HIV-1 adapts to lost IP6 coordination through second-site mutations that restore conical capsid assembly

Alex Kleinpeter; Donna L Mallery; Nadine Renner; Anna Albecka; J Ole Klarhof; Eric O Freed; Leo C James

doi:10.1038/s41467-024-51971-w

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HIV-1 adapts to lost IP6 coordination through second-site mutations that restore conical capsid assembly

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HIV-1 adapts to lost IP6 coordination through second-site mutations that restore conical capsid assembly

Alex Kleinpeter, Donna L Mallery, Nadine Renner, Anna Albecka, J Ole Klarhof, Eric O Freed and Leo C James

Nature communications, Vol.15(1), pp.8017-15

09/13/2024

DOI: 10.1038/s41467-024-51971-w

PMCID: PMC11399258

PMID: 39271696

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Abstract

The HIV-1 capsid is composed of capsid (CA) protein hexamers and pentamers (capsomers) that contain a central pore hypothesised to regulate capsid assembly and facilitate nucleotide import early during post-infection. These pore functions are mediated by two positively charged rings created by CA Arg-18 (R18) and Lys-25 (K25). Here we describe the forced evolution of viruses containing mutations in R18 and K25. Whilst R18 mutants fail to replicate, K25A viruses acquire compensating mutations that restore nearly wild-type replication fitness. These compensating mutations, which rescue reverse transcription and infection without reintroducing lost pore charges, map to three adaptation hot-spots located within and between capsomers. The second-site suppressor mutations act by restoring the formation of pentamers lost upon K25 mutation, enabling closed conical capsid assembly both in vitro and inside virions. These results indicate that there is no intrinsic requirement for K25 in either nucleotide import or capsid assembly. We propose that whilst HIV-1 must maintain a precise hexamer:pentamer equilibrium for proper capsid assembly, compensatory mutations can tune this equilibrium to restore fitness lost by mutation of the central pore.

Capsid - metabolism

Capsid Proteins - chemistry

Capsid Proteins - genetics

Capsid Proteins - metabolism

HEK293 Cells

HIV Infections - genetics

HIV Infections - virology

HIV-1 - genetics

HIV-1 - physiology

Humans

Mutation

Virion - genetics

Virion - metabolism

Virus Assembly - genetics

Virus Replication - genetics

Details

Title: Subtitle: HIV-1 adapts to lost IP6 coordination through second-site mutations that restore conical capsid assembly
Creators: Alex Kleinpeter - National Cancer Institute
Donna L Mallery - MRC Laboratory of Molecular Biology
Nadine Renner - MRC Laboratory of Molecular Biology
Anna Albecka - MRC Laboratory of Molecular Biology
J Ole Klarhof - MRC Laboratory of Molecular Biology
Eric O Freed - National Cancer Institute
Leo C James - MRC Laboratory of Molecular Biology
Resource Type: Journal article
Publication Details: Nature communications, Vol.15(1), pp.8017-15
DOI: 10.1038/s41467-024-51971-w
PMID: 39271696
PMCID: PMC11399258
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: U54 AI170791 / NIAID NIH HHS
Language: English
Date published: 09/13/2024
Academic Unit: Microbiology and Immunology
Record Identifier: 9984826360502771

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