Specific Substitutions in Region V2 of gp120 env confer SHIV Neutralisation Resistance

Pathogens
Yalcin PisilTomoyuki Miura

Abstract

A tier 2 SHIV-MK38 strain was obtained after two in vivo passages of tier 1 SHIV-MK1. SHIV-MK38#818, cloned from the MK38 strain, was neutralisation-resistant, like the parental MK38 strain, to SHIV-infected monkey plasma (MP), HIV-1-infected human pooled plasma (HPP), and KD247 monoclonal antibody (mAb) (anti-V3 gp120 env). We investigated the mechanisms underlying the resistance of #818, specifically the amino acid substitutions that confer resistance to MK1. We introduced amino acid substitutions in the MK1 envelope by in vitro mutagenesis and then compared the neutralisation resistance to MP, HPP, and KD247 mAb with #818 in a neutralisation assay using TZM-bl cells. We selected 11 substitutions in the V1, V2, C2, V4, C4, and V5 regions based on the alignment of env of MK1 and #818. The neutralisation resistance of the mutant MK1s with 7 of 11 substitutions in the V1, C2, C4, and V5 regions did not change significantly. These substitutions did not alter any negative charges or N-glycans. The substitutions N169D and K187E, which added negative charges, and S190N in the V2 region of gp120 and A389T in V4, which created sites for N-glycan, conferred high neutralisation resistance. The combinations N169D+K187E, N169D+S190N, and ...Continue Reading

References

Jan 1, 1987·Molecular and Cellular Biology·R B DuBridgeM P Calos
Aug 19, 2011·Nature·Laura M WalkerPascal Poignard
Dec 22, 2017·Current Opinion in HIV and AIDS·David C MontefioriMichael S Seaman
Nov 27, 2018·Science Advances·Linling HeJiang Zhu

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Methods Mentioned

BETA
glycosylation
protein folding

Software Mentioned

ENTA
UCSF Chimera

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