Differences in molecular evolution between switch (R5 to R5X4/X4-tropic) and non-switch (R5-tropic only) HIV-1 populations during infection

Mild, Mattias; Kvist, Anders; Esbjörnsson, Joakim; Karlsson, Ingrid; Fenyõ, Éva Mária; Medstrand, Patrik

doi:10.1016/j.meegid.2009.05.003

Cited by 42 publications

(43 citation statements)

References 38 publications

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“…When evaluating sequences coincident with an R5 phenotype from patients with early-and end-stage disease, we noted that a trend toward the elongation of V2 regions was found in L-R5 sequences. This finding is consistent with the possibility that the V2 region length influences virus coreceptor usage (14,17). In our experience, the increase in V2 length appeared to be linked to insertions at position 186, thereby contributing new information to the controversy of whether the accumulation of insertions in V2 (HXB positions 185 to 189) is related to either phenotype changes or disease progression (12).…”

Section: Discussionsupporting

confidence: 89%

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

Monno

Saracino

Scudeller

et al. 2011

Antimicrob Agents Chemother

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HIV 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.Based on coreceptor usage, HIV-1 isolates currently are classified as R5 tropic (using only the CCR5 receptor to enter cells), X4 tropic (using only CXCR4), and dual/mixed (DM) (able to use both coreceptor types). Maraviroc (MVC), the only currently licensed CCR5 antagonist, is ineffective in patients harboring non-R5 strains (28), therefore its prescription requires that the presence of R5-tropic virus is ascertained.Until recently, the only recommended method for tropism determination was by phenotypic assay (Trofile; Monogram Biosciences), which has been extensively used to provide tropism information in MVC clinical trials (6, 11). Trofile is a recombinant virus assay in which a pseudovirus is generated from the full-length env gene amplified from the patient's virus population and subsequently used to infect U87 cell lines expressing either the CXCR4 or CCR5 receptor on their surfaces. A new version of the test (enhanced-sensitivity Trofile assay [ESTA]) with a 0.3% sensitivity for X4 variants (24) was made available in 2008; however, the Trofile assay is not suitable for routine patient care. In fact, the assay is expensive and labor-intensive and is performed in only a single reference laboratory in the United States. Genotypic methods represent a more feasible alternative due to their greater accessibility, lower cost, and fast...

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Section: Discussionsupporting

confidence: 89%

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

Monno

Saracino

Scudeller

et al. 2011

Antimicrob Agents Chemother

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“…Furthermore, while the determination of HIV-1 tropism has focused on the V3 loop, other features of gp120 could influence virus affinity for a particular coreceptor, including N-glycosylation sites and variations in extensions of the V1/V2 region 8,12 . Information on the three-dimensional structure of the V3 loop and clinical and laboratory data from patients, such as T cells counts and viral load, could also substantially improve tropism predictions 19 .…”

Section: Discussionmentioning

confidence: 99%

Determination of Viral Tropism by Genotyping and Phenotyping Assays in Brazilian Hiv-1-Infected Patients

Arruda

Araújo

Martinez

et al. 2014

Rev. Inst. Med. trop. S. Paulo

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The clinical application of CCR5 antagonists involves first determining the coreceptor usage by the infecting viral strain. Bioinformatics programs that predict coreceptor usage could provide an alternative method to screen candidates for treatment with CCR5 antagonists, particularly in countries with limited financial resources. Thus, the present study aims to identify the best approach using bioinformatics tools for determining HIV-1 coreceptor usage in clinical practice. Proviral DNA sequences and Trofile results from 99 HIV-1-infected subjects under clinical monitoring were analyzed in this study. Based on the Trofile results, the viral variants present were 81.1% R5, 21.4% R5X4 and 1.8% X4. Determination of tropism using a Geno2pheno[coreceptor] analysis with a false positive rate of 10% gave the most suitable performance in this sampling: the R5 and X4 strains were found at frequencies of 78.5% and 28.4%, respectively, and there was 78.6% concordance between the phenotypic and genotypic results. Further studies are needed to clarify how genetic diversity amongst virus strains affects bioinformatics-driven approaches for determining tropism. Although this strategy could be useful for screening patients in developing countries, some limitations remain that restrict the wider application of coreceptor usage tests in clinical practice.

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“…30 Studies on subtype B virus have shown that the number of potential N-linked glycosylation sites increased significantly over time in individuals who do not switch from R5 to X4, whereas no change was observed for those who switched. 31 Since glycans are an important part of the viral defense against antibodies, it is possible that the difference in evolution of potential N-linked glycosylation sites may reflect differences in antibody responses directed toward switching and nonswitching populations. 32 These data show that HIV-1 R5 coreceptor usage is the most predominant genotype among pregnant women and is associated with a highly conserved GPGQ crown motif and glycosylation site.…”

Section: Discussionmentioning

confidence: 99%

Genotypic Analysis of Human Immunodeficiency Virus Type 1envV3 Loop Sequences: Bioinformatics Prediction of Coreceptor Usage Among 28 Infected Mother–Infant Pairs in a Drug-Naive Population

Duri

Soko²,

Gumbo³

et al. 2011

AIDS Research and Human Retroviruses

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We sought to predict virus coreceptor utilization using a simple bioinformatics method based on genotypic analysis of human immunodeficiency virus types 1 (HIV-1) env V3 loop sequences of 28 infected but drug-naive women during pregnancy and their infected infants and to better understand coreceptor usage in vertical transmission dynamics. The HIV-1 env V3 loop was sequenced from plasma samples and analyzed for viral coreceptor usage and subtype in a cohort of HIV-1-infected pregnant women. Predicted maternal frequencies of the X4, R5X4, and R5 genotypes were 7%, 11%, and 82%, respectively. Antenatal plasma viral load was higher, with a mean log(10) (SD) of 4.8 (1.6) and 3.6 (1.2) for women with the X4 and R5 genotypes, respectively, p = 0.078. Amino acid substitution from the conserved V3 loop crown motif GPGQ to GPGR and lymphadenopathy were associated with the X4 genotype, p = 0.031 and 0.043, respectively. The maternal viral coreceptor genotype was generally preserved in vertical transmission and was predictive of the newborn's viral genotype. Infants born to mothers with X4 genotypes were more likely to have lower birth weights relative to those born to mothers with the R5 genotype, with a mean weight (SD) of 2870 (±332) and 3069 (±300) g, respectively. These data show that at least in HIV-1 subtype C, R5 coreceptor usage is the most predominant genotype, which is generally preserved following vertical transmission and is associated with the V3 GPGQ crown motif. Therefore, antiretroviral-naive pregnant women and their infants can benefit from ARV combination therapies that include R5 entry inhibitors following prediction of their coreceptor genotype using simple bioinformatics methods.

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Differences in molecular evolution between switch (R5 to R5X4/X4-tropic) and non-switch (R5-tropic only) HIV-1 populations during infection

Cited by 42 publications

References 38 publications

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

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

Determination of Viral Tropism by Genotyping and Phenotyping Assays in Brazilian Hiv-1-Infected Patients

Genotypic Analysis of Human Immunodeficiency Virus Type 1envV3 Loop Sequences: Bioinformatics Prediction of Coreceptor Usage Among 28 Infected Mother–Infant Pairs in a Drug-Naive Population

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