Updated HIV-1 Consensus Sequences Change but Stay Within Similar Distance From Worldwide Samples

Linchangco, Gregorio V.; Foley, Brian; Leitner, Thomas

doi:10.3389/fmicb.2021.828765

Cited by 11 publications

(12 citation statements)

References 20 publications

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“…The consensus sequences of HIV proteins and their conservation studies allow a better understanding of structural, functional, and immunogenic potential differences across HIV-1 groups, subtypes, sub-subtypes, and recombinants and have been previously analyzed in other HIV-1 proteins ( Li et al, 2013 ; Sliepen et al, 2019 ; Zhang et al, 2021 ). A recent work by Linchangco et al reconstructed 90 HIV-1 subtype and CRF consensus sequences from 3,470 full HIV genomes downloaded from LANL ( Linchangco et al, 2021 ). Our study updates and expands the knowledge regarding HIV Pol variability, including 59,733 PR, 6,437 RT, and 6,059 IN sequences from more than 100 different variants, including all the currently available HIV-1 groups, subtypes, and CRF in LANL.…”

Section: Discussionmentioning

confidence: 99%

Genetic Diversity and Low Therapeutic Impact of Variant-Specific Markers in HIV-1 Pol Proteins

2022

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The emergence and spread of new HIV-1 variants pose a challenge for the effectiveness of antiretrovirals (ARV) targeting Pol proteins. During viral evolution, non-synonymous mutations have fixed along the viral genome, leading to amino acid (aa) changes that can be variant-specific (V-markers). Those V-markers fixed in positions associated with drug resistance mutations (DRM), or R-markers, can impact drug susceptibility and resistance pathways. All available HIV-1 Pol sequences from ARV-naïve subjects were downloaded from the United States Los Alamos HIV Sequence Database, selecting 59,733 protease (PR), 6,437 retrotranscriptase (RT), and 6,059 integrase (IN) complete sequences ascribed to the four HIV-1 groups and group M subtypes and circulating recombinant forms (CRFs). Using a bioinformatics tool developed in our laboratory (EpiMolBio), we inferred the consensus sequences for each Pol protein and HIV-1 variant to analyze the aa conservation in Pol. We analyzed the Wu–Kabat protein variability coefficient (WK) in PR, RT, and IN group M to study the susceptibility of each site to evolutionary replacements. We identified as V-markers the variant-specific aa changes present in >75% of the sequences in variants with >5 available sequences, considering R-markers those V-markers that corresponded to DRM according to the IAS-USA2019 and Stanford-Database 9.0. The mean aa conservation of HIV-1 and group M consensus was 82.60%/93.11% in PR, 88.81%/94.07% in RT, and 90.98%/96.02% in IN. The median group M WK was 10 in PR, 4 in RT, and 5 in IN. The residues involved in binding or catalytic sites showed a variability <0.5%. We identified 106 V-markers: 31 in PR, 28 in RT, and 47 in IN, present in 11, 12, and 13 variants, respectively. Among them, eight (7.5%) were R-markers, present in five variants, being minor DRM with little potential effect on ARV susceptibility. We present a thorough analysis of Pol variability among all HIV-1 variants circulating to date. The relatively high aa conservation observed in Pol proteins across HIV-1 variants highlights their critical role in the viral cycle. However, further studies are needed to understand the V-markers’ impact on the Pol proteins structure, viral cycle, or treatment strategies, and periodic variability surveillance studies are also required to understand PR, RT, and IN evolution.

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Section: Discussionmentioning

confidence: 99%

Genetic Diversity and Low Therapeutic Impact of Variant-Specific Markers in HIV-1 Pol Proteins

