Journal article
Mutations in the HIV-1 envelope glycoprotein can broadly rescue blocks at multiple steps in the virus replication cycle
Proceedings of the National Academy of Sciences - PNAS, v 116(18), pp 9040-9049
30 Apr 2019
PMID: 30975760
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
HIV-1 adapts over time to bypass blocks imposed by genetic lesions in the viral genome, typically by acquiring compensatory mutations in the defective gene itself. Here we report that HIV-1 can evade replication blocks by acquiring mutations in the envelope (Env) glycoprotein that enhance cell-to-cell transmission. We identified mutations in Env that arose in the presence of the antiretroviral inhibitor Dolutegravir, thereby circumventing restriction. These data, which demonstrate that mutations in Env can provide escape from an anti–HIV-1 drug in vitro, could have broad implications for HIV-1 drug resistance and viral transmission.
The p6 domain of HIV-1 Gag contains highly conserved peptide motifs that recruit host machinery to sites of virus assembly, thereby promoting particle release from the infected cell. We previously reported that mutations in the YPX
n
L motif of p6, which binds the host protein Alix, severely impair HIV-1 replication. Propagation of the p6–Alix binding site mutants in the Jurkat T cell line led to the emergence of viral revertants containing compensatory mutations not in Gag but in Vpu and the envelope (Env) glycoprotein subunits gp120 and gp41. The Env compensatory mutants replicate in Jurkat T cells and primary human peripheral blood mononuclear cells, despite exhibiting severe defects in cell-free particle infectivity and Env-mediated fusogenicity. Remarkably, the Env compensatory mutants can also rescue a replication-delayed integrase (IN) mutant, and exhibit reduced sensitivity to the IN inhibitor Dolutegravir (DTG), demonstrating that they confer a global replication advantage. In addition, confirming the ability of Env mutants to confer escape from DTG, we performed de novo selection for DTG resistance and observed resistance mutations in Env. These results identify amino acid substitutions in Env that confer broad escape from defects in virus replication imposed by either mutations in the HIV-1 genome or by an antiretroviral inhibitor. We attribute this phenotype to the ability of the Env mutants to mediate highly efficient cell-to-cell transmission, resulting in an increase in the multiplicity of infection. These findings have broad implications for our understanding of Env function and the evolution of HIV-1 drug resistance.
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Details
- Title
- Mutations in the HIV-1 envelope glycoprotein can broadly rescue blocks at multiple steps in the virus replication cycle
- Creators
- Rachel Van Duyne - Center for Cancer ResearchLillian S. Kuo - National Cancer InstitutePhuong Pham - Center for Cancer ResearchKen Fujii - Center for Cancer ResearchEric O. Freed - Center for Cancer Research
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 116(18), pp 9040-9049
- Series
- PNAS Plus
- Publisher
- National Academy of Sciences
- Number of pages
- 10
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000466446500059
- Scopus ID
- 2-s2.0-85065511657
- Other Identifier
- 991021902526704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology