title: Susceptibility of HIV type 2 primary isolates to CCR5 and CXCR4 monoclonal antibodies, ligands, and small molecule inhibitors.
abstract: Human immunodeficiency virus (HIV) entry into susceptible cells involves the interaction between viral envelope glycoproteins with CD4 and a chemokine receptor (coreceptor), namely CCR5 and CXCR4. This interaction has been studied to enable the discovery of a new class of antiretroviral drugs that targets the envelope glycoprotein-coreceptor interaction. However, very few data exist regarding HIV-2 susceptibility to these coreceptor inhibitors. With this work we aimed to identify this susceptibility in order to assess the potential use of these molecules to treat HIV-2-infected patients and to further understand the molecular basis of HIV-2 envelope glycoprotein interactions with CCR5 and CXCR4. We found that CCR5-using HIV-2 isolates are readily inhibited by maraviroc, TAK-779, and PF-227153, while monoclonal antibody 2D7 shows only residual or no inhibitory effects. The anti-HIV-2 activity of CXCR4-targeted molecules reveals that SDF-1α/CXCL12 inhibited all HIV-2 tested except one, while mAb 12G5 inhibited the replication of only two isolates, showing residual inhibitory effects with all the other CXCR4-using viruses. A major conclusion from our results is that infection by HIV-2 primary isolates is readily blocked in vitro by maraviroc, at concentrations similar to those required for HIV-1. The susceptibility to maraviroc was independent of CD4(+) T cell counts or clinical stage of the patient from which the virus was obtained. These findings indicate that maraviroc could constitute a reliable therapeutic alternative for HIV-2-infected patients, as long as they are infected with CCR5-using variants, and this may have direct implications for the clinical management of HIV-2-infected patients.
authors: Centro de Patogénese Molecular, Unidade de Retrovírus e Infecções Associadas, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, Lisbon, Portugal.
authors: Maria
authors: M
authors: Espirito-Santo
authors: Quirina
authors: Q
authors: Santos-Costa
authors: Marta
authors: M
authors: Calado
authors: Patrick
authors: P
authors: Dorr
authors: J Miguel
authors: JM
authors: Azevedo-Pereira
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D003510:Cyclohexanes / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015498:HIV-2 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D008024:Ligands; D000077592:Maraviroc; D019713:Receptors, CCR5 / Q000187:drug effects / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000276:immunology*; D014230:Triazoles / Q000494:pharmacology*; D014779:Virus Replication
chemical_list: D000911:Antibodies, Monoclonal; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D008024:Ligands; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014230:Triazoles; D000077592:Maraviroc