Boutwell, Christian L. and Carlson, Jonathan M. and Lin, Tien-Ho and Seese, Aaron and Power, Karen A. and Peng, Jian and Tang, Yanhua and Brumme, Zabrina L. and Heckerman, David and Schneidewind, Arne and Allen, Todd M. (2013) Frequent and Variable Cytotoxic-T-Lymphocyte Escape-Associated Fitness Costs in the Human Immunodeficiency Virus Type 1 Subtype B Gag Proteins. JOURNAL OF VIROLOGY, 87 (7). pp. 3952-3965. ISSN 0022-538X,
Full text not available from this repository. (Request a copy)Abstract
Cytotoxic-T-lymphocyte (CTL) escape mutations undermine the durability of effective human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) T cell responses. The rate of CTL escape from a given response is largely governed by the net of all escape-associated viral fitness costs and benefits. The observation that CTL escape mutations can carry an associated fitness cost in terms of reduced virus replication capacity (RC) suggests a fitness cost-benefit trade-off that could delay CTL escape and thereby prolong CD8 response effectiveness. However, our understanding of this potential fitness trade-off is limited by the small number of CTL escape mutations for which a fitness cost has been quantified. Here, we quantified the fitness cost of the 29 most common HIV-1B Gag CTL escape mutations using an in vitro RC assay. The majority (20/29) of mutations reduced RC by more than the benchmark M184V antiretroviral drug resistance mutation, with impacts ranging from 8% to 69%. Notably, the reduction in RC was significantly greater for CTL escape mutations associated with protective HLA class I alleles than for those associated with nonprotective alleles. To speed the future evaluation of CTL escape costs, we also developed an in silico approach for inferring the relative impact of a mutation on RC based on its computed impact on protein thermodynamic stability. These data illustrate that the magnitude of CTL escape-associated fitness costs, and thus the barrier to CTL escape, varies widely even in the conserved Gag proteins and suggest that differential escape costs may contribute to the relative efficacy of CD8 responses.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HIV-1 REVERSE-TRANSCRIPTASE; VIRAL REPLICATION CAPACITY; CLASS-I ALLELES; CELL RESPONSES; PRIMARY INFECTION; CRYSTAL-STRUCTURES; IMMUNE-RESPONSES; POPULATION-LEVEL; SET-POINT; P24 GAG; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Apr 2020 10:30 |
| Last Modified: | 22 Apr 2020 10:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/16955 |
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