Elucidation of the Molecular Consequences of Two Unique p6Gag Mutations Derived from HIV-1 CRF07_BC-infected Patients
Research Square (Research Square)(2020)
Abstract
Abstract Background We previously observed that individuals infected with HIV-1 CRF07_BC showed slower disease progression than those infected with HIV-1 subtype B or CRF01_AE. CRF07_BC viruses carry two unique mutations in the p6 Gag protein: insertion of PTAPPE sequences downstream of the original Tsg101 binding domain, and deletion of a seven-amino-acid sequence ( 30 PIDKELY 36 ) that partially overlaps with the Alix binding domain. To further define the role of these mutations in virus release and replication, we introduced them into the HIV-1 proviral clone pNL4-3 for functional characterization. Results We found that the seven-amino-acid deletion, but not the PTAPPE insertion, significantly decreased virus release, Gag processing, and virus infectivity. The seven-amino-acid deletion also resulted in a virus replication defect in both T-cell lines and peripheral blood mononuclear cells. We found that these defects were caused by the seven-amino-acid deletion in p6 Gag , especially deletion of Tyr-36 of p6 Gag , not the deletion of the overlapping p6* sequence in the HIV-1 GagPol protein. The p6 Gag deletion mutant was resistant to a dominant-negative Alix fragment, suggesting a loss of binding between p6 Gag and Alix. Conclusions Our results indicate that the patient-derived seven-amino-acid deletion in p6 Gag of HIV-1 CRF07_BC virus affects virus release, infectivity and replication capacity by disrupting the interaction between HIV-1 p6 Gag and host protein Alix. These results may explain the slower disease progression observed in the subjects infected with HIV-1 CRF07_BC bearing this unique mutation.
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Key words
two unique p6gag mutations,_bc-infected
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