Abstract
Binding of HIV-1 capsid (CA) to cleavage and polyadenylation specificity factor 6 (CPSF6) is hypothesized to provide a significant fitness advantage to in vivo viral replication, explaining why CA-CPSF6 interactions are strictly conserved in primate lentiviruses. We recently identified a Q4R mutation in CA after propagation of an interferon (IFN)-β-hypersensitive CA mutant, RGDA/Q112D (H87R, A88G, P90D, P93A and Q112D) virus, in IFN-β-treated cells. The Q4R substitution conferred significant IFN-β resistance to the RGDA/Q112D virus by affecting several properties of the virus, including the sensitivity to myxovirus resistance protein B (MxB), the kinetics of reverse transcription, and the initiation of uncoating. Notably, the Q4R substitution restored the CPSF6 interaction of the RGDA/Q112D virus. To better understand how the Q4R substitution modulated the CA-CPSF6 interaction, we generated a series of CA mutants harboring substitutions at the 4th and 112th residues. In contrast to the effect in the RGDA/Q112D background, the Q4R substitution diminished CA-CPSF6 interaction in an otherwise wild-type virus. Our genetic and structural analyses revealed that while either the Q4R or Q112D substitution impaired CA-CPSF6 interaction, the combination of these substitutions restored this interaction. These results suggest that the 4th and 112th residues in HIV-1 CA cooperatively modulate CA-CPSF6 interactions, further highlighting the tremendous levels of plasticity in primate lentivirus CA, which is one of the barriers to antiretroviral therapy in HIV-1-infected individuals.
Highlights
Primate lentiviruses, including HIV-1, depend on numerous host factors for optimal replication
We recently showed that the Q4R substitution restored the CA-cleavage and polyadenylation specificity factor 6 (CPSF6) interaction of the RGDA/Q112D (H87R, A88G, P90D, P93A, and Q112D) virus.[11]
We demonstrated that HIV-1-lineage viruses have selected specific combinations of 4th and 112th residues to cooperatively maintain CA-CPSF6 interactions
Summary
Primate lentiviruses, including HIV-1, depend on numerous host factors for optimal replication. The binding process includes an interaction with CPSF6 through the CA N-terminal domain (NTD)[4,5] as well as through the CA C-terminal domain (CTD)[6,7,8,9]; 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. Either the single or double mutation was sufficient to confer IFN-b resistance to the RGDA/Q112D virus. The Q4R substitution significantly restored interaction of the RGDA/Q112D virus with CPSF6, as shown by decreased resistance of the RGDA/Q112D virus to the inhibitory effect of a truncated form of CPSF6, CSPF6-358. It remained unclear how the Q4R substitution modulated CSPF6358 resistance in the RGDA/Q112D virus
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