HIV-1 Gag evolution in recently infected human leukocyte antigen-B*57 patients with low-level viremia

Durand, Christine M.; O’Connell, Karen A.; Apuzzo, Linda; Langan, Susan; Imteyaz, Hejab; Ahonkhai, Aima A.; Ceccato, Christina; Williams, Thomas M.; Margolick, Joseph B.; Blankson, Joel N.

doi:10.1097/qad.0b013e32833d8a38

Cited by 11 publications

(9 citation statements)

References 19 publications

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“…Previous studies have failed to find a correlation between the development of specific escape mutations and disease progression (18). This is, perhaps, not surprising if we consider the combinatorial explosion of possible mutations within HLA-restricted epitopes, which may contribute to immune escape, and in flanking regions, which may compensate for reduced viral fitness.…”

Section: Fig 4 Median Nucleotide Substitution Rate and 95% Hpd Intervmentioning

confidence: 77%

“…HLA-B*5701 subjects with a baseline of Ͼ750 CD4 ϩ T cells/ mm 3 (LRPs) were characterized by the gradual emergence of variants during sequential population bottlenecks (18,53,75) along restricted pathways. No mutants were detected in the QW9 epitope, possibly due to strong purifying selection, while mutations in ISW9, TW10, and CypA appeared to be driven by genetic drift rather than positive selection.…”

Section: Fig 4 Median Nucleotide Substitution Rate and 95% Hpd Intervmentioning

confidence: 99%

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Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

Norström

Buggert

Tauriainen

et al. 2012

J Virol

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HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1in vivoevolution and epitope-specific CD8+T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4+T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8+T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8+T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.

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Section: Fig 4 Median Nucleotide Substitution Rate and 95% Hpd Intervmentioning

confidence: 77%

Section: Fig 4 Median Nucleotide Substitution Rate and 95% Hpd Intervmentioning

confidence: 99%

Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

Norström

Buggert

Tauriainen

et al. 2012

J Virol

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“…These findings suggest that the beneficial effects of G248A in reducing hTRIM5␣ sensitivity and improving viral replicative capacity (38,82) may contribute to its selection. In viruses that express both mutations, the order of appearance is usually not known, although several examples of G248A preceding T242N have been described (62,73,80,81), consistent with the possibility that G248A may facilitate the subsequent emergence of T242N in some patients. Additional sites, including both intrasubtype and subtype-specific polymorphisms, also influenced hTRIM5␣ sensitivity, emphasizing the context dependence of this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…Viruses from one of the HLA-B*57 ϩ controller patients (patient 57C3; see Table S1 in the supplemental material) carried the unusual Q244R and G248D mutations in theTW10 epitope, mutations that have previously been observed exclusively in patients with spontaneous control of HIV replication (20,(72)(73)(74). Viruses from this patient had low sensitivity to hTRIM5␣, consistent with the absence of the T242N mutation.…”

Section: Figmentioning

confidence: 89%

“…One such mutation identified by us is G248A in the TW10 epitope. This mutation is almost always found in association with T242N in viruses from HLA-B*57 ϩ patients but can occur alone (20,62,73,74,80,81). Unlike T242N, G248A alone is often not an effective escape variant for patients infected with subtype B viruses (19,25), and its presence has little impact on CTL escape provided by T242N (62).…”

Section: Discussionmentioning

confidence: 99%

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Pressure from TRIM5α Contributes to Control of HIV-1 Replication by Individuals Expressing Protective HLA-B Alleles

Granier

Battivelli

Lécuroux

et al. 2013

J Virol

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؉ patients who spontaneously controlled viral replication, but not viruses from viremic patients expressing these alleles, was significantly greater than that of viruses from patients not expressing these protective HLA-B alleles. Overall, a significant negative correlation between hTRIM5␣ sensitivity and viral load was observed. In HLA-B*57 ؉ patients, the T242N mutation in the HLA-B*57-restricted TW10 CD8 ؉ T lymphocyte (CTL) epitope was strongly associated with hTRIM5␣ sensitivity. In HLA-B*27 ؉ controllers, hTRIM5␣ sensitivity was associated with a significant reduction in emergence of key CTL mutations. In several patients, viral evolution to avoid hTRIM5␣ sensitivity was observed but could be associated with reduced viral replicative capacity. Thus, in individuals expressing protective HLA-B alleles, the combined pressures exerted by CTL, hTRIM5␣, and capsid structural constraints can prevent viral escape both by impeding the selection of necessary resistance/compensatory mutations and forcing the selection of escape mutations that increase hTRIM5␣ sensitivity or impair viral replicative capacity.

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The implications of viral reservoirs on the elite control of HIV-1 infection

Buckheit

Salgado

Martins

et al. 2012

Cell. Mol. Life Sci.

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The mechanisms by which a small percentage of HIV-1 infected individuals known as elite suppressors or controllers are able to control viral replication are not fully understood. Early cases of viremic control were attributed to infection with defective virus, but subsequent work has demonstrated that infection with a defective virus is not the exclusive cause of control. Replication-competent virus has been isolated from patients who control viral replication, and studies have demonstrated that evolution occurs in plasma virus but not in virus isolates from the latent reservoir. Additionally, transmission pair studies have demonstrated that patients infected with similar viruses can have dramatically different outcomes of infection. An increased understanding of the viral factors associated with control is important to understand the interplay between viral replication and host control, and has implications for the design of an effective therapeutic vaccine that can lead to a functional cure of HIV-1 infection.

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HIV-1 Gag evolution in recently infected human leukocyte antigen-B*57 patients with low-level viremia

Cited by 11 publications

References 19 publications

Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

Pressure from TRIM5α Contributes to Control of HIV-1 Replication by Individuals Expressing Protective HLA-B Alleles

The implications of viral reservoirs on the elite control of HIV-1 infection

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