Susceptibility to Antiretroviral Drugs of CRF01_AE, CRF02_AG, and Subtype C Viruses from Untreated Patients of Africa and Asia: Comparative Genotypic and Phenotypic Data

Fleury, Hervé; Toni, Thomas; Lan, Nguyen Thi Hoang; Hưng, Phạm Văn; Deshpande, Alaka; Recordon-Pinson, Patrícia; Boucher, Sébastien; Lazaro, Estibaliz; Jauvin, Valérie; Lavignolle-Aurillac, Valérie; Lebel‐Binay, Sophie; Chéret, Arnaud; Masquelier, Bernard

doi:10.1089/aid.2006.22.357

Cited by 34 publications

(20 citation statements)

References 27 publications

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“…Indeed, viruses from most subtypes are susceptible to enfuvirtide in vitro. 68,[72][73][74] Thus, substantial differences in enfuvirtide susceptibility in the clinic would not be expected based on viral subtype.…”

Section: Mutational Patterns In Gp41 Across Subtypesmentioning

confidence: 99%

Appreciating HIV Type 1 Diversity: Subtype Differences in Env

Lynch

Shen

Gnanakaran

et al. 2009

AIDS Research and Human Retroviruses

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Human immunodeficiency virus type 1 (HIV-1) group M is responsible for the current AIDS pandemic and exhibits exceedingly high levels of viral genetic diversity around the world, necessitating categorization of viruses into distinct lineages, or subtypes. These subtypes can differ by around 35% in the envelope (Env) glycoproteins of the virus, which are displayed on the surface of the virion and are targets for both neutralizing antibody and cell-mediated immune responses. This diversity reflects the remarkable ability of the virus to adapt to selective pressures, the bulk of which is applied by the host immune response, and represents a serious obstacle for developing an effective vaccine with broad coverage. Thus, it is important to understand the underlying biological consequences of intersubtype diversity. Recent studies have revealed that some of the HIV-1 subtypes exhibit phenotypic differences stemming from subtle changes in Env structure, particularly within the highly immunogenic V3 domain, which participates directly in viral entry. This review will therefore explore current research that describes subtype differences in Env at the genetic and phenotypic level, focusing in particular on V3, and highlighting recent discoveries about the unique features of subtype C Env, which is the most globally prevalent subtype.

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Section: Mutational Patterns In Gp41 Across Subtypesmentioning

confidence: 99%

Appreciating HIV Type 1 Diversity: Subtype Differences in Env

Lynch

Shen

Gnanakaran

et al. 2009

AIDS Research and Human Retroviruses

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“…Interestingly, individuals infected with CRF01_AE HIV-1 can progress to disease faster than those infected with other HIV-1 subtypes or CRFs (52), yet the mechanism(s) responsible for this phenomenon remains unknown. Drug efficacy may also vary according to subtype classification (20,27).…”

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confidence: 99%

HIV gp120 H375 Is Unique to HIV-1 Subtype CRF01_AE and Confers Strong Resistance to the Entry Inhibitor BMS-599793, a Candidate Microbicide Drug

Schader

Colby-Germinario

Quashie

et al. 2012

Antimicrob Agents Chemother

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b BMS-599793 is a small molecule entry inhibitor that binds to human immunodeficiency virus type 1 (HIV-1) gp120, resulting in the inhibition of CD4-dependent entry into cells. Since BMS-599793 is currently considered a candidate microbicide drug, we evaluated its efficacy against a number of primary patient HIV isolates from different subtypes and circulating recombinant forms (CRFs) and showed that activity varied between ϳ3 M and 7 M at 50% effective concentrations (EC 50 s). Interestingly, CRF01_AE HIV-1 isolates consistently demonstrated natural resistance against this compound. Genotypic analysis of >1,600 sequences (Los Alamos HIV sequence database) indicated that a single amino acid polymorphism in Env, H375, may account for the observed BMS-599793 resistance in CRF01_AE HIV-1. Results of site-directed mutagenesis experiments confirmed this hypothesis, and in silico drug docking simulations identified a drug resistance mechanism at the molecular level. In addition, CRF01_AE viruses were shown to be resistant to multiple broadly neutralizing monoclonal antibodies. Thus, our results not only provide insight into how Env polymorphisms may contribute to entry inhibitor resistance but also may help to elucidate how HIV can evade some broadly neutralizing antibodies. Furthermore, the high frequency of H375 in CRF01_AE HIV-1, and its apparent nonoccurrence in other subtypes, could serve as a means for rapid identification of CRF01_AE infections.

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“…In vitro decreased susceptibility to PIs was reported in a limited number of CRF02_AG isolates from therapy-naïve individuals (Fleury et al 2006;Kinomoto et al 2005). Caution is warranted by interpretation of these results since deletion clones and phenotypic resistance cutoffs applied are based on subtype B virus backbones.…”

Section: The Influence Of Genetic Diversity On Protease Inhibitor Effmentioning

confidence: 96%

HIV Protease Inhibitor Resistance

Wensing

Fun

Nijhuis

2014

Handbook of Antimicrobial Resistance

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HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs), based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of structure-based drug design. The introduction of first-generation PIs marked the start of combination antiretroviral therapy. However, low bioavailability, high pill burden, and toxicity ultimately reduced adherence and limited long-term viral inhibition. Therapy failure was often associated with multiple protease inhibitor resistance mutations, both in the viral protease and its substrate (HIV gag protein), displaying a broad spectrum of resistance mechanisms. Unfortunately, selection of protease inhibitor resistance mutations often resulted in cross-resistance to other PIs.Therefore, second-generation approaches were imperative. Coadministration of a cytochrome P-450 3A4 inhibitor greatly improved the plasma concentration of PIs in the patient. A second advance was the development of PIs that were efficacious against first-generation PI-resistant HIV. Both approaches increased the number of protease mutations required by the virus to develop clinically relevant resistance, thereby raising the genetic barrier towards PI resistance. These improvements greatly contributed to the success of PI-based therapy.

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Susceptibility to Antiretroviral Drugs of CRF01_AE, CRF02_AG, and Subtype C Viruses from Untreated Patients of Africa and Asia: Comparative Genotypic and Phenotypic Data

Cited by 34 publications

References 27 publications

Appreciating HIV Type 1 Diversity: Subtype Differences in Env

Appreciating HIV Type 1 Diversity: Subtype Differences in Env

HIV gp120 H375 Is Unique to HIV-1 Subtype CRF01_AE and Confers Strong Resistance to the Entry Inhibitor BMS-599793, a Candidate Microbicide Drug

HIV Protease Inhibitor Resistance

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