2022

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“…We generated consensus sequences for subtypes/CRFs for each sampling period, except when there were fewer than 10 sequences available (Table S2; File S4 to S6). We compared our derived consensus sequences with the consensus sequences available at LANL: the recently generated LANL 2021 consensus sequences (based on 3,470 high-quality, representative HIV-1 genomes selected from the 2019 filtered web alignment) ( 22 ) and the previously available LANL 2004 consensus sequences (similarly derived from a filtered set of sequences available at the time). Compared with the LANL 2004 Env consensus sequence, our consensus sequences showed a mean of 37 (only subtype B), 30.29 (min = 11, max = 49), 33.50 (18,52), and 35.86 (27,43) mismatched residues between the consensuses we generated for 1980–1990, 1991–2000, 2001–2010, and 2011–2020, respectively, which decreased to 24, 26 (17,33), 24.80 (11,40), and 30.33 (15,46) when compared with the new LANL 2021 consensus sequences ( 11 ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recent molecular epidemiology studies systematically evaluated the proportion of each subtype and CRF globally and regionally and shifts in these proportions over time ( 6 , 7 ). Linchangco and colleagues at the LANL HIV database, which maintains curated data sets of HIV-1 sequences (among other resources), recently updated the consensus for all HIV-1 subtypes and CRFs using 3,470 high-quality, representative HIV-1 genomes selected from the LANL HIV database 2019 filtered web alignments ( 22 ). They showed that an average of 2.3% (range 0.8%–10%) of sites changed across the consensus genomes designed in 2002 and in 2021 (with similar proportions of substitutions vs. insertions or deletions) and concluded that 2021 consensus sequences were good representations of the typical subtype/CRF genomes.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Gag, Pol, and Env diversified with limited adaptation since the 1980s

Lewitus,

Li,

Bai

et al. 2024

mBio

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Global surveillance of HIV-1 sequences is critical for designing relevant prophylactic and therapeutic interventions to infection. We designed an open-source platform, Hervé, for analyzing and visualizing the diversification dynamics of HIV-1 protein sequences. We characterized the evolution of over 12,000 HIV-1 Env, Gag, and Pol protein sequences from 1980–2020 and found that, despite a steady increase in intra-subtype and circulating recombinant form diversity, the most frequent residue at each site, i.e., the consensus, has varied only moderately.

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“…There are 4 recognized requirements for subtype references classification: (1) one or more complete sequence(s); (2) at least three epidemiologically unrelated isolates; (3) distinct clusters in a phylogenetic tree; (4) exclusion of intersubtypic recombination, whether the components were classified or not (22, 24, 25). Because sequences included in Subtype Reference Alignments have been strictly screened and recognized as standard references and widely used in related research of the field (51-53), they were named gold-standard sequences in this study. We found that among the 302 screened 5’ LTRs with full-length sequences, 20 sequences belong to gold-standard sequences (Supplementary Dataset 4).…”

Section: Resultsmentioning

confidence: 99%

A unified classification system for HIV-1 5’ long terminal repeats

Guo

Liu

et al. 2022

Preprint

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The HIV-1 provirus mainly consists of internal coding region flanked by the 2 same long terminal repeats (LTRs) at each terminus. The LTRs play important roles in HIV-1 reverse transcription, integration, and transcription by the association with host factors. However, despite of the significant study advances of the internal coding regions of HIV-1 by using definite reference classification, there are no systematic classifications for HIV-1 5' LTRs, which hinders our elaboration on 5' LTR and a better understanding of the viral origin, spread and therapy. Here, by analyzing all available resources of 5' LTR sequences in public databases following 4 recognized principles for the reference classification, 83 representatives and 14 consensus sequences were identified as representatives of 2 groups, 6 subtypes, 6 sub-subtypes, and 9 CRFs. To test the reliability of our established classification system, the constructed references were applied to identify the 5' LTR assignment of the 22 clinical isolates in China. The results revealed that 16 out of 22 tested strains showed a consistent subtype classification with the previous LTR-independent classification system. However, 6 strains, for which recombination events within 5' LTR were demonstrated, unexpectedly showed a different subtype classification, leading a significant change of binding sites for important transcription factors including SP1, p53, and NF-κB. The binding change of these transcriptional factors would probably affect the transcriptional activity of 5' LTR. This study established a unified classification system for HIV-1 5' LTRs, which will facilitate HIV-1 characterization and be helpful for both basic and clinical research fields.

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Updated HIV-1 Consensus Sequences Change but Stay Within Similar Distance From Worldwide Samples

Cited by 11 publications

References 20 publications

Genetic Diversity and Low Therapeutic Impact of Variant-Specific Markers in HIV-1 Pol Proteins

Genetic Diversity and Low Therapeutic Impact of Variant-Specific Markers in HIV-1 Pol Proteins

HIV-1 Gag, Pol, and Env diversified with limited adaptation since the 1980s

A unified classification system for HIV-1 5’ long terminal repeats

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