P09-19 LB. CTL escape mutations in gag epitopes restricted by protective HLA class I alleles cause substantial reductions in viral replication capacity

Boutwell, CL; Schneidewind, Arne; Brumme, ZL; Brockman, Mark A.; Streeck, Hendrik; Brumme, C.J.; Dudek, Timothy; Kane, Katherine; Kemper, Michael; Walker, Bruce D.; Altfeld, Marcus; Allen, Todd M.

doi:10.1186/1742-4690-6-s3-p399

Cited by 5 publications

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“…First, by proposing a very simple model of early HIV dynamics we were able to more clearly identify the sources of some of the effects observed, such as ERD. Second, there seem to exist few high-cost escape mutations [ 97 ] and the selective pressures during early HIV are high compared to the fitness costs [ 24 ]. This suggests a small role for fitness costs during the phase of HIV infection studied here.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Consequences of Interference between Multiple CD8+ T Cell Escape Mutations in Early HIV Infection

2016

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During early human immunodeficiency virus (HIV) infection multiple CD8+ T cell responses are elicited almost simultaneously. These responses exert strong selective pressures on different parts of HIV’s genome, and select for mutations that escape recognition and are thus beneficial to the virus. Some studies reveal that the later these escape mutations emerge, the more slowly they go to fixation. This pattern of escape rate decrease(ERD) can arise by distinct mechanisms. In particular, in large populations with high beneficial mutation rates interference among different escape strains –an effect that can emerge in evolution with asexual reproduction and results in delayed fixation times of beneficial mutations compared to sexual reproduction– could significantly impact the escape rates of mutations. In this paper, we investigated how interference between these concurrent escape mutations affects their escape rates in systems with multiple epitopes, and whether it could be a source of the ERD pattern. To address these issues, we developed a multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference. We also derived an interference-free null model assuming initial neutral evolution before immune response elicitation. We found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern. We also found that the number of loci, as well as recombination rates substantially affect ERD. These effects can be explained by the underexponential decline of escape rates over time. Lastly, we found that the observed ERD pattern in HIV infected individuals is consistent with both independent, interference-free mutations as well as interference effects. Our results confirm that interference effects should be considered when analyzing HIV escape mutations. The challenge in estimating escape rates and mutation-associated selective coefficients posed by interference effects cannot simply be overcome by improved sampling frequencies or sizes. This problem is a consequence of the fundamental shortcomings of current estimation techniques under interference regimes. Hence, accounting for the stochastic nature of competition between mutations demands novel estimation methodologies based on the analysis of HIV strains, rather than mutation frequencies.

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Section: Discussionmentioning

confidence: 99%

Investigating the Consequences of Interference between Multiple CD8+ T Cell Escape Mutations in Early HIV Infection

2016

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“…Macaque and human studies have also demonstrated that escape from T-cell immunity leads to ongoing HIV or SIV infection [ 27 ]. The latest investigation of the effect on viral replication of twenty CTL escape mutations in Gag epitopes established only three escape mutations that resulted in substantial reductions in viral replication capacity, indicating that high-cost escape mutations are rather rare [ 28 ]. More importantly, these three highly effective CTL escape mutations appeared in epitopes primarily targeted during acute infection by protective HLA class I alleles [ 29 ].…”

Section: Ctl Escape and The Road To Reduced Viral Fitnessmentioning

confidence: 99%

Antibody-Dependent Cellular Cytotoxicity and NK Cell-Driven Immune Escape in HIV Infection: Implications for HIV Vaccine Development

Isitman

Stratov

Kent

2012

Advances in Virology

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The HIV-1 genome is malleable and a difficult target tot vaccinate against. It has long been recognised that cytotoxic T lymphocytes and neutralising antibodies readily select for immune escape HIV variants. It is now also clear that NK cells can also select for immune escape. NK cells force immune escape through both direct Killer-immunoglobulin-like receptor (KIR)-mediated killing as well as through facilitating antibody-dependent cellular cytotoxicity (ADCC). These newer finding suggest NK cells and ADCC responses apply significant pressure to the virus. There is an opportunity to harness these immune responses in the design of more effective HIV vaccines.

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“…This result is consistent with the lack of a fitness cost associated with virus escape from neutralizing antibodies [34] and suggests that differential functional constraints play a role in determining escape mutation-associated fitness costs. In addition, a recent analysis of the impact on viral replication capacity of twenty CTL escape mutations in Gag epitopes identified only three escape mutations that caused substantial reductions in viral replication capacity, suggesting that high-cost escape mutations are relatively rare [35]. Interestingly, the three high-cost CTL escape mutations occurred in epitopes dominantly targeted by protective HLA class I alleles during acute infection [1].…”

Section: Immune Escape-associated Viral Fitness Costsmentioning

confidence: 99%

Viral Evolution and Escape during Acute HIV‐1 Infection

et al. 2010

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The extensive genetic diversity of HIV-1 presents a significant barrier to the development of an effective and durable HIV vaccine. This variability not only makes it difficult to identify the targets against which immune responses should be directed, but it also confers on the virus the capacity for rapid escape from effective immune responses. Here, we describe recent investigations of the genetic diversity of HIV-1 at transmission and of the evolution of the virus as it adapts to the host immune environment during the acute phase of HIV-1 infection. These studies increase our understanding of the virology of the earliest stages of HIV-1 infection and provide critical insights into the mechanisms underlying viral replication and immune control of diverse HIV-1 strains. Such knowledge will inform the design of smarter, more effective, vaccines capable of inducing immune control of HIV-1.

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P09-19 LB. CTL escape mutations in gag epitopes restricted by protective HLA class I alleles cause substantial reductions in viral replication capacity

Cited by 5 publications

References 0 publications

Investigating the Consequences of Interference between Multiple CD8+ T Cell Escape Mutations in Early HIV Infection

Investigating the Consequences of Interference between Multiple CD8+ T Cell Escape Mutations in Early HIV Infection

Antibody-Dependent Cellular Cytotoxicity and NK Cell-Driven Immune Escape in HIV Infection: Implications for HIV Vaccine Development

Viral Evolution and Escape during Acute HIV‐1 Infection

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