scholarly journals Phylogenetic measures of indel rate variation among the HIV-1 group M subtypes

2019 ◽  
Vol 5 (2) ◽  
Author(s):  
John Palmer ◽  
Art F Y Poon
Keyword(s):  
Large Scale ◽  
Poisson Model ◽  
Purifying Selection ◽  
Nucleotide Composition ◽  
Rate Variation ◽  
Flanking Sequence ◽  
Variable Regions ◽  
Subtype B ◽  
Glycoprotein Gp120 ◽  
Hiv 1

Abstract The transmission fitness and pathogenesis of HIV-1 is disproportionately influenced by evolution in the five variable regions (V1–V5) of the surface envelope glycoprotein (gp120). Insertions and deletions (indels) are a significant source of evolutionary change in these regions. However, the rate and composition of indels has not yet been quantified through a large-scale comparative analysis of HIV-1 sequences. Here, we develop and report results from a phylogenetic method to estimate indel rates for the gp120 variable regions across five major subtypes and two circulating recombinant forms (CRFs) of HIV-1 group M. We processed over 26,000 published HIV-1 gp120 sequences, from which we extracted 6,605 sequences for phylogenetic analysis. We reconstructed time-scaled phylogenies by maximum likelihood and fit a binomial-Poisson model to the observed distribution of indels between closely related pairs of sequences in each tree (cherries). By focusing on cherries in each tree, we obtained phylogenetically independent indel reconstructions, and the shorter time scales in cherries reduced the bias due to purifying selection. Rate estimates ranged from 3.0×10−5 to 1.5×10−3 indels/nt/year and varied significantly among variable regions and subtypes. Indel rates were significantly lower in V3 relative to V1, and were also lower in HIV-1 subtype B relative to the 01_AE reference. We also found that V1, V2, and V4 tended to accumulate significantly longer indels. Furthermore, we observed that the nucleotide composition of indels was distinct from the flanking sequence, with higher frequencies of G and lower frequencies of T. Indels affected N-linked glycosylation sites more often in V1 and V2 than expected by chance, consistent with positive selection on glycosylation patterns within these regions. These results represent the first comprehensive measures of indel rates in HIV-1 gp120 across multiple subtypes and CRFs, and identifies novel and unexpected patterns for further research in the molecular evolution of HIV-1.

scholarly journals Phylogenetic measures of indel rate variation among the HIV-1 group M subtypes

2018 ◽  
Author(s):  
John Palmer ◽  
Art Poon
Keyword(s):  
Sequence Data ◽  
Poisson Model ◽  
Nucleotide Composition ◽  
Rate Variation ◽  
Flanking Sequence ◽  
Nucleotide Substitutions ◽  
Virus Surface ◽  
Variable Regions ◽  
Subtype B ◽  
Hiv 1

The transmission and pathogenesis of human immunodeficiency virus type 1 (HIV-1) is disproportionately influenced by evolution in the five variable regions of the virus surface envelope glycoprotein (gp120). Insertions and deletions (indels) are a significant source of evolutionary change in these regions. However, the influx of indels relative to nucleotide substitutions has not yet been quantified through a comparative analysis of HIV-1 sequence data. Here we develop and report results from a phylogenetic method to estimate indel rates for the gp120 variable regions across five major subtypes and two circulating recombinant forms (CRFs) of HIV-1 group M. We processed over 26,000 published HIV-1 gp120 sequences, from which we extracted 6,605 sequences for phylogenetic analysis. In brief, our method employs maximum likelihood to reconstruct phylogenies scaled in time and fits a Poisson model to the observed distribution of indels between closely related pairs of sequences in the tree (cherries). The rate estimates ranged from 3.0e-5 to 1.5e-3 indels/nt/year and varied significantly among variable regions and subtypes. Indel rates were significantly lower in the region encoding variable loop V3, and also lower for HIV-1 subtype B relative to other subtypes. We also found that variable loops V1, V2 and V4 tended to accumulate significantly longer indels. Further, we observed that the nucleotide composition of indel sequences was significantly distinct from that of the flanking sequence in HIV-1 gp120. Indels affected potential N-linked glycosylation sites substantially more often in V1 and V2 than expected by chance, which is consistent with positive selection on glycosylation patterns within these regions of gp120. These results represent the first comprehensive measures of indel rates in HIV-1 gp120 across multiple subtypes and CRFs, and identifies novel and unexpected patterns for further research in the molecular evolution of HIV-1.

