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.

FIG. 1.

Dose–response curves for HIV-2 susceptibility to different CCR5- and CXCR4-targeted inhibitors. In these assays, HIV-2 primary isolates were normalized by RT activity levels, and equivalent amounts of each isolate were added to GHOST-CD4/CCR5 (a–d) or GHOST-CD4/CXCR4 (e and f). Data represent the mean percent inhibition±standard error of the mean (bars). The extent of inhibition of viral replication is presented as a percentage of control (no inhibitor=0%). Data were analyzed using nonlinear regression, four-parameter logistic curve fit analysis with GraphPad Prism software, version 4.0, and are representative of at least three independent assays. The laboratory-adapted strains HIV-1_Ba-L and HIV-1_LAI were used as controls. Dose–response curves for (a) monoclonal antibody 2D7 (MAb 2D7), (b) TAK-779, (c) maraviroc (MVC), (d) PF-227153, (e) monoclonal antibody 12G5 (MAb 12G5), and (f) SDF-1α/CXCL12.