Lack of a significant impact of Gag-Protease-mediated HIV-1 replication capacity on clinical parameters in treatment-naive Japanese individuals

Sakai, Keiko; Chikata, Takayuki; Brumme, Zabrina L.; Brumme, Chanson J.; Gatanaga, Hiroyuki; Oka, Shinichi; Takiguchi, Masafumi

doi:10.1186/s12977-015-0223-z

Cited by 4 publications

(4 citation statements)

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“…Despite the difference between B and C clade viruses at Gag-280 in the consensus sequence (valine in C clade and threonine in B clade viruses) (Table 2), the distinctive HLA-B*52:01 footprint in Gag at position 6 in the RI8 epitope (RMTSPVSI) was observed within these C-clade-infected individuals, similar to the findings in B-clade-infected cohorts (Fig. 1B and Table 3) (10,16). The frequency of V280X T/S/A variants (where X is either serine, threonine, or alanine) was 71% in HLA-B*52:01-positive individuals in contrast to 30% in HLA-B*52:01-negative individuals (Fig.…”

Section: Resultssupporting

confidence: 79%

“…However, our understanding of the underlying mechanisms of HLA-B*52:01-mediated immune control of HIV has been limited due to the low prevalence of the allele in the populations most commonly studied. The analyses that have been undertaken to date are based on B clade cohorts in Japan, where the HLA-B*52:01 is relatively prevalent (8)(9)(10)(11). In the current study, we focus on a North Indian population in which HLA-B*52:01 is expressed in more than 20% of subjects (http://www.allelefrequencies.net/) and where the C clade is the predominant subtype (12).…”

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confidence: 99%

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Impact of HLA-B*52:01-Driven Escape Mutations on Viral Replicative Capacity

Tsai

Singh

Adland

et al. 2020

J Virol

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HLA-B*52:01 is strongly associated with protection against HIV disease progression. However, the mechanisms of HLA-B*52:01-mediated immune control have not been well studied. We here describe a cohort with a majority of HIV C-clade-infected individuals from Delhi, India, where HLA-B*52:01 is highly prevalent (phenotypic frequency, 22.5%). Consistent with studies of other cohorts, expression of HLA-B*52:01 was associated with high absolute CD4 counts and therefore a lack of HIV disease progression. We here examined the impact of HLA-B*52:01-associated viral polymorphisms within the immunodominant C clade Gag epitope RMTSPVSI (here, RI8; Gag residues 275 to 282) on viral replicative capacity (VRC) since HLA-mediated reduction in VRC is a central mechanism implicated in HLA-associated control of HIV. We observed in HLA-B*52:01-positive individuals a higher frequency of V280T, V280S, and V280A variants within RI8 (P = 0.0001). Each of these variants reduced viral replicative capacity in C clade viruses, particularly the V280A variant (P < 0.0001 in both the C clade consensus and in the Indian study cohort consensus p24 Gag backbone), which was also associated with significantly higher absolute CD4 counts in the donors (median, 941.5 cells/mm3; P = 0.004). A second HLA-B*52:01-associated mutation, K286R, flanking HLA-B*52:01-RI8, was also analyzed. Although selected in HLA-B*52:01-positive subjects often in combination with the V280X variants, this mutation did not act as a compensatory mutant but, indeed, further reduced VRC. These data are therefore consistent with previous work showing that HLA-B molecules that are associated with immune control of HIV principally target conserved epitopes within the capsid protein, escape from which results in a significant reduction in VRC. IMPORTANCE Few studies have addressed the mechanisms of immune control in HIV-infected subjects in India, where an estimated 2.7 million people are living with HIV. We focus here on a study cohort in Delhi on one of the most prevalent HLA-B alleles, HLA-B*52:01, present in 22.5% of infected individuals. HLA-B*52:01 has consistently been shown in other cohorts to be associated with protection against HIV disease progression, but studies have been limited by the low prevalence of this allele in North America and Europe. Among the C-clade-infected individuals, we show that HLA-B*52:01 is the most protective of all the HLA-B alleles expressed in the Indian cohort and is associated with the highest absolute CD4 counts. Further, we show that the mechanism by which HLA-B*52:01 mediates immune protection is, at least in part, related to the inability of HIV to evade the HLA-B*52:01-restricted p24 Gag-specific CD8+ T-cell response without incurring a significant loss to viral replicative capacity.

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Section: Resultssupporting

confidence: 79%

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confidence: 99%

Impact of HLA-B*52:01-Driven Escape Mutations on Viral Replicative Capacity

Tsai

Singh

Adland

et al. 2020

J Virol

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“…In contrast, the signature position 357, with a serine in the Pakistani strain, was found to reduce the number of CD4 + /CD8 + T-cell epitopes compared with the Kenyan strain that had a glycine in this position. This observation is supported by a previous study indicating that the set of four substitutions (79F+228L+286K+357G) can reduce the replicative capacity of NL4-3 (mutant) by 2-fold [ 54 ]. However, due to limited in vitro and in vivo data on epitopes specific for HIV-1 sub-subtype A1, a detailed assessment of the relationship between signature mutations and immune escape cannot be established and warrants further in vitro studies to confirm this phenomenon.…”

Section: Discussionsupporting

confidence: 79%

Phylogenetic Characterization of HIV-1 Sub-Subtype A1 in Karachi, Pakistan

Tariq

Nazziwa

Sasinovich

et al. 2022

Viruses

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(1) Background: HIV-1 sub-subtype A1 is common in parts of Africa, Russia, former Soviet Union countries, and Eastern Europe. In Pakistan, sub-subtype A1 is the predominant HIV-1 subtype. Preliminary evidence suggests that distinct strains of HIV-1 sub-subtype A1 are circulating in Pakistan; however, an in-depth molecular phylogenetic characterization of HIV-1 sub-subtype A1 strains in Pakistan have not been presented. We performed a detailed characterization of the HIV-1 sub-subtype A1 epidemic in Pakistan using state-of-the-art molecular epidemiology and phylodynamics. (2) Methods: A total of 143 HIV-1 sub-subtype A1 gag sequences, including 61 sequences generated specifically for this study from PLHIVs part of our cohort, representing all sub-subtype A1 gag sequences from Pakistan, were analyzed. Maximum-likelihood phylogenetic cluster analysis was used to determine the relationship between Pakistani sub-subtype A1 strains and pandemic sub-subtype A1 strains. Furthermore, we used signature variation, charge distribution, selection pressures, and epitope prediction analyses to characterize variations unique to Pakistani HIV-1 strains and establish the association between signature variations and Gag epitope profile. (3) Results: The HIV-1 sub-subtype A1 sequences from Pakistan formed three main clusters: two that clustered with Kenyan sequences (7 and 10 sequences, respectively) and one that formed a Pakistan-specific cluster of 123 sequences that were much less related to other sub-subtype A1 sequences available in the database. The sequences in the Pakistan-specific cluster and the Kenyan reference strains exhibited several signature variations, especially at amino acid positions 312, 319, 331, 372, 373, 383, and 402. Structural protein modeling suggested that amino acid changes in these positions result in alterations of the Gag protein structure as well as in Gag-specific T-cell epitopes. (4) Conclusions: Our results suggest that the majority of the Pakistan HIV-1 sub-subtype A1 strains were unique to Pakistan and with a specific mutation pattern in Gag.

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“…The original version of this article [ 1 ] unfortunately contained a mistake. In the author list, the surname of author Hiroyuki Gatanaga was incorrectly spelled.…”

Section: Erratum To: Retrovirology (2015) 12:98 Doi 101186/s12977-01mentioning

confidence: 99%