The Hypervariable HIV-1 Capsid Protein Residues Comprise HLA-Driven CD8
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            T-Cell Escape Mutations and Covarying HLA-Independent Polymorphisms

Crawford, Hayley; Matthews, Philippa C.; Schaefer, Malinda; Carlson, Jonathan M.; Leslie, Alasdair; Kilembe, William; Allen, Susan; Ndung’u, Thumbi; Heckerman, David; Hunter, Eric; Goulder, Philip

doi:10.1128/jvi.01879-10

Cited by 26 publications

(25 citation statements)

References 38 publications

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“…Global compensatory mutations do exist that can compensate multiple deleterious mutations, such as those within the cyclophilin binding loop [42], [46]. Some of the rare fitness increasing mutations may be of this type, although those reported previously have generally been quite common in the population.…”

Section: Discussionmentioning

confidence: 97%

Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis

et al. 2012

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Initial studies of 88 transmission pairs in the Zambia Emory HIV Research Project cohort demonstrated that the number of transmitted HLA-B associated polymorphisms in Gag, but not Nef, was negatively correlated to set point viral load (VL) in the newly infected partners. These results suggested that accumulation of CTL escape mutations in Gag might attenuate viral replication and provide a clinical benefit during early stages of infection. Using a novel approach, we have cloned gag sequences isolated from the earliest seroconversion plasma sample from the acutely infected recipient of 149 epidemiologically linked Zambian transmission pairs into a primary isolate, subtype C proviral vector, MJ4. We determined the replicative capacity (RC) of these Gag-MJ4 chimeras by infecting the GXR25 cell line and quantifying virion production in supernatants via a radiolabeled reverse transcriptase assay. We observed a statistically significant positive correlation between RC conferred by the transmitted Gag sequence and set point VL in newly infected individuals (p = 0.02). Furthermore, the RC of Gag-MJ4 chimeras also correlated with the VL of chronically infected donors near the estimated date of infection (p = 0.01), demonstrating that virus replication contributes to VL in both acute and chronic infection. These studies also allowed for the elucidation of novel sites in Gag associated with changes in RC, where rare mutations had the greatest effect on fitness. Although we observed both advantageous and deleterious rare mutations, the latter could point to vulnerable targets in the HIV-1 genome. Importantly, RC correlated significantly (p = 0.029) with the rate of CD4+ T cell decline over the first 3 years of infection in a manner that is partially independent of VL, suggesting that the replication capacity of HIV-1 during the earliest stages of infection is a determinant of pathogenesis beyond what might be expected based on set point VL alone.

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Section: Discussionmentioning

confidence: 97%

Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis

et al. 2012

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“…One consideration is that CA would be predicted to be under greater immunological pressure than IN because Gag is expressed at 10-to 20-fold-higher levels than Pol in infected cells. While both IN and CA have been documented to be under selective pressure generated by host immune CD8 ϩ CTL responses, there is more evidence of CTL-imposed reductions in fitness in Gag/CA than in Pol/IN, suggesting the fragility exhibited by CA makes it particularly vulnerable to this type of pressure (86)(87)(88)(89)(90)(91). Thus, the similar degrees of natural sequence variation exhibited by IN and CA could simply reflect a similar balance of opposing forces, namely, immunological selective pressure (driving sequence diversification) and fragility (driving sequence conservation).…”

Section: Discussionmentioning

confidence: 99%

Uneven Genetic Robustness of HIV-1 Integrase

Rihn

Hughes

Wilson

et al. 2015

J Virol

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Genetic robustness (tolerance of mutation) may be a naturally selected property in some viruses, because it should enhance adaptability. Robustness should be especially beneficial to viruses like HIV-1 that exhibit high mutation rates and exist in immunologically hostile environments. Surprisingly, however, the HIV-1 capsid protein (CA) exhibits extreme fragility. To determine whether fragility is a general property of HIV-1 proteins, we created a large library of random, single-amino-acid mutants in HIV-1 integrase (IN), covering >40% of amino acid positions. Despite similar degrees of sequence variation in naturally occurring IN and CA sequences, we found that HIV-1 IN was significantly more robust than CA, with random nonsilent IN mutations only half as likely to cause lethal defects. Interestingly, IN and CA were similar in that a subset of mutations with high in vitro fitness were rare in natural populations. IN mutations of this type were more likely to occur in the buried interior of the modeled HIV-1 intasome, suggesting that even very subtle fitness effects suppress variation in natural HIV-1 populations. Lethal mutations, in particular those that perturbed particle production, proteolytic processing, and particle-associated IN levels, were strikingly localized at specific IN subunit interfaces. This observation strongly suggests that binding interactions between particular IN subunits regulate proteolysis during HIV-1 virion morphogenesis. Overall, use of the IN mutant library in conjunction with structural models demonstrates the overall robustness of IN and highlights particular regions of vulnerability that may be targeted in therapeutic interventions. IMPORTANCEThe HIV-1 integrase (IN) protein is responsible for the integration of the viral genome into the host cell chromosome. To measure the capacity of IN to maintain function in the face of mutation, and to probe structure/function relationships, we created a library of random single-amino-acid IN mutations that could mimic the types of mutations that naturally occur during HIV-1 infection. Previously, we measured the robustness of HIV-1 capsid in this manner and determined that it is extremely intolerant of mutation. In contrast to CA, HIV-1 IN proved relatively robust, with far fewer mutations causing lethal defects. However, when we subsequently mapped the lethal mutations onto a model of the structure of the multisubunit IN-viral DNA complex, we found the lethal mutations that caused virus morphogenesis defects tended to be highly localized at subunit interfaces. This discovery of vulnerable regions of HIV-1 IN could inform development of novel therapeutics.

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“…In a covariation analysis (14), we identified 9 statistically significant associations (q Ͻ 0.05) between Gag-260D and variation at other positions (see Table S3 in the supplemental material), which may indicate that the D260E escape in C-clade virus may require compensatory mutations to minimize the impact on viral replicative capacity.…”

Section: Discussionmentioning

confidence: 99%

Differential Clade-Specific HLA-B*3501 Association with HIV-1 Disease Outcome Is Linked to Immunogenicity of a Single Gag Epitope

Matthews

Koyanagi

Kløverpris

et al. 2012

J Virol

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The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade-infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8 ؉ T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope NPPIPVGDIY (NY10, Gag positions 253 to 262) (P ‫؍‬ 2 ؋ 10 ؊5 ). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response toward NY10 was associated with a significantly lower viral set point. Nonimmunogenicity of NY10 in B-clade-infected subjects derives from the Gag-D260E polymorphism present in ϳ90% of B-clade sequences, which critically reduces recognition of the Gag NY10 epitope. These data suggest that in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8 ؉ T-cell response, by the addition of even a single epitope, may be of overriding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8 ؉ T-cell response in all individuals, irrespective of HLA type.

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The Hypervariable HIV-1 Capsid Protein Residues Comprise HLA-Driven CD8 ⁺ T-Cell Escape Mutations and Covarying HLA-Independent Polymorphisms

Cited by 26 publications

References 38 publications

Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis

Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis

Uneven Genetic Robustness of HIV-1 Integrase

Differential Clade-Specific HLA-B*3501 Association with HIV-1 Disease Outcome Is Linked to Immunogenicity of a Single Gag Epitope

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The Hypervariable HIV-1 Capsid Protein Residues Comprise HLA-Driven CD8 + T-Cell Escape Mutations and Covarying HLA-Independent Polymorphisms

Cited by 26 publications

References 38 publications

Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis

Role of Transmitted Gag CTL Polymorphisms in Defining Replicative Capacity and Early HIV-1 Pathogenesis

Uneven Genetic Robustness of HIV-1 Integrase

Differential Clade-Specific HLA-B*3501 Association with HIV-1 Disease Outcome Is Linked to Immunogenicity of a Single Gag Epitope

Contact Info

Product

Resources

About

The Hypervariable HIV-1 Capsid Protein Residues Comprise HLA-Driven CD8 ⁺ T-Cell Escape Mutations and Covarying HLA-Independent Polymorphisms