The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1.
PMID: 31941344
2020
AIDS research and human retroviruses
Introduction: The binding process includes an interaction with CPSF6 through the CA N-terminal domain (NTD) as well as through the CA C-terminal domain (CTD); specifically, mutations in the respective CA domains, such as N57A or N74D (NTD) or K182R (CTD), have been shown to reduce CPSF6 binding by HIV-1 CA.
TRIM34 restricts HIV-1 and SIV capsids in a TRIM5alpha-dependent manner.
Method: The pLAI GFP3* WT, pLAI GFP3* N74D, pLAI GFP3* A77V and pLAI GFP3* N57A proviruses were provided by Masahiro Yamashita and are described in.
Result: In contrast to the restriction of the N74D capsid mutant virus measured in TRIM34-overexpressing cells, we do not observe any restriction of the N57A capsid mutant (Fig 3C).
Result: To further explore the CPSF6-independence of TRIM34 restriction, we also assayed replication of another CPSF6-binding deficient mutant, N57A, in our ectopic overexpression system.
Figure: C: THP-1 cells stably-overexpressing TRIM34 (gray bars) or control cells (white bars) were infected with WT, N74D or CA Mutation N57A Has Distinct Strain-Specific HIV-1 Capsid Uncoating and Infectivity Phenotypes.
Abstract: Adaptation of N57A HIV-1LAI selected for a second CA mutation, G94D, which rescued the N57A infectivity defect in HIV-1LAI but not HIV-1NL4-3 The rescue of N57A by G94D in HIV-1LAI is abrogated by CsA treatment in some cell types, demonstrating that this rescue is CypA dependent.
Abstract: The mutation N57A in the viral CA
Abstract: We have shown that two widely used HIV-1 molecular clones exhibit significantly different N57A infectivity phenotypes due to fewer than a handful of CA amino acid differences and that these clones are both represented in HIV-infected individuals.
HIV-1 capsid is involved in post-nuclear entry steps.
Result: The T54A and the T54A/N57A capsid mutant HIV-1 vectors showed substantially reduced infectivity compared to wild type virus, however they were also less dependent on Tnp3 for infection (Figure 10).
Figure: Note that the T54A and T54A/N57A have ~20 fold lower infectivity than wild type virus.
Result: As, N57A is less sensitive to both Nup358 and TRN-SR2 depletion (Figure 3A), we hypothesize that its infectivity defect is caused by an inability to engage these proteins.
Result: The N74D and N57A substitutions are less sensitive to depletion of both Nup358 and TRN-SR2, and N74D gains sensitivity to depletion of other nuclear pore proteins.
Result: The HIV-1 CA mutant N57A is more severely defective in arrested cells than dividing cells (Figure 3A), suggesting that this residue may have a role in nucl
Result: We found that N57A was still restricted by TRIMNup358 (Figure S5), suggesting that increased avidity through Nup358Cyp dimerization in the context of TRIMNup358 may overcome the reduced affinity to monomeric Nup358Cyp.
HIV mutation literature information.
PMID: 
2020
AIDS research and human retroviruses
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