P09-19 LB. CTL escape mutations in gag epitopes restricted by protective HLA class I alleles cause substantial reductions in viral replication capacity
TL;DR: It is hypothesized that escape costs contribute to the protective effect exhibited by some HLA alleles; protective alleles restrict early, immunodominant CD8+ T cell responses from which HIV can only escape with substantial associated reductions in viral replication capacity.
Abstract: Background CD8+ T cell responses, particularly those targeting Gag epitopes, play a critical role in the control of HIV during early infection, but the capacity of HIV to rapidly escape from such responses can undermine effective CTL-mediated control. In some cases, however, the CTL escape mutation causes a reduction in viral replication capacity. We hypothesize that such escape costs contribute to the protective effect exhibited by some HLA alleles; protective alleles restrict early, immunodominant CD8+ T cell responses from which HIV can only escape with substantial associated reductions in viral replication capacity.
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TL;DR: A multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference is developed and it is found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern.
Abstract: 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.
222 citations
TL;DR: 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 are described.
Abstract: The extensive genetic diversity of human immunodeficiency virus type 1 (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.
98 citations
Cites background from "P09-19 LB. CTL escape mutations in ..."
...In addition, a recent analysis of the impact on viral replication capacity of 20 CTL escape mutations in Gag epitopes identified only 3 escape mutations that caused substantial reductions in viral replication capacity, suggesting that high-cost escape mutations are relatively rare [35]....
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TL;DR: These newer finding suggest NK cells and ADCC responses apply significant pressure to the virus and there is an opportunity to harness these immune responses in the design of more effective HIV vaccines.
Abstract: 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.
23 citations
Cites background from "P09-19 LB. CTL escape mutations in ..."
...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]....
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TL;DR: The computational sequence–structure stability approach proposed here might therefore be useful for identifying immutable sites in a protein for experimental validation as potential targets for drug and vaccine development.
Abstract: Rapid evolution and high sequence diversity enable Human Immunodeficiency Virus (HIV) populations to acquire mutations to escape antiretroviral drugs and host immune responses, and thus are major obstacles for the control of the pandemic. One strategy to overcome this problem is to focus drugs and vaccines on regions of the viral genome in which mutations are likely to cripple function through destabilization of viral proteins. Studies relying on sequence conservation alone have had only limited success in determining critically important regions. We tested the ability of two structure-based computational models to assign sites in the HIV-1 capsid protein (CA) that would be refractory to mutational change. The destabilizing mutations predicted by these models were rarely found in a database of 5811 HIV-1 CA coding sequences, with none being present at a frequency greater than 2%. Furthermore, 90% of variants with the low predicted stability (from a set of 184 CA variants whose replication fitness or infectivity has been studied in vitro) had aberrant capsid structures and reduced viral infectivity. Based on the predicted stability, we identified 45 CA sites prone to destabilizing mutations. More than half of these sites are targets of one or more known CA inhibitors. The CA regions enriched with these sites also overlap with peptides shown to induce cellular immune responses associated with lower viral loads in infected individuals. Lastly, a joint scoring metric that takes into account both sequence conservation and protein structure stability performed better at identifying deleterious mutations than sequence conservation or structure stability information alone. The computational sequence-structure stability approach proposed here might therefore be useful for identifying immutable sites in a protein for experimental validation as potential targets for drug and vaccine development.
8 citations
TL;DR: A previously developed simulation model of HIV is extended to include different distributions of fitness effects (DFEs) and inter-mutational genomic distances and it is found that across the DFEs analyzed, the aggregation procedure alters the detectability of escape mutations: large-effect mutations are overrepresented while small- effect mutations are concealed.
Abstract: As human immunodeficiency virus (HIV) begins to replicate within hosts, immune responses are elicited against it. Escape mutations in viral epitopes -immunogenic peptide parts presented on the surface of infected cells- allow HIV to partially evade these responses, and thus rapidly go to fixation. The faster they go to fixation, i.e. the higher their escape rate, the larger the selective pressure exerted by the immune system is assumed to be. This relation underpins the rationale for using escapes to assess the strength of immune responses. However, escape rate estimates are often obtained by employing an aggregation procedure, where several mutations that affect the same epitope are aggregated into a single, composite epitope mutation. The aggregation procedure thus rests upon the assumption that all within-epitope mutations have indistinguishable effects on immune recognition. In this study, we investigate how the violation of this assumption affects escape rate estimates. To this end, we extend a previously developed simulation model of HIV that accounts for mutation, selection and recombination to include different distributions of fitness effects (DFEs) and inter-mutational genomic distances. We use this discrete-time Wright-Fisher based model to simulate early within-host evolution of HIV for DFEs and apply standard estimation methods to infer the escape rates. We then compare true with estimated escape rate values. We also compare escape rate values obtained while applying the aggregation procedure with values estimated without use of that procedure. We find that across the DFEs analyzed, the aggregation procedure alters the detectability of escape mutations: large-effect mutations are over-represented while small-effect mutations are concealed. The effect of the aggregation procedure is similar to extracting the largest-effect mutation appearing within an epitope. Furthermore, the more pronounced the over-exponential decay of the DFEs, the more severely true escape rates are underestimated. We conclude that the aggregation procedure has two main consequences. On the one hand, it leads to a misrepresentation of the DFE of fixed mutations. On the other hand, it conceals within-epitope interactions that may generate irregularities in mutation frequency trajectories that are thus left unexplained.
5 citations
Cites background from "P09-19 LB. CTL escape mutations in ..."
...We neglect the effect of compensatory mutations due to the assumptions that compensatory mutations arise and go to fixation rapidly, that high-cost mutations are rare (54) and that their fitness effects are small relative to CTL pressures (2)....
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