Extraepitopic Compensatory Substitutions Partially Restore Fitness to Simian Immunodeficiency Virus Variants That Escape from an Immunodominant Cytotoxic-T-Lymphocyte Response

Abstract

Selection for escape mutant immunodeficiency viruses by cytotoxic T lymphocytes (CTL) has been well characterized and may be associated with disease progression. CTL epitopes accrue escape mutations at different rates in vivo. Interestingly, certain high-frequency CTL do not select for escape until the chronic phase of infection. Here we show that mutations conferring escape from immunodominant CTL directed against an epitope in the viral Gag protein are strongly associated with extraepitopic mutations in gag in vivo. The extraepitopic mutations partially restore in vitro replicative fitness of viruses bearing the escape mutations. Constraints on epitope sequences may therefore play a role in determining the rate of escape from CTL responses in vivo.

Involvement of Multiple Epitope-Specific Cytotoxic T-Lymphocyte Responses in Vaccine-Based Control of Simian Immunodeficiency Virus Replication in Rhesus Macaques

“…Because the rapidly selected Gag 206-216 -CTL-escape mutant virus with the GagL216S mutation showed diminished replicative ability, it was expected that the additional mutations accumulated in macaques V5 and V3 might contribute to recovery of viral fitness. Indeed, some CTL escape mutant viruses with lower viral fitness are known to require additional compensatory mutations to restore their replicative competence (13,21,34,43). However, our results have revealed that mutations accumulated in macaques V5 and V3 did not result in recovery of viral fitness.…”

Estimation of the rate of killing by cytotoxic T lymphocytesin vivo

“…Escape mutants may, however, carry a fitness cost that leads to an underestimation of CTL efficacy. Empirical studies estimating the fitness cost of CTL escape mutants (28)(29)(30)(31) suggest that it will not be high enough to explain much of the discrepancy in the estimates. We note that all of these effects could contribute (to varying degrees) to the higher killing rate estimate in our article as compared with those in previous studies.…”

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

“…Such differences in sequence evolution may be due to variation in CTL efficacy or may reflect deleterious effects of particular escape mutations on the virus. Recent reports for HIV-1 and SIV illustrate that CTL escape mutations can impact viral replication (30,46,55,56), revert upon transmission to a new host (5,17,29,44,45), or require the development of numerous compensatory mutations (30,41,44,55,56). Each of these observations implies a negative impact of immune escape on the replicative capacity of the virus.…”