Concordance of HIV Type 1 Tropism Phenotype to Predictions Using Web-Based Analysis of V3 Sequences: Composite Algorithms May Be Needed to Properly Assess Viral Tropism

Cabral, Gabriela Bastos; Ferreira, João Leandro de Paula; Coelho, Luana Portes Osório; Fonsi, Mylva; Estevam, Denise Lotufo; Cavalcanti, Jaqueline Souza; Brígido, Luis Fernando de Macedo

doi:10.1089/aid.2011.0251

Cited by 6 publications

(6 citation statements)

References 14 publications

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“…Geno2Pheno[coreceptor FPR:10-20%], [8] and WebPSSM X4R5 [10] were highly concordant 88% (95%CI 79%-90%), in line with previous studies which demonstrated the best concordance (>85%) between these 2 algorithms. [32][33][34] There was poor agreement among the WebPSSM matrixes: X4R5, SINSI, and SINSI C at 52% due to overestimation of CXCR4 coreceptor usage by WebPSSM SINSI_C which was trained on subtype C which were under-represented in this study. [35] The global distribution and genetic complexity of HIV-1 subtypes and circulating recombinant forms (CRFs) have continued to evolve, exhibiting altered transmissibility, cellular tropism, kinetics of viral replication, and disease progression.…”

Section: Discussionmentioning

confidence: 63%

Net charge and position 22 of the V3 loop are associated with HIV-1 tropism in recently infected female sex workers in Nairobi, Kenya

et al. 2022

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Human immunodeficiency virus (HIV) infection affects around 37 million people worldwide, and in Kenya, key populations especially female sex workers (FSW), are thought to play a substantial role in the wider, mostly heterosexual HIV-1 transmission structure. Notably, HIV tropism has been found to correlate with HIV-1 transmission and disease progression in HIV-infected patients. In this study, recently infected FSWs from Nairobi, Kenya, were assessed for HIV tropism and the factors related to it. We used a crosssectional study design to analyze 76 HIV-1 positive plasma samples obtained from FSWs enrolled in sex worker outreach program clinics in Nairobi between November 2020 and April 2021. The effects of clinical, demographic, and viral genetic characteristics were determined using multivariable logistic regression. HIV-1 subtype A1 accounted for 89.5% of all cases, with a prevalence of CXCR4-tropic viruses of 26.3%. WebPSSMR5X4 and Geno2Pheno [G2P:10-15% false positive rate] showed high concordance of 88%. Subjects infected with CXCR4-tropic viruses had statistically significant lower baseline CD4 + T-cell counts than those infected with CCR5-tropic viruses (P = .044). Using multivariable logistic regression and adjusting for potential confounders, we found that net charge, the amino acid at position 22 of the V3 loop, and the geographic location of the subject were associated with tropism. A unit increase in V3 loop's net-charge increased the odds of a virus being CXCR4-tropic by 2.4 times (OR = 2.40, 95%CI = 1.35-5.00, P = .007). Second, amino acid threonine at position 22 of V3 loop increased the odds of a strain being X4 by 55.7 times compared to the alanine which occurred in CCR5-tropic strains (OR = 55.7, 95%CI = 4.04-84.1, P < .003). The Kawangware sex worker outreach program clinic was associated with CXCR4-tropic strains (P = .034), but there was there was no evidence of a distinct CXCR4-tropic transmission cluster. In conclusion, this study revealed a high concordance of WebPSSMR5X4 and Geno2Pheno in predicting HIV tropism. The most striking finding was that amino acid position 22 of the V3 loop is linked to tropism in HIV-1 subtype A1. Additional studies with a large dataset are warranted to confirm our findings.Abbreviations: CCR5 = C-C motif chemokine receptor 5, CXCR4 = CXCR4 C-X-C motif chemokine receptor 4, env = envelope gene, FPR = false positive rate, G2P = geno2pheno, FSW = female sex worker; HIV-1 = human immunodeficiency virus type 1, PSSM = position specific scoring matrix, SWOP = sex work outreach program, V3 = third variable region of gp120.

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Section: Discussionmentioning

confidence: 63%

Net charge and position 22 of the V3 loop are associated with HIV-1 tropism in recently infected female sex workers in Nairobi, Kenya

et al. 2022

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“…Although overestimation can occur with use of a single algorithm , a combination of Geno2Pheno (false positive rate = 5%) and PSMM reportedly improves specificity . In the future, confirmation by phenotypic assays needs to be developed; this would further incorporate intermediate transitional dual/mixed‐tropic (CXCR4 and/or CCR5) virus .…”

Section: Discussionmentioning

confidence: 99%

After 18 months of antiretroviral therapy, total HIV DNA decreases more pronouncedly in patients infected by CRF01_AE than in those infected by subtype B and CRF07_BC

Jiao

et al. 2018

Microbiology and Immunology

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Whether the amount of HIV DNA is associated with the subtype of HIV-1 after antiretroviral therapy (ART) has not been reported. In the present study, the amount of HIV DNA and RNA and CD4+T counts in blood and semen prior to and after 18 months of ART were compared in 48 patients infected by CRF01_AE, subtype B or CRF07_BC of HIV-1. Viral RNA was suppressed and CD4 cell count recovery achieved in all patients. The level of HIV DNA were similar before ART; however, patients with CRF01_AE had less HIV DNA after ART than those with subtype B and CRF07_BC infection. According to prediction of co-receptor usage by Geno2Pheno and PSSM in combination, more than 35.6% of clones for CRF01_AE were predicted as CXCR4-using before ART, whereas less than 6% of those for subtype B and CRF07_BC were predicted as CXCR4-using. After 18 months of ART, no CXCR4-using clones were predicted in any of the subtypes. Despite more HIV RNA and fewer CD4 + T cells in patients with CRF01_AE before therapy, no significant differences (P > 0.05) in viral RNA or CD4 cell counts were observed between the subtypes after 18 months of ART. Thus, 18 months of antiretroviral therapy was more efficient in patients with CRF01_AE. Considering that successful ART dramatically reduces the viral load in both blood and semen, risks of sexual transmission of HIV were reduced, contributing to prevention of rapid spread of HIV among men who have sex with men in the region.

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“…In fact, this is the main reason for a certain inherent limitation of any genotypic prediction of an HIV tropism. Nevertheless, clinical comparisons have clearly demonstrated that for the vast majority of cases, genotyping and phenotypic methods are in quite good agreement, particularly for R5-tropic virus (25,42). In an HTA approach, the degree of matching between patient-derived virus and the known sequence probes defines discrete migration zones.…”

Section: Resultsmentioning

confidence: 99%

“…The apparent complexity of the subject is exemplified in a recent publication by Cabral et al, who compared genotypic methods with Trofile as the phenotypic standard and concluded that "composite algorithms may be needed" for predictively assessing the viral tropism when only V3 sequences are analyzed (25). Comparative studies of the commercial genotypic test with the validated Trofile assay found the SensiTrop test to be inferior in identifying CXCR4 tropism in clinical specimens.…”

mentioning

confidence: 99%

A Diagnostic HIV-1 Tropism System Based on Sequence Relatedness

et al. 2015

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dKey clinical studies for HIV coreceptor antagonists have used the phenotyping-based Trofile test. Meanwhile various simplerto-do genotypic tests have become available that are compatible with standard laboratory equipment and Web-based interpretation tools. However, these systems typically analyze only the most prominent virus sequence in a specimen. We present a new diagnostic HIV tropism test not needing DNA sequencing. The system, XTrack, uses physical properties of DNA duplexes after hybridization of single-stranded HIV-1 env V3 loop probes to the clinical specimen. Resulting "heteroduplexes" possess unique properties driven by sequence relatedness to the reference and resulting in a discrete electrophoretic mobility. A detailed optimization process identified diagnostic probe candidates relating best to a large number of HIV-1 sequences with known tropism. From over 500 V3 sequences representing all main HIV-1 subtypes (Los Alamos database), we obtained a small set of probes to determine the tropism in clinical samples. We found a high concordance with the commercial TrofileES test (84.9%) and the Web-based tool Geno2Pheno (83.0%). Moreover, the new system reveals mixed virus populations, and it was successful on specimens with low virus loads or on provirus from leukocytes. A replicative phenotyping system was used for validation. Our data show that the XTrack test is favorably suitable for routine diagnostics. It detects and dissects mixed virus populations and viral minorities; samples with viral loads (VL) of <200 copies/ml are successfully analyzed. We further expect that the principles of the platform can be adapted also to other sequence-divergent pathogens, such as hepatitis B and C viruses. The predominant virus variant in early stages of the clinical manifestation of disease, CCR5-tropic HIV, is found in approximately 80% of treatment-naive patients (1, 2). Although this number can vary for the different virus subtypes, the percentage of CXCR4-tropic HIV isolates is generally low and tends to rise with disease progression (3-6). Nevertheless, the fraction of CCR5-tropic viruses in clinical specimens continues to stay at Ͼ50% throughout the course of infection (7,8). As such, the molecular interactions between the viral envelope and the cellular chemokine receptor CCR5 were recognized as potentially attractive targets for drug development and have yielded compounds and drugs able to specifically block CCR5-tropic HIV (9-11). It is this selectivity of the inhibition of one (CCR5) and not the other (CXCR4) viral coreceptor that necessitates tropism testing prior to prescribing drugs of this particular class. Although the chemokine receptor binding site in the HIV envelope is constituted mainly by the V3 loop, the V1/V2 regions, and the C4 conserved region in the HIV protein gp120, coreceptor tropism is dictated predominantly by amino acid sequences of the V3 region (12, 13). But also sequences of other variable env regions can contribute as secondary sites to the viral tropism (14-17).Initially, all...

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Concordance of HIV Type 1 Tropism Phenotype to Predictions Using Web-Based Analysis of V3 Sequences: Composite Algorithms May Be Needed to Properly Assess Viral Tropism

Cited by 6 publications

References 14 publications

Net charge and position 22 of the V3 loop are associated with HIV-1 tropism in recently infected female sex workers in Nairobi, Kenya

Net charge and position 22 of the V3 loop are associated with HIV-1 tropism in recently infected female sex workers in Nairobi, Kenya

After 18 months of antiretroviral therapy, total HIV DNA decreases more pronouncedly in patients infected by CRF01_AE than in those infected by subtype B and CRF07_BC

A Diagnostic HIV-1 Tropism System Based on Sequence Relatedness

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