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Abstract
The V3 loop of human immunodeficiency virus type 1 (HIV-1) is critical for coreceptor binding and is the main determinant of which of the cellular coreceptors, CCR5 or CXCR4, the virus uses for cell entry. The aim of this study is to provide a large-scale data driven analysis of HIV-1 coreceptor usage with respect to the V3 loop evolution and to characterize CCR5- and CXCR4-tropic viral phenotypes previously studied in small- and medium-scale settings. We use different sequence similarity measures, phylogenetic and clustering methods in order to analyze the distribution in sequence space of roughly 1000 V3 loop sequences and their tropism phenotypes. This analysis affords a means of characterizing those sequences that are misclassified by several sequence-based coreceptor prediction methods, as well as predicting the coreceptor using