Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation.
Abstract
BACKGROUND: Fitness costs and slower disease progression are associated with a cytolytic
T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying
HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains
on the fitness costs due to the T242N mutation has not been well characterized. To
better understand the extent of fitness costs of the T242N mutation and the repair
of fitness loss through compensatory amino acids, we investigated its fitness impact
in different transmitted/founder (T/F) viruses. RESULTS: The T242N mutation resulted
in various levels of fitness loss in four different T/F viruses. However, the fitness
costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine
at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover,
the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T
mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome
resulted in significant fitness cost, suggesting the fitness loss caused by the T242N
mutation had been fully repaired in the donor at transmission. Analysis of the global
circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high
prevalence of compensatory amino acids for the T242N mutation and other T cell escape
mutations. CONCLUSIONS: Our results show that the preexisting compensatory amino acids
in the majority of circulating HIV-1 strains could significantly compromise the fitness
loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.
Type
Journal articleSubject
Amino AcidsHIV-1
Humans
Immune Evasion
Mutation, Missense
T-Lymphocytes
Virus Replication
gag Gene Products, Human Immunodeficiency Virus
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https://hdl.handle.net/10161/10437Published Version (Please cite this version)
10.1186/s12977-014-0101-0Publication Info
Liu, Donglai; Zuo, Tao; Hora, Bhavna; Song, Hongshuo; Kong, Wei; Yu, Xianghui; ...
Gao, Feng (2014). Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape
mutation. Retrovirology, 11. pp. 101. 10.1186/s12977-014-0101-0. Retrieved from https://hdl.handle.net/10161/10437.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Feng Gao
Professor Emeritus in Medicine
Dr. Feng Gao is Professor of Medicine at Duke University. The Gao laboratory has a
long-standing interest in elucidating the origins and evolution of human and simian
inmmunodeficiency viruses (HIV and SIV), and in studying HIV/SIV gene function and
pathogenic mechanisms from the evolutionary perspective. These studies have led to
new strategies to better understand HIV origins, biology, pathogenesis and drug resistance,
and to design new AIDS vaccines.
Barton Ford Haynes
Frederic M. Hanes Distinguished Professor of Medicine
The Haynes lab is studying host innate and adaptive immune responses to the human
immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the
enabling technology to make preventive vaccines against these three major infectious
diseases. Mucosal Immune Responses in Acute HIV Infection The Haynes lab is working
to determine why broadly neutralizing antibodies are rarely made in acute HIV infection
(AHI), currently a major obstacle in the de
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