title: HIV-1 Group O Genotypes and Phenotypes: Relationship to Fitness and Susceptibility to Antiretroviral Drugs.
abstract: Despite only 30,000 group O HIV-1 infections, a similar genetic diversity is observed among the O subgroups H (head) and T (tail) (previously described as subtypes A, B) as in the 9 group M subtypes (A-K). Group O isolates bearing a cysteine at reverse transcriptase (RT) position 181, predominantly the H strains are intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, their susceptibility to newer antiretroviral drugs such as etravirine, maraviroc, raltegravir (RAL), and elvitegravir (EVG) remains relatively unknown. We tested a large collection of HIV-1 group O strains for their susceptibility to four classes of antiretroviral drugs namely nucleoside RT, non-nucleoside RT, integrase, and entry inhibitors knowing in advance the intrinsic resistance to NNRTIs. Drug target regions were sequenced to determine various polymorphisms and were phylogenetically analyzed. Replication kinetics and fitness assays were performed in U87-CD4(+)CCR5 and CXCR4 cells and peripheral blood mononuclear cells. With all antiretroviral drugs, group O HIV-1 showed higher variability in IC50 values than group M HIV-1. The mean IC50 values for entry and nucleoside reverse transcriptase inhibitor (NRTI) were similar for group O and M HIV-1 isolates. Despite similar susceptibility to maraviroc, the various phenotypic algorithms failed to predict CXCR4 usage based on the V3 Env sequences of group O HIV-1 isolates. Decreased sensitivity of group O HIV-1 to integrase or NNRTIs had no relation to replicative fitness. Group O HIV-1 isolates were 10-fold less sensitive to EVG inhibition than group M HIV-1. These findings suggest that in regions where HIV-1 group O is endemic, first line treatment regimens combining two NRTIs with RAL may provide more sustained virologic responses than the standard regimens involving an NNRTI or protease inhibitors.
authors: 1 Division of Infectious Diseases, Case Western Reserve University , Cleveland, Ohio.
authors: Denis M
authors: DM
authors: Tebit
authors: 1 Division of Infectious Diseases, Case Western Reserve University , Cleveland, Ohio.
authors: Hamish
authors: H
authors: Patel
authors: 1 Division of Infectious Diseases, Case Western Reserve University , Cleveland, Ohio.
authors: Annette
authors: A
authors: Ratcliff
authors: 2 Laboratory of Virology, Rouen University Hospital , Rouen, France .
authors: Elodie
authors: E
authors: Alessandri
authors: 1 Division of Infectious Diseases, Case Western Reserve University , Cleveland, Ohio.
authors: Joseph
authors: J
authors: Liu
authors: 1 Division of Infectious Diseases, Case Western Reserve University , Cleveland, Ohio.
authors: Crystal
authors: C
authors: Carpenter
authors: 2 Laboratory of Virology, Rouen University Hospital , Rouen, France .
authors: Jean-Christophe
authors: JC
authors: Plantier
authors: 1 Division of Infectious Diseases, Case Western Reserve University , Cleveland, Ohio.
authors: Eric J
authors: EJ
authors: Arts
mesh_terms: D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D024882:Drug Resistance, Viral; D005838:Genotype; D015497:HIV-1 / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D010802:Phylogeny; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D014779:Virus Replication
chemical_list: D044966:Anti-Retroviral Agents