Neutralization Sensitivity of a Novel HIV-1 CRF01_AE Panel of Infectious Molecular Clones

Chenine, Agnès‐Laurence; Merbah, Mélanie; Wieczorek, Lindsay; Molnar, Sebastian; Mann, Brendan T.; Lee, Jenica; O’Sullivan, Anne Marie; Bose, Meera; Sanders‐Buell, Eric; Kijak, Gustavo H.; Herrera, Carolina; McLinden, Robert; O’Connell, Robert J.; Michael, Nelson L.; Robb, Merlin L.; Kim, Jerome H.; Polonis, Victoria R.; Tovanabutra, Sodsai

doi:10.1097/qai.0000000000001675

Cited by 8 publications

(6 citation statements)

References 43 publications

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“…HIV-1 is known to rapidly evolve and adapt within its host regarding cell type targeting, drug resistance, or immune escape. As a possible consequence of escape from the humoral response at the individual level, a drift toward increased resistance to antibody neutralization over the course of the epidemic was observed at the population level in two different cohorts in Europe for subtype B and in one cohort in sub-Saharan Africa for subtype C (34)(35)(36)49), as well as in a small panel of CRF01_AE viruses from Thailand (60). The data observed in the present report suggest a similar phenomenon for the CRF02_AG clade.…”

Section: Discussionsupporting

confidence: 79%

Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time

Stéfic

Bouvin-Pley

Essat

et al. 2019

J Virol

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Broadly neutralizing antibodies (bnAbs) are promising agents for prevention and/or treatment of HIV-1 infection. However, the diversity among HIV-1 envelope (Env) glycoproteins impacts bnAb potency and breadth. Neutralization data on the CRF02_AG clade are scarce although it is highly prevalent in West Africa and Europe. We assessed the sensitivity to bnAbs of a panel of 33 early transmitted CRF02_AG viruses over a 15-year period of the French epidemic (1997 to 2012). Env pseudotyped CRF02_AG viruses were best neutralized by the CD4 binding site (CD4bs)-directed bnAbs (VRC01, 3BNC117, NIH45-46 G54W , and N6) and the gp41 membrane-proximal external region (MPER)-directed bnAb 10E8 in terms of both potency and breadth. We observed a higher resistance to bnAbs targeting the V1V2glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Combinations were required to achieve full coverage across this subtype. We observed increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the epidemic, a phenomenon which was previously described for subtypes B and C. These data on the sensitivity to bnAbs of CRF02_AG viruses, including only recently transmitted viruses, will inform future passive immunization studies. Considering the drift of the HIV-1 species toward higher resistance to neutralizing antibodies, it appears necessary to keep updating existing panels for evaluation of future vaccine and passive immunization studies. IMPORTANCE Major progress occurred during the last decade leading to the isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are under way in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to neutralizing antibodies of all genotypes, especially those more widespread in regions where the prevalence of HIV-1 infection is high. Here, we assembled a large panel of clade CRF02_AG viruses, the most frequent genotype circulating in West Africa and the second most frequent found in several European countries. We evaluated their sensitivities to bnAbs, including those most advanced in clinical trials, and looked for the best combinations. In addition, we observed a trend toward increased resistance to bnAbs over the course of the epidemic.

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Section: Discussionsupporting

confidence: 79%

Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time

Stéfic

Bouvin-Pley

Essat

et al. 2019

J Virol

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“…Vesicular stomatitis virus G (VSV-G)-encoding plasmid pSVCMV-IN-VSV-G was previously described (90). For crystallographic studies, the plasmid used to express gp120 extended core (core e ) from CRF01_AE strain 93TH057 (gp120 lacking the N and C termini and variable loops 1, 2, and 3) was previously described (49).The transmitted/founder (TF) CRF01_AE 40061 full viral genome was retrieved by single-genome amplification and cloned to generate full-length infectious molecular clone (IMC) as previously reported (91). TF and chronic IMCs of patients CH40, CH58, CH77, CH167, CH185, CH198, CH236, CH470, CH505, CH850, RHGA, and STCO were inferred, constructed, and biologically characterized as previously described (92)(93)(94)(95)(96)(97)(98).…”

Section: Methodsmentioning

confidence: 99%

The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site

Prévost

Tolbert

Medjahed

et al. 2020

mBio

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The HIV-1 envelope glycoproteins (Env) undergo conformational changes upon interaction of the gp120 exterior glycoprotein with the CD4 receptor. The gp120 inner domain topological layers facilitate the transition of Env to the CD4-bound conformation. CD4 engages gp120 by introducing its phenylalanine 43 (Phe43) in a cavity (“the Phe43 cavity”) located at the interface between the inner and outer gp120 domains. Small CD4-mimetic compounds (CD4mc) can bind within the Phe43 cavity and trigger conformational changes similar to those induced by CD4. Crystal structures of CD4mc in complex with a modified CRF01_AE gp120 core revealed the importance of these gp120 inner domain layers in stabilizing the Phe43 cavity and shaping the CD4 binding site. Our studies reveal a complex interplay between the gp120 inner domain and the Phe43 cavity and generate useful information for the development of more-potent CD4mc. IMPORTANCE The Phe43 cavity of HIV-1 envelope glycoproteins (Env) is an attractive druggable target. New promising compounds, including small CD4 mimetics (CD4mc), were shown to insert deeply into this cavity. Here, we identify a new network of residues that helps to shape this highly conserved CD4 binding pocket and characterize the structural determinants responsible for Env sensitivity to small CD4 mimetics.

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“…Transmitted/Founder (T/F) and chronic infectious molecular clones (IMCs) of patients CH040, CH058, CH077, CH131, CH141, CH167, CH185, CH198, CH236, CH269, CH293, CH440, CH470, CH505, CH534, CH850, CM235, MCST, REJO, RHGA, RHPA, STCO, SUMA, TRJO, WARO, WITO, WR27, 40061, 703357 and 851891 were inferred, constructed, and biologically characterized as previously described (119,(131)(132)(133)(134)(135)(136)(137)(138)(139)(140). The IMCs encoding for HIV-1 reference strains AD8, JR-FL, JR-CSF, NL4-3, YU-2 were described elsewhere (141)(142)(143)(144)(145)(146).…”

Section: Plasmids and Proviral Constructsmentioning

confidence: 99%

Detection of the HIV-1 accessory proteins Nef and Vpu by flow cytometry represents a new tool to study their functional interplay within a single infected CD4+ T cell

Prévost

Richard

Gasser

et al. 2021

Preprint

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The HIV-1 Nef and Vpu accessory proteins are known to protect infected cells from antibody-dependent cellular cytotoxicity (ADCC) responses by limiting exposure of CD4-induced (CD4i) envelope (Env) epitopes at the cell surface. Although both proteins target the host receptor CD4 for degradation, the extent of their functional redundancy is unknown. Here, we developed an intracellular staining technique that permits the intracellular detection of both Nef and Vpu in primary CD4+ T cells by flow cytometry. Using this method, we show that the combined expression of Nef and Vpu predicts the susceptibility of HIV-1-infected primary CD4+ T cells to ADCC by HIV+ plasma. We also show that Vpu cannot compensate for the absence of Nef, thus providing an explanation for why some infectious molecular clones that carry a LucR reporter gene upstream of Nef render infected cells more susceptible to ADCC responses. Our method thus represents a new tool to dissect the biological activity of Nef and Vpu in the context of other host and viral proteins within single infected CD4+ T cells.IMPORTANCEHIV-1 Nef and Vpu exert several biological functions that are important for viral immune evasion, release and replication. Here, we developed a new method allowing simultaneous detection of these accessory proteins in their native form together with some of their cellular substrates. This allowed us to show that Vpu cannot compensate the lack of a functional Nef, which has implication for studies that use Nef-defective viruses to study ADCC responses.

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Neutralization Sensitivity of a Novel HIV-1 CRF01_AE Panel of Infectious Molecular Clones

Cited by 8 publications

References 43 publications

Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time

Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time

The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site

Detection of the HIV-1 accessory proteins Nef and Vpu by flow cytometry represents a new tool to study their functional interplay within a single infected CD4+ T cell

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