Characterization of Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Variants Selected for Resistance to a CD4-Mimetic Compound

Anang, Saumya; Richard, Jonathan; Bourassa, Catherine; Goyette, Guillaume; Chiu, Ta-Jung; Chen, Hung-Ching; Smith, Amos B.; Madani, Navid; Finzi, Andrés; Sodroski, Joseph

doi:10.1128/jvi.00636-22

Cited by 13 publications

(21 citation statements)

References 113 publications

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“…The non-covalent association of gp120 with the Env trimer is prone to disruption, either spontaneously or in response to the binding of ligands (sCD4, CD4-mimetic compounds) that induce Env conformations downstream of State 1 (137-139,161,171). We set out to study the shedding of gp120 from Envs with different degrees of State-1 stability on virus particles produced by IMCs.…”

Section: Resultsmentioning

confidence: 99%

“…Conversely, State-1-destabilizing Env changes or treatment with sCD4 or CD4-mimetic compounds (CD4mcs) drive Env trimers out of State 1 and increase the level of virion Envs in more open conformations (green plus sign). When in close proximity to a potential target cell expressing CCR5 or CXCR4 coreceptors, virions with Envs in these open (State-2/3) conformations can infect the cell (168,169,171,187,188). However, compared with Envs that engage CD4 on a target membrane, Envs opened by other means are more prone to either spontaneous inactivation or neutralization by pNAbs (36,49,187,188,195).…”

Section: Discussionmentioning

confidence: 99%

“…The cells were then washed and fresh medium was added to dilute the cells to a density of 2.5 x 10 5 cells/mL. At three days after infection, one-quarter of the cells/medium was saved and conformations can infect the cell (168,169,171,187,188). However, compared with Envs that engage CD4 on a target membrane, Envs opened by other means are more prone to either spontaneous inactivation or neutralization by pNAbs (36,49,187,188,195)…”

Section: Methodsmentioning

confidence: 99%

“…Precipitated particles and clarified cell lysates were Western blotted with a goat anti-gp120 antibody, the 4E10 anti-gp41 antibody, the rabbit anti-hsp70 antibody and the mouse anti-p24 serum. conformations can infect the cell (168,169,171,187,188). However, compared with Envs that engage CD4 on a target membrane, Envs opened by other means are more prone to either spontaneous inactivation or neutralization by pNAbs (36,49,187,188,195) .…”

Section: Figure Legends Figmentioning

confidence: 99%

Section: Shedding Of Gp120 From Virus Particlesmentioning

confidence: 99%

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Characterization of the Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Conformational States on Infectious Virus Particles

Nguyen

Wang

Anang

et al. 2022

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Human immunodeficiency virus (HIV-1) entry into cells involves triggering of the viral envelope glycoprotein (Env) trimer ((gp120/gp41)3) by the primary receptor, CD4, and coreceptors, CCR5 or CXCR4. The pretriggered (State-1) conformation of the mature (cleaved) Env is targeted by broadly neutralizing antibodies (bNAbs), which are inefficiently elicited compared with poorly neutralizing antibodies (pNAbs). Here we characterize variants of the moderately triggerable HIV-1AD8Env on virions produced by an infectious molecular proviral clone; such virions contain more cleaved Env than pseudotyped viruses. We identified three types of cleaved wild-type AD8 Env trimers on virions: 1) State-1-like trimers preferentially recognized by bNAbs and exhibiting strong subunit association; 2) trimers recognized by pNAbs directed against the gp120 coreceptor-binding region and exhibiting weak, detergent-sensitive subunit association; and 3) a minor gp41-only population. The first Env population was enriched and the other Env populations reduced by introducing State-1-stabilizing changes in the AD8 Env or by treatment of the virions with crosslinker or the State-1-preferring entry inhibitor, BMS-806. These stabilized AD8 Envs were also more resistant to gp120 shedding induced by a CD4-mimetic compound or by incubation on ice. Conversely, a State-1-destabilized, CD4-independent AD8 Env variant exhibited weaker bNAb recognition and stronger pNAb recognition. Similar relationships between Env triggerability and antigenicity/shedding propensity on virions were observed for other HIV-1 strains. Our results show that State-1 Envs on virions can be significantly enriched by optimizing Env cleavage; stabilizing the pretriggered conformation by Env modification, crosslinking or BMS-806 treatment; strengthening Env subunit interactions; and using CD4-negative producer cells.

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