Molecular Determinants of HIV-2 R5-X4 Tropism in the V3 Loop: Development of a New Genotypic Tool

Visseaux, Benoît; Hurtado-Nédelec, Margarita; Charpentier, Charlotte; Collin, Gilles; Storto, Alexandre; Matheron, Sophie; Larrouy, Lucile; Damond, Florence; Brun‐Vézinet, Françoise; Descamps, Diane

doi:10.1093/infdis/jir698

Cited by 39 publications

(39 citation statements)

References 34 publications

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“… a As determined phenotypically in TZMbl cells [22] or genotypically based on V3 loop sequence patterns [36]; b According to the CDC revised classification system for HIV infection in children; c First blood collection was at day 39 after birth; d First blood collection was at day 27 after birth; e Isolate obtained at birth was syncytium inducing as determined in PBMCs and several cell lines [32]; d4T–stavudine, 3TC–lamivudine, LPV–lopinavir, RTV–ritonavir, ABC–abacavir, AZT–zidovudine; nd–not determined.…”

Section: Resultsmentioning

confidence: 99%

“…Potential N-linked glycans (occurring at NXT/S) are represented in open boxes. Amino acids highlighted in light grey are involved in tropism change [36]. Blue boxes in the consensus sequence represent published linear neutralizing epitopes in V1 [28] and V3 [26]; red boxes in the consensus sequence represent a conformational epitope in V3 [26].…”

Section: Resultsmentioning

confidence: 99%

“…In V3, mutations occurred almost exclusively within previously described neutralizing epitopes [26], and at residues 18, 19 and 27 that have been associated with R5 and X4 tropism [36-38]. One amino acid insertion occurred in the same position in both children and involved a hydrophobic residue (V in child 1; I in child 2).…”

Section: Resultsmentioning

confidence: 99%

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Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody response

et al. 2013

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BackgroundDifferently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4+ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth.ResultsCD4+ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5-to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a β-hairpin structure were related with rate of escape from the neutralizing antibodies.ConclusionOur data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody response

et al. 2013

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“…We recently developed an HIV-2 tropism phenotypic assay (TPA) using two GHOST(3) cell lines expressing CD4-plus-CCR5 or CD4-plus-CXCR4 coreceptors, with a HIV-2 long terminal repeat (LTR)-driven green fluorescent protein (GFP) gene which is activated upon infection (18). Infection efficiency was quantified by flow cytometric analysis for GFP detection.…”

Section: Methodsmentioning

confidence: 99%

In VitroPhenotypic Susceptibility of HIV-2 Clinical Isolates to CCR5 Inhibitors

Visseaux

Charpentier

Hurtado-Nédelec

et al. 2012

Antimicrob Agents Chemother

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HIV-2 is naturally resistant to nonnucleoside reverse transcriptase inhibitors, to a fusion inhibitor, and to some of the protease inhibitors. Maraviroc is the first drug of the new anti-CCR5 drug class and is effective only on CCR5-tropic (R5) HIV-1. No previous studies concerning HIV-2 susceptibility to maraviroc have been reported yet. We developed a phenotypic maraviroc susceptibility test using a peripheral blood mononuclear cell (PBMC) model. We analyzed the maraviroc susceptibility of 13 R5 HIV-2, 2 X4R5 (dual) HIV-2, and 2 CXCR4-tropic (X4) HIV-2 clinical isolates. We also tested, with the same protocol, 1 X4 HIV-1 and 4 R5 HIV-1 clinical isolates. For the R5 HIV-2 clinical isolates, the 50% effective concentration (EC 50 ) for maraviroc was 0.80 nM (interquartile range [IQR], 0.48 to 1.39 nM), similar to that observed for the R5 HIV-1 isolates. The median maximum percentage of inhibition in the R5 HIV-2 isolates was 93% (IQR, 84 to 98%), similar to that observed in the R5 HIV-1 isolates. As expected, both X4 HIV-1 and HIV-2 were highly resistant to maraviroc. Our study showed for the first time that maraviroc is active in vitro against R5 HIV-2. The new tools we developed will allow identification of HIV-2-infected patients eligible for CCR5 inhibitor use and management of virological failure when receiving a maraviroc-based regimen.

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“…Some studies had claimed an association between V3 loop sequence and CCR5 or CXCR4 usage [133][134][135][136][137], while others had found no genetic signature underlying coreceptors usage [138][139][140]. Particularly, the C-terminal region of the V3 loop, a global net charge above +6 and the presence of mutations in amino acids 18 and 19, appear to dictate the ability to use CXCR4 alone or in addition to CCR5 [134,137]. However, those studies have some limitations due to the low number of X4 or R5X4 strains and because they restricted the coreceptors usage to the dichotomy R5 vs. X4, without considering the concomitant or alternative use of other coreceptors.…”

Section: Molecular Determinants Of Coreceptor Usagementioning

confidence: 99%

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic than HIV-1

Azevedo‐Pereira¹

2013

Current Perspectives in HIV Infection

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Molecular Determinants of HIV-2 R5-X4 Tropism in the V3 Loop: Development of a New Genotypic Tool

Abstract: We established a strong association between HIV-2 phenotypic tropism and V3-loop sequences, allowing for the prediction of R5- and/or X4-tropic viruses in HIV-2 infection.

Cited by 39 publications

References 34 publications

Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody response

Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody response

In VitroPhenotypic Susceptibility of HIV-2 Clinical Isolates to CCR5 Inhibitors

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic than HIV-1

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