Recombinant CXCR4/CCR5 hybrid receptors as tools for studies of HIV-1 receptor usage
type: CreativeWork
description: The chemokine receptors CCR5 and CXCR4 are required, together with CD4, for the entry of HIV-1 into target cells. CCR5 using HIV-1 dominates during transmission and the asymptomatic phase of infection. During progression, virus phenotypes with the ability to use CXCR4 emerge in about 50% of infected individuals. Individuals continuously harbouring CCR5-restricted isolates still progress to AIDS. Differences among CCR5 using isolates, has been found and an evolution towards an altered mode of CCR5 coreceptor use and a reduced sensitivity to inhibition by natural CCR5 ligands has also been described. With the aim to study interactions of natural ligands and HIV-1 isolates with these chemokine receptors, a set of hybrid CXCR4/CCR5 receptors were constructed. Signalling response to their respective natural ligands, SDF-1 and RANTES were studied and prototypic R5 and X4 isolates (HIV-1BaL and HIV-1IIIB) were tested for their ability to use these chimeric receptors. The results showed that ligands and virus use different receptor epitopes which, in turn, vary between the two receptors. Further, the evolution of primary HIV-1 isolates was studied. A total of 246 sequential primary HIV-1 isolates were studied. Using our chimeric CXCR4/CCR5 receptors, we showed that R5 isolates from immunosuppressed individuals are distinct from those isolated from individuals with higher CD4+ T-cell counts, with regards to coreceptor usage. The analysis also showed that the ability to utilize chimeric receptors correlated inversely with the sensitivity to RANTES inhibition of infection. The R5 isolates used receptor chimeras to various degrees. Based on these results, the R5 viruses could be subdivided into two groups: the R5narrow phenotype and the R5broad phenotype. The R5narrow phenotype is defined as viruses that use wt CCR5 but no chimeric receptors, whereas viruses using at least one chimeric receptor in addition to CCR5, are designated R5broad viruses. The mode of coreceptor use by p…
abstract: The chemokine receptors CCR5 and CXCR4 are required, together with CD4, for the entry of HIV-1 into target cells. CCR5 using HIV-1 dominates during transmission and the asymptomatic phase of infection. During progression, virus phenotypes with the ability to use CXCR4 emerge in about 50% of infected individuals. Individuals continuously harbouring CCR5-restricted isolates still progress to AIDS. Differences among CCR5 using isolates, has been found and an evolution towards an altered mode of CCR5 coreceptor use and a reduced sensitivity to inhibition by natural CCR5 ligands has also been described. With the aim to study interactions of natural ligands and HIV-1 isolates with these chemokine receptors, a set of hybrid CXCR4/CCR5 receptors were constructed. Signalling response to their respective natural ligands, SDF-1 and RANTES were studied and prototypic R5 and X4 isolates (HIV-1BaL and HIV-1IIIB) were tested for their ability to use these chimeric receptors. The results showed that ligands and virus use different receptor epitopes which, in turn, vary between the two receptors. Further, the evolution of primary HIV-1 isolates was studied. A total of 246 sequential primary HIV-1 isolates were studied. Using our chimeric CXCR4/CCR5 receptors, we showed that R5 isolates from immunosuppressed individuals are distinct from those isolated from individuals with higher CD4+ T-cell counts, with regards to coreceptor usage. The analysis also showed that the ability to utilize chimeric receptors correlated inversely with the sensitivity to RANTES inhibition of infection. The R5 isolates used receptor chimeras to various degrees. Based on these results, the R5 viruses could be subdivided into two groups: the R5narrow phenotype and the R5broad phenotype. The R5narrow phenotype is defined as viruses that use wt CCR5 but no chimeric receptors, whereas viruses using at least one chimeric receptor in addition to CCR5, are designated R5broad viruses. The mode of coreceptor use by p…
author: Antonsson, Liselotte
language: eng
keywords: Basic Medicine, Medicin (människa och djur), evolution, pathogenesis, cerebrospinal fluid, Medicine (human and vertebrates), TAK-779, RANTES, CXCR4, CCR5, coreceptor, GPCR, HIV-1
date published: 2007
date modified: 2026-07-24T03:00:02Z
provider: University of Lund
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Department of Experimental Medical Science, Lund Univeristy