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PLoS One. 2014 Apr 8;9(4):e94240. doi: 10.1371/journal.pone.0094240. eCollection 2014.

Impact of mutations in highly conserved amino acids of the HIV-1 Gag-p24 and Env-gp120 proteins on viral replication in different genetic backgrounds.

Author information

1
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.
2
Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
3
Program in Biostatistics and Biomathematics, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
4
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America; Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.

Abstract

It has been hypothesized that a single mutation at a highly conserved amino acid site (HCS) can be severely deleterious to HIV in most if not all isolate-specific genetic backgrounds. Consequently, potentially universal HIV-1 vaccines exclusively targeting highly conserved regions of the viral proteome have been proposed. To test this hypothesis, we examined the impact of 10 Gag-p24 and 9 Env-gp120 HCS single mutations on viral fitness. In the original founder sequence of the subject in whom these mutations were identified, all Gag-p24 HCS mutations significantly reduced viral replication fitness, including 7 that were lethal. Similar results were obtained at 9/10 sites when the same mutations were introduced into the founder sequences of two epidemiologically unlinked subjects. In contrast, none of the 9 Env-gp120 HCS mutations were lethal in the original founder sequence, and four had no fitness cost. Hence, HCS mutations in Gag-p24 are likely to be severely deleterious in different HIV-1 subtype B backgrounds; however, some HCS mutations in both Gag-p24 and Env-gp120 fragments can be well tolerated. Therefore, when designing HIV-1 immunogens that are intended to force the virus to nonviable escape pathways, the fitness constraints on the HIV segments included should be considered beyond their conservation level.

PMID:
24713822
PMCID:
PMC3979772
DOI:
10.1371/journal.pone.0094240
[Indexed for MEDLINE]
Free PMC Article

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