scholarly journals Patterns of Human Immunodeficiency Virus Type 1 Recombination Ex Vivo Provide Evidence for Coadaptation of Distant Sites, Resulting in Purifying Selection for Intersubtype Recombinants during Replication

2010 ◽  
Vol 84 (15) ◽  
pp. 7651-7661 ◽  
Author(s):  
Andrea Galli ◽  
Mary Kearney ◽  
Olga A. Nikolaitchik ◽  
Sloane Yu ◽  
Mario P. S. Chin ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Purifying Selection ◽  
Human Populations ◽  
Major Barrier ◽  
Subtype B ◽  
Single Genome ◽  
Immunodeficiency Virus ◽  
Multiple Cycle ◽  
Hiv 1

ABSTRACT High-frequency recombination is a hallmark of HIV-1 replication. Recombination can occur between two members of the same subtype or between viruses from two different subtypes, generating intra- or intersubtype recombinants, respectively. Many intersubtype recombinants have been shown to circulate in human populations. We hypothesize that sequence diversity affects the emergence of viable recombinants by decreasing recombination events and reducing the ability of the recombinants to replicate. To test our hypothesis, we compared recombination between two viruses containing subtype B pol genes (B/B) and between viruses with pol genes from subtype B or F (B/F). Recombination events generated during a single cycle of infection without selection pressure on pol gene function were analyzed by single-genome sequencing. We found that recombination occurred slightly (∼30%) less frequently in B/F than in B/B viruses, and the overall distribution of crossover junctions in pol was similar for the two classes of recombinants. We then examined the emergence of recombinants in a multiple cycle assay, so that functional pol gene products were selected. We found that the emerging B/B recombinants had complex patterns, and the crossover junctions were distributed throughout the pol gene. In contrast, selected B/F recombinants had limited recombination patterns and restricted crossover junction distribution. These results provide evidence for the evolved coadapted sites in variants from different subtypes; these sites may be segregated by recombination events, causing the newly generated intersubtype recombinants to undergo purifying selection. Therefore, the ability of the recombinants to replicate is the major barrier for many of these viruses.

scholarly journals In Search of Covariates of HIV-1 Subtype B Spread in the United States—A Cautionary Tale of Large-Scale Bayesian Phylogeography

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 182 ◽  
Author(s):  
Samuel L. Hong ◽  
Simon Dellicour ◽  
Bram Vrancken ◽  
Marc A. Suchard ◽  
Michael T. Pyne ◽  
...  
Keyword(s):  
United States ◽  
New York ◽  
Large Scale ◽  
The United States ◽  
Resistance Testing ◽  
Western World ◽  
Phylogenetic Structure ◽  
Subtype B ◽  
The Us ◽  
Hiv 1

Infections with HIV-1 group M subtype B viruses account for the majority of the HIV epidemic in the Western world. Phylogeographic studies have placed the introduction of subtype B in the United States in New York around 1970, where it grew into a major source of spread. Currently, it is estimated that over one million people are living with HIV in the US and that most are infected with subtype B variants. Here, we aim to identify the drivers of HIV-1 subtype B dispersal in the United States by analyzing a collection of 23,588 pol sequences, collected for drug resistance testing from 45 states during 2004–2011. To this end, we introduce a workflow to reduce this large collection of data to more computationally-manageable sample sizes and apply the BEAST framework to test which covariates associate with the spread of HIV-1 across state borders. Our results show that we are able to consistently identify certain predictors of spread under reasonable run times across datasets of up to 10,000 sequences. However, the general lack of phylogenetic structure and the high uncertainty associated with HIV trees make it difficult to interpret the epidemiological relevance of the drivers of spread we are able to identify. While the workflow we present here could be applied to other virus datasets of a similar scale, the characteristic star-like shape of HIV-1 phylogenies poses a serious obstacle to reconstructing a detailed evolutionary and spatial history for HIV-1 subtype B in the US.

scholarly journals NGlyAlign: an automated library building tool to align highly divergent HIV envelope sequences

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Elma H. Akand ◽  
John M. Murray
Keyword(s):  
Mathematical Biology ◽  
Immune Surveillance ◽  
Variable Region ◽  
Virus Envelope ◽  
Multiple Sequence ◽  
Variable Regions ◽  
Subtype B ◽  
Glycosylation Sites ◽  
Hiv Envelope ◽  
Hiv 1

Abstract Background The high variability in envelope regions of some viruses such as HIV allow the virus to establish infection and to escape subsequent immune surveillance. This variability, as well as increasing incorporation of N-linked glycosylation sites, is fundamental to this evasion. It also creates difficulties for multiple sequence alignment methods (MSA) that provide the first step in their analysis. Existing MSA tools often fail to properly align highly variable HIV envelope sequences requiring extensive manual editing that is impractical with even a moderate number of these variable sequences. Results We developed an automated library building tool NGlyAlign, that organizes similar N-linked glycosylation sites as block constraints and statistically conserved global sites as single site constraints to automatically enforce partial columns in consistency-based MSA methods such as Dialign. This combined method accurately aligns variable HIV-1 envelope sequences. We tested the method on two datasets: a set of 156 founder and chronic gp160 HIV-1 subtype B sequences as well as a set of reference sequences of gp120 in the highly variable region 1. On measures such as entropy scores, sum of pair scores, column score, and similarity heat maps, NGlyAlign+Dialign proved superior against methods such as T-Coffee, ClustalOmega, ClustalW, Praline, HIValign and Muscle. The method is scalable to large sequence sets producing accurate alignments without requiring manual editing. As well as this application to HIV, our method can be used for other highly variable glycoproteins such as hepatitis C virus envelope. Conclusions NGlyAlign is an automated tool for mapping and building glycosylation motif libraries to accurately align highly variable regions in HIV sequences. It can provide the basis for many studies reliant on single robust alignments. NGlyAlign has been developed as an open-source tool and is freely available at https://github.com/UNSW-Mathematical-Biology/NGlyAlign_v1.0 .

scholarly journals Impact of Mutations Outside the V3 Region on Coreceptor Tropism Phenotypically Assessed in Patients Infected with HIV-1 Subtype B

2011 ◽  
Vol 55 (11) ◽  
pp. 5078-5084 ◽  
Author(s):  
Laura Monno ◽  
Annalisa Saracino ◽  
Luigia Scudeller ◽  
Grazia Punzi ◽  
Gaetano Brindicci ◽  
...  
Keyword(s):  
Amino Acid ◽  
Statistical Significance ◽  
Net Charge ◽  
Variable Regions ◽  
Coreceptor Tropism ◽  
Enhanced Sensitivity ◽  
Subtype B ◽  
End Stage ◽  
The Impact ◽  
Hiv 1

ABSTRACTHIV coreceptor tropism (CTR) testing is a prerequisite for prescribing a coreceptor antagonist. CTR is increasingly deduced by analyzing the V3 loop sequence of gp120. We investigated the impact of mutations outside V3 on CTR as determined by the enhanced-sensitivity Trofile assay (ESTA). Paired ESTA and gp120 sequencing (population sequencing; from codon 32 of the conserved C1 to the variable V5 domains) were obtained from 60 antiretroviral treatment (ART)-naïve patients (15 with AIDS) infected with subtype B HIV-1. For gp120 sequence analysis, nucleotide mixtures were considered when the second highest electropherogram peak was >25%; sequences were translated into all possible permutations and classified as X4, dual/mixed (DM), and R5 based on coincident ESTA results. ESTA identified R5 and DM viruses in 72 and 28% of patients, respectively; no pure X4 was labeled. Forty percent of AIDS patients had R5 strains. Thirty-two positions, mostly outside V3, were significantly (P< 0.05) different between R5 and DM sequences. According to multivariate analysis, amino acid changes at 9 and 7 positions within the C1 to C4 and V1 to V5 regions, respectively, maintained a statistical significance, as did the net charge of V3 and C4. When analyzing only R5 sequences, 6 positions in the variable regions were found which, along with the V4 net charge, were significantly different for sequences from early- and end-stage disease patients. This study identifies specific amino acid changes outside V3 which contribute to CTR. Extending the analysis to include pure X4 and increasing the sample size would be desirable to define gp120 variables/changes which should be included in predictive algorithms.

scholarly journals Sequence Length of HIV-1 Subtype B Increases over Time: Analysis of a Cohort of Patients with Hemophilia over 30 Years

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 806
Author(s):  
Young-Keol Cho ◽  
Jung-Eun Kim ◽  
Brian T. Foley
Keyword(s):  
Direct Sequencing ◽  
Sequence Length ◽  
Coding Region ◽  
Rt Pcr ◽  
Time Analysis ◽  
Variable Regions ◽  
Subtype B ◽  
Signature Pattern ◽  
Hiv 1 ◽  
Over Time

We aimed to investigate whether the sequence length of HIV-1 increases over time. We performed a longitudinal analysis of full-length coding region sequences (FLs) during an HIV-1 outbreak among patients with hemophilia and local controls infected with the Korean subclade B of HIV-1 (KSB). Genes were amplified by overlapping RT-PCR or nested PCR and subjected to direct sequencing. Overall, 141 FLs were sequentially determined over 30 years in 62 KSB-infected patients. Phylogenetic analysis indicated that within KSB, two FLs from plasma donors O and P comprised two clusters, together with 8 and 12 patients with hemophilia, respectively. Signature pattern analysis of the KSB of HIV-1 revealed 91 signature nucleotide residues (1.1%). In total, 48 and 43 signature nucleotides originated from clusters O and P, respectively. Six positions contained 100% specific nucleotide(s) in clusters O and P. In-depth FL analysis for over 30 years indicated that the KSB FL significantly increased over time before combination antiretroviral therapy (cART) and decreased with cART. This increase occurred due to the significant increase in env and nef genes, originating in the variable regions of both genes. The increase in sequence length of HIV-1 over time suggests an evolutionary direction.

scholarly journals Antiviral Breadth and Combination Potential of Peptide Triazole HIV-1 Entry Inhibitors

2011 ◽  
Vol 56 (2) ◽  
pp. 1073-1080 ◽  
Author(s):  
Karyn McFadden ◽  
Patricia Fletcher ◽  
Fiorella Rossi ◽  
Kantharaju ◽  
Muddagowda Umashankara ◽  
...  
Keyword(s):  
Transcriptase Inhibitor ◽  
Viral Envelope ◽  
Cell Infection ◽  
Entry Inhibitors ◽  
Antiviral Compounds ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Glycoprotein Gp120 ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACTThe first stage of human immunodeficiency virus type 1 (HIV-1) infection involves the fusion of viral and host cellular membranes mediated by viral envelope glycoprotein gp120. Inhibitors that specifically target gp120 are gaining increased attention as therapeutics or preventatives to prevent the spread of HIV-1. One promising new group of inhibitors is the peptide triazoles, which bind to gp120 and simultaneously block its interaction with both CD4 and the coreceptor. In this study, we assessed the most potent peptide triazole, HNG-156, for inhibitory breadth, cytotoxicity, and efficacy, both alone and in combination with other antiviral compounds, against HIV-1. HNG-156 inhibited a panel of 16 subtype B and C isolates of HIV-1 in a single-round infection assay. Inhibition of cell infection by replication-competent clinical isolates of HIV-1 was also observed with HNG-156. We found that HNG-156 had a greater than predicted effect when combined with several other entry inhibitors or the reverse transcriptase inhibitor tenofovir. Overall, we find that HNG-156 is noncytotoxic, has a broad inhibition profile, and provides a positive combination with several inhibitors of the HIV-1 life cycle. These results support the pursuit of efficacy and toxicity analyses in more advanced cell and animal models to develop peptide triazole family inhibitors of HIV-1 into antagonists of HIV-1 infection.

scholarly journals Sequence Length of HIV-1 Subtype B Increases Over Time: Analysis of a Cohort of Patients With Hemophilia Over 30 Years

2021 ◽  
Author(s):  
Young-Keol Cho ◽  
Jung-Eun Kim ◽  
Brian Foley
Keyword(s):  
Direct Sequencing ◽  
Sequence Length ◽  
Coding Region ◽  
Rt Pcr ◽  
Variable Regions ◽  
Subtype B ◽  
Combined Antiretroviral Therapy ◽  
Signature Pattern ◽  
Hiv 1 ◽  
Over Time

We aimed to investigate whether the sequence length of HIV-1 increases over time. A longitudinal analysis of full-length coding region sequences (FLs) during an HIV-1 outbreak among pa-tients with hemophilia and local controls infected with the Korean subclade B of HIV-1 (KSB) was performed. Genes were amplified by overlapping RT-PCR or nested PCR and subjected to direct sequencing. Overall, 141 FLs were sequentially determined over 30 years in 62 KSB-infected patients. Phylogenetic analysis indicated that within KSB, two FLs from plasma donors O and P comprised two clusters together with 8 and 12 patients with hemophilia, respectively. Signature pattern analysis for the KSB of HIV-1 revealed 91 signature nucleotide residues (1.05%). In total, 48 and 43 signature nucleotides originated from clusters O and P, respectively. Only six positions contained 100% specific nucleotide(s) in clusters O and P. Additionally, in-depth FL analysis over 30 years indicates that the KSB FL significantly increased over time before combined antiretroviral therapy (cART) and decreased with cART. The increase occurred due to a significant increase in env and nef genes, originating in the variable regions of both genes. The increase in the sequence length of HIV-1 over time suggests that it has an evolutionary direction.

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