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.
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.
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.
Yi
Y
Liu
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.
Ushnal
U
Rao
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.
Jan
J
McClure
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.
Philip
P
Konopa
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.
Siriphan
S
Manocheewa
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.
Moon
M
Kim
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.
Lennie
L
Chen
Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
Ryan M
RM
Troyer
Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
Denis M
DM
Tebit
Program in Biostatistics and Biomathematics, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Sarah
S
Holte
Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
Eric J
EJ
Arts
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.
James I
JI
Mullins
D000595:Amino Acid Sequence; D017124:Conserved Sequence; D056084:Genetic Fitness; D016655:HIV Core Protein p24 / Q000737:chemistry / Q000235:genetics*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016415:Sequence Alignment; D014779:Virus Replication
D016655:HIV Core Protein p24; D015699:HIV Envelope Protein gp120