was replaced by VCV-sensitive viruses whose V3 loop sequences differed from the dominant pretreatment forms. A deep-sequencing analysis showed that the week 48 VCV-sensitive V3 loop form emerged from a preexisting viral variant. Enfuvirtide was added to the antiretroviral regimen at week 30; by week 48, enfuvirtide treatment selected for either the G36D or N43D HR-1 mutation. Growth competition experiments demonstrated that viruses incorporating the dominant week 28 VCV-resistant env were less fit than week 0 viruses in the absence of VCV but more fit than week 48 viruses. This week 48 fitness deficit persisted when G36D was corrected by either site-directed mutagenesis or week 48 gp41 domain swapping. The correction of N43D, in contrast, restored fitness relative to that of week 28, but not week 0, viruses. Virus entry kinetics correlated with observed fitness differences; the slower entry of enfuvirtide-resistant viruses corrected to wild-type rates in the presence of enfuvirtide. These findings suggest that while VCV and enfuvirtide select for resistance mutations in only one env subunit, gp120 and gp41 coevolve to maximize viral fitness under sequential drug selection pressures.

Topics: Anti-HIV Agents; Cell Line; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Molecular Sequence Data; Mutation; Peptide Fragments; Phylogeny; Piperazines; Pyrimidines; Virus Internalization; Virus Replication