Temporal Association of HLA-B*81:01- and HLA-B*39:10-Mediated HIV-1 p24 Sequence Evolution with Disease Progression

Ntale, Roman; Chopera, Denis; Ngandu, Nobubelo K.; Rosa, Debra Assis de; Zembe, Lycias; Gamieldien, Hoyam; Mlotshwa, Mandla; Werner, Lise.; Woodman, Zenda; Mlisana, Koleka; Karim, Salim Safurdeen. Abdool; Gray, Clive M.; Williamson, Carolyn

doi:10.1128/jvi.00539-12

Cited by 20 publications

(22 citation statements)

References 57 publications

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“…However, VL did not decreased in CH58 either, although the T242N escape mutant was significantly less fit than the T/F virus (Figure 4 ). Similar lack of VL decrease was also observed in other studies [ 4 , 30 ]. This pervasive lack of association between the fixation of the T242N mutation and the VL decrease suggested that the significant fitness costs were generally compensated during fixation.…”

Section: Resultssupporting

confidence: 91%

Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation

et al. 2014

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BackgroundFitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses.ResultsThe T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations.ConclusionsOur results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.

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Section: Resultssupporting

confidence: 91%

Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation

et al. 2014

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“…Second, the CTL response itself adapts to the changing virus through the emergence of new TCR variants that either recognize the escaped epitope or shift focus to new epitopes 11 – 15 . Indeed, while case studies report increased VL following escape from highly immunodominant epitopes 11 , 16 – 19 , the overall impact of within-host escape is unknown.…”

Section: Introductionmentioning

confidence: 99%

Impact of pre-adapted HIV transmission

Carlson

Pfeifer

et al. 2016

Nat Med

120

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Human Leukocyte Antigen class I (HLA) restricted CD8+ T lymphocyte (CTL) responses are critical to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, since these variants can also reduce intrinsic viral fitness. To address this question, we here develop a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated CD4 decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to expression of certain HLA alleles. Thus, viral pre-adaptation exploits “holes” in the immune response. Accounting for these holes may be critical for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies requiring broad CTL responses to achieve successful eradication of HIV reservoirs.

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“…The clinical profile and the study objectives of the cohort have been reported previously [32, 33]. The gag sequences of subtype C origin were derived from 75 subjects, constituting a subset of the CAPRISA 002 cohort.…”

Section: Resultsmentioning

confidence: 99%

The PTAP sequence duplication in HIV-1 subtype C Gag p6 in drug-naive subjects of India and South Africa

et al. 2017

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BackgroundHIV-1 subtype C demonstrates several biological properties distinct from other viral subtypes. One such variation is the duplication of PTAP motif in p6 Gag. PTAP motif is a key player in viral budding. Here, we studied the prevalence of PTAP motif duplication in subtype C viral strains in a longitudinal study.MethodsIn a prospective follow-up study, 65 HIV-1 seropositive drug-naive subjects were monitored in two different clinical cohorts of India for 2 years with repeated sampling at 6-month intervals. The viral RNA was extracted from plasma, the gag segment was amplified and sequenced. From a subset of viral isolates the sequences of pol, env and LTR were sequenced. Using HIV-1 gag amino acid sequences available from public databases and additional sequences derived from the Indian and South-African cohorts, we examined the nature of PTAP motif duplication in subtype C.ResultsIn 16% (8 of 50) of the primary viral strains of India, we identified a sequence duplication of the PTAP motif in Gag p6. The length of the sequence duplication varied from 6 to 14 amino acids in the viral isolates but remained fixed within a subject over a period of 24–36 month follow-up. In the duplicated motif, the core PTAP motif was invariable, but the flanking residues were highly variable. In an acute phase clinical cohort of South Africa, in a subset of 75 subjects, we found the presence of the PTAP duplication at a frequency of 29.3%. An analysis of the gag sequences from the extant databases showed that unlike other subtypes of HIV-1, subtype C has a natural propensity to generate the PTAP motif duplication at a significantly higher frequency and of greater length. Additionally, the global prevalence of PTAP duplication in subtype C appears to be increasing progressively over the past 30 years.ConclusionWe showed that in subtype C, the duplication of the PTAP motif in p6 Gag involves sequence stretches of greater length, and at a much higher frequency as compared to other HIV-1 subtypes. Given that subtype C naturally lacks the Alix binding motif, the acquisition of an additional PTAP motif may confer replication advantage on this HIV-1 subtype. Further investigation is warranted to examine the significance of PTAP motif duplication on the replicative fitness of HIV-1.

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Temporal Association of HLA-B81:01- and HLA-B39:10-Mediated HIV-1 p24 Sequence Evolution with Disease Progression

Cited by 20 publications

References 57 publications

Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation

Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation

Impact of pre-adapted HIV transmission

The PTAP sequence duplication in HIV-1 subtype C Gag p6 in drug-naive subjects of India and South Africa

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