HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors

Poveda, Eva; Briz, Verónica; Quiñones‐Mateu, Miguel E.; Soriano, Vincent

doi:10.1097/01.aids.0000233569.74769.69

Cited by 77 publications

(71 citation statements)

References 75 publications

(73 reference statements)

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“…HIV-1 was then classified, according to its coreceptor usage or tropism, as a CCR5-or CXCR4-tropic virus (R5 or X4, respectively), while HIV-1 strains able to use both coreceptors were termed dual tropic (R5/ X4) (6). Since then, HIV-1 coreceptor tropism has been associated with virus transmission and disease progression, i.e., R5 variants are commonly associated with the establishment of infection (7)(8)(9), while X4 variants seem to emerge in later disease stages and have been linked to a more rapid CD4 ϩ T-cell depletion and progression to AIDS (10)(11)(12).…”

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confidence: 99%

“…Given their mechanism of action, treatment with CCR5 antagonists requires the prior knowledge of the HIV-1 coreceptor tropism in the patient (12,15). Phenotypic assays usually involve the generation of patientderived env recombinant viruses to determine their ability to infect reporter cell lines expressing HIV-1 receptors and coreceptors (16)(17)(18), while others are based in the quantification of cell-to-cell fusion events (19,20).…”

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confidence: 99%

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Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism

Weber

Vázquez²,

Winner³

et al. 2013

J Clin Microbiol

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Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism

Weber

Vázquez²,

Winner³

et al. 2013

J Clin Microbiol

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“…In addition to the relationship between coreceptor use and HIV pathogenesis, the interest in HIV tropism has recently been raised because of the introduction of CCR5 antagonists in the HIV armamentarium. Two agents, maraviroc and vicriviroc, are the agents within this family in the latest steps of clinical development (25,36). Since these drugs show activity against R5 viruses only, viral tropism testing should be made before their prescription and eventually during treatment in order to exclude the presence of X4 viruses.…”

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confidence: 99%

“…Moreover, positions outside the V3 loop may also influence viral tropism (21). More importantly, most genotypic predictors have been designed based on the genetic characteristics of HIV-1 clade B (25,33). Since non-B subtypes show a wide genetic variability in the V3 region and since X4 viruses might be more prevalent in some clades than others (1,17,22,34,35), there is an urgent need to know the reliability of genotypic tools for inferring HIV-1 tropism in non-B subtypes, especially in regions where these HIV-1 variants are quite prevalent and may soon have access to CCR5 antagonists.…”

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Evaluation of Eight Different Bioinformatics Tools To Predict Viral Tropism in Different Human Immunodeficiency Virus Type 1 Subtypes

et al. 2008

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Human immunodeficiency virus type 1 (HIV-1) tropism can be assessed using phenotypic assays, but this is quite laborious, expensive, and time-consuming and can be made only in sophisticated laboratories. More accessible albeit reliable tools for testing of HIV-1 tropism are needed in view of the prompt introduction of CCR5 antagonists in clinical practice. Bioinformatics tools based on V3 sequences might help to predict HIV-1 tropism; however, most of these methods have been designed by taking only genetic information derived from HIV-1 subtype B into consideration. The aim of this study was to evaluate the performances of several genotypic tools to predict HIV-1 tropism in non-B subtypes, as data on this issue are scarce. Plasma samples were tested using a new phenotypic tropism assay (Phenoscript-tropism; Eurofins), and results were compared with estimates of coreceptor usage using eight different genotypic predictor softwares (Support Vector Machine [SVM], C4.5, C4.5 with positions 8 to 12 only, PART, Charge Rule, geno2pheno coreceptor, Position-Specific Scoring Matrix X4R5 [PSSM X4R5 ], and PSSM sinsi ). A total of 150 samples were tested, with 115 belonging to patients infected with non-B subtypes and 35 drawn from subtype B-infected patients, which were taken as controls. When non-B subtypes were tested, the concordances between the results obtained using the phenotypic assay and distinct genotypic tools were as follows: 78.8% for SVM, 77.5% for C4.5, 82.5% for C4.5 with positions 8 to 12 only, 82.5% for PART, 82.5% for Charge Rule, 82.5% for PSSM X4R5 , 83.8% for PSSM sinsi , and 71.3% for geno2pheno. When clade B viruses were tested, the best concordances were seen for PSSM X4R5 (91.4%), PSSM sinsi (88.6%), and geno2pheno (88.6%). The sensitivity for detecting X4 variants was lower for non-B than for B viruses, especially in the case of PSSM sinsi (38.4% versus 100%, respectively), SVM wetcat (46% versus 100%, respectively), and PART (30% versus 90%, respectively). In summary, while inferences of HIV-1 coreceptor usage using genotypic tools seem to be reliable for clade B viruses, their performances are poor for non-B subtypes, in which they particularly fail to detect X4 variants.

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“…For the fusion inhibitor part of the chimeric protein, we chose the C-peptide C37. C37 and the nearly identical C34 are well characterized C-peptides and are highly effective at nanomolar concentrations in vitro (4,12,22,25,26). It has also been shown that covalently linking C34 to a range of unrelated proteins did not diminish their anti-HIV activity, and in one case the linked C-peptide showed a longer in vivo lifetime (27,28).…”

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Highly Potent Chimeric Inhibitors Targeting Two Steps of HIV Cell Entry

Zhao

Mankowski

Snyder

et al. 2011

Journal of Biological Chemistry

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Blocking HIV-1 cell entry has long been a major goal of anti-HIV drug development. Here, we report a successful design of two highly potent chimeric HIV entry inhibitors composed of one CCR5-targeting RANTES (regulated on activation normal T cell expressed and secreted) variant (5P12-RANTES or 5P14-RANTES (Gaertner, H., Cerini, F., Escola, J. M., Kuenzi, G., Melotti, A., Offord, R., Rossitto-Borlat, I., Nedellec, R., Salkowitz, J., Gorochov, G., Mosier, D., and Hartley, O. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 17706 -17711)) linked to a gp41 fusion inhibitor, C37. Chimeric inhibitors 5P12-linker-C37 and 5P14-linker-C37 showed extremely high antiviral potency in single cycle and replication-competent viral assays against R5-tropic viruses, with IC 50 values as low as 0.004 nM. This inhibition was somewhat strain-dependent and was up to 100-fold better than the RANTES variant alone or in combination with unlinked C37. The chimeric inhibitors also fully retained the antiviral activity of C37 against X4-tropic viruses, and this inhibition can be further enhanced significantly if the target cell co-expresses CCR5 receptor. On human peripheral blood mononuclear cells, the inhibitors showed very strong inhibition against R5-tropic Ba-L strain and X4-tropic IIIB strain, with IC 50 values as low as 0.015 and 0.44 nM, which are 45-and 16-fold better than the parent inhibitors, respectively. A clear delivery mechanism requiring a covalent linkage between the two segments of the chimera was observed and characterized. Furthermore, the two chimeric inhibitors are fully recombinant and are easily produced at low cost. These attributes make them excellent candidates for anti-HIV microbicides. The results of this study also suggest a potent approach for optimizing existing HIV entry inhibitors or designing new inhibitors.Approximately 33 million people are living with HIV, and millions more are infected each year.2 There is currently no vaccine, and treatments usually involve inhibiting viral activity post-infection by inhibiting the HIV protease or reverse transcriptase. More recently, therapies that target other parts of the viral life cycle have been approved, including an HIV integrase inhibitor (3).One of the most promising areas in the fight against HIV/ AIDS has been the development of entry inhibitors, which generally bind to either the viral surface or the human cell surface to stop HIV before it can enter a cell. The HIV surface protein gp120 first makes contact with the human cell surface protein CD4, which causes a conformational rearrangement in gp120, allowing the protein to then bind its co-receptor on the cell surface (either the chemokine receptor CCR5 or CXCR4). During this process, the HIV protein gp41 is exposed, and its fusion peptide enters the cell surface. Toward the end of the infection process, the C-terminal helical trimer folds over to contact the N-terminal trimer of gp41, forming a 6-helix bundle that likely pulls the membranes of the two entities in closer proximity to assist fusion of the vir...

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HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors

Cited by 77 publications

References 75 publications

Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism

Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism

Evaluation of Eight Different Bioinformatics Tools To Predict Viral Tropism in Different Human Immunodeficiency Virus Type 1 Subtypes

Highly Potent Chimeric Inhibitors Targeting Two Steps of HIV Cell Entry

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