Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell–cell viral transmission and cell–cell fusion

Narasimhulu, Vani G.S.; Bellamy-McIntyre, Anna; Laumaea, Annemarie; Lay, Chan-Sien; Harrison, David N.; King, Hannah A. D.; Drummer, Heidi E.; Poumbourios, Pantelis

doi:10.1074/jbc.ra117.000537

Cited by 12 publications

(11 citation statements)

References 144 publications

(176 reference statements)

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“…As observed with the NL4-3 Env mutants, K3016 Env-T541I exhibited faster-than-WT replication and conferred resistance to ARVs in spreading infections. These results highlight the context dependence of resistance-conferring Env mutations, consistent with the suggestion that residues in the gp41 ectodomain are functionally linked with gp120 and modulate conformational dynamics of Env in a strain-dependent manner (52,62,105,106). As shown in Fig.…”

Section: Discussionsupporting

confidence: 89%

Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations

Hikichi

Duyne

Pham

et al. 2021

mBio

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Despite the effectiveness of antiretroviral (ARV) therapy, virological failure can occur in some HIV-1-infected patients in the absence of mutations in drug target genes. We previously reported that, in vitro, the lab-adapted HIV-1 NL4-3 strain can acquire resistance to the integrase inhibitor dolutegravir (DTG) by acquiring mutations in the envelope glycoprotein (Env) that enhance viral cell-cell transmission. In this study, we investigated whether Env-mediated drug resistance extends to ARVs other than DTG and whether it occurs in other HIV-1 isolates. We demonstrate that Env mutations can reduce susceptibility to multiple classes of ARVs and also increase resistance to ARVs when coupled with target-gene mutations. We observe that the NL4-3 Env mutants display a more stable and closed Env conformation and lower rates of gp120 shedding than the WT virus. We also selected for Env mutations in clinically relevant HIV-1 isolates in the presence of ARVs. These Env mutants exhibit reduced susceptibility to DTG, with effects on replication and Env structure that are HIV-1 strain dependent. Finally, to examine a possible in vivo relevance of Env-mediated drug resistance, we performed single-genome sequencing of plasma-derived virus from five patients failing an integrase inhibitor-containing regimen. This analysis revealed the presence of several mutations in the highly conserved gp120-gp41 interface despite low frequency of resistance mutations in integrase. These results suggest that mutations in Env that enhance the ability of HIV-1 to spread via a cell-cell route may increase the opportunity for the virus to acquire high-level drug resistance mutations in ARV target genes. IMPORTANCE Although combination antiretroviral (ARV) therapy is highly effective in controlling the progression of HIV disease, drug resistance can be a major obstacle. Recent findings suggest that resistance can develop without ARV target gene mutations. We previously reported that mutations in the HIV-1 envelope glycoprotein (Env) confer resistance to an integrase inhibitor. Here, we investigated the mechanism of Env-mediated drug resistance and the possible contribution of Env to virological failure in vivo. We demonstrate that Env mutations can reduce sensitivity to major classes of ARVs in multiple viral isolates and define the effect of the Env mutations on Env subunit interactions. We observed that many Env mutations accumulated in individuals failing integrase inhibitor therapy despite a low frequency of resistance mutations in integrase. Our findings suggest that broad-based Env-mediated drug resistance may impact therapeutic strategies and provide clues toward understanding how ARV-treated individuals fail therapy without acquiring mutations in drug target genes.

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Section: Discussionsupporting

confidence: 89%

Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations

Hikichi

Duyne

Pham

et al. 2021

mBio

View full text Add to dashboard Cite

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“…Although this mutant replicated more slowly than WT K3016 it exhibited reduced susceptibility to DTG. These results highlight the context dependence of resistance-conferring Env mutations, consistent with the suggestion that residues in the gp41 ectodomain are functionally linked with gp120 and modulate conformational dynamics of Env in a strain-dependent manner [52, 62, 97, 98]. As shown in S2 and S3 Figs, the stability of the gp120-gp41 interaction and the conformational dynamics of NL(AD8) Env are different from those of NL4-3 Env, suggesting that the differences in intra- and interprotomer interactions of Env are likely to affect the viral phenotypes of the Env mutants in terms of their fitness and ability to confer broad ARV resistance.…”

Section: Discussionsupporting

confidence: 83%

Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations

Hikichi¹,

Duyne²,

Pham³

et al. 2020

Preprint

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Despite the effectiveness of antiretroviral (ARV) therapy, virological failure can occur in some HIV-1 infected patients in the absence of mutations in the proteins targeted by these drugs. We previously reported that, in vitro, the lab-adapted NL4-3 strain of HIV-1 can acquire resistance to the integrase inhibitor dolutegravir (DTG) by acquiring mutations in the envelope glycoprotein (Env) that enhance the ability of HIV-1 to spread via cell-cell transmission. In this study, we investigated whether Env-mediated drug resistance extends to ARVs other than DTG and whether it occurs in other HIV-1 isolates. We demonstrate that Env mutations can broadly confer resistance to multiple classes of ARVs in the context of cell-cell but not cell-free infection and also increase resistance to ARVs when coupled with target-gene drug resistance mutations. To investigate the mechanism of Env-mediated drug resistance, we evaluated the impact of the Env mutations on Env stability and conformational dynamics. We observe that the NL4-3 Env mutants display a more stable and closed Env conformation compared to WT virus and reduced rates of gp120 shedding. We also selected for mutations in the gp41 ectodomain of clinically relevant, CCR5-tropic isolates in the presence of DTG. These Env mutants exhibit reduced susceptibility to DTG, with effects on replication kinetics and Env structure that are HIV-1 strain-dependent. Finally, to examine a possible in vivo relevance of Env-mediated drug resistance, we performed single-genome sequencing of plasma-derived virus from five patients failing an integrase inhibitor-containing regimen. This analysis revealed the presence of several mutations in the highly conserved gp120-gp41 interface despite low frequency of resistance mutations in integrase. These results suggest a “stepping-stone” model whereby mutations in Env that enhance the ability of HIV-1 to spread via a cell-cell route increase the opportunity for the virus to acquire high-level drug resistance mutations in ARV-target genes.Author summaryAlthough combination antiretroviral (ARV) therapy has proven highly effective in controlling the progression of HIV disease, drug resistance can be a major obstacle to long-term treatment, particularly in resource-limited settings. In most cases, resistance arises from the accumulation of mutations in the ARV-target genes; however, in some cases, resistance develops without ARV target-gene mutations. We previously reported that mutations in the HIV-1 envelope glycoprotein (Env) confer resistance to an integrase inhibitor. Here we investigated the mechanism of Env-mediated drug resistance and the possible contribution of Env to virological failure in vivo. We demonstrate that Env mutations can confer broad resistance to multiple classes of ARVs and define the effect of the Env mutations on Env subunit interactions and sensitivity to neutralizing antibodies. We also selected for drug resistance mutations in Env in clinically relevant HIV-1 isolates. We observed that many Env mutations accumulated in individuals failing integrase inhibitor therapy despite a low frequency of resistance mutations in integrase. Our findings suggest that broad-based, Env-mediated drug resistance may impact current and possibly future therapeutic strategies. Our findings also provide clues towards understanding how ARV-treated patients can experience virological failure without acquiring drug resistance mutations in ARV-target genes.

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“…The MPER is generally poorly accessible, but accessibility increases transiently when Env binds receptors, gp120 is shed, and gp41 undergoes the structural rearrangements that ultimately facilitate viral entry into the cell. While the mechanistic role of MPER in HIV-1 entry remains an active field of pursuit, so does the potential of MPER as an immunogen ( 30 , 33 ). In an analysis of LN01, it was discovered that the MPER-TM, if placed in the membrane and stabilized, may be a useful immunogen for HIV-1 ( 31 ).…”

Section: The Case For S2: the Parallels In Structure And Function Betmentioning

confidence: 99%

The Case for S2: The Potential Benefits of the S2 Subunit of the SARS-CoV-2 Spike Protein as an Immunogen in Fighting the COVID-19 Pandemic

et al. 2021

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As COVID-19 cases continue to rise, it is imperative to learn more about antibodies and T-cells produced against the causative virus, SARS-CoV-2, in order to guide the rapid development of therapies and vaccines. While much of the current antibody and vaccine research focuses on the receptor-binding domain of S1, a less-recognized opportunity is to harness the potential benefits of the more conserved S2 subunit. Similarities between the spike proteins of both SARS-CoV-2 and HIV-1 warrant exploring S2. Possible benefits of employing S2 in therapies and vaccines include the structural conservation of S2, extant cross-reactive neutralizing antibodies in populations (due to prior exposure to common cold coronaviruses), the steric neutralization potential of antibodies against S2, and the stronger memory B-cell and T-cell responses. More research is necessary on the effect of glycans on the accessibility and stability of S2, SARS-CoV-2 mutants that may affect infectivity, the neutralization potential of antibodies produced by memory B-cells, cross-reactive T-cell responses, antibody-dependent enhancement, and antigen competition. This perspective aims to highlight the evidence for the potential advantages of using S2 as a target of therapy or vaccine design.

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Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell–cell viral transmission and cell–cell fusion

Cited by 12 publications

References 144 publications

Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations

Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations

Mechanistic Analysis of the Broad Antiretroviral Resistance Conferred by HIV-1 Envelope Glycoprotein Mutations

The Case for S2: The Potential Benefits of the S2 Subunit of the SARS-CoV-2 Spike Protein as an Immunogen in Fighting the COVID-19 Pandemic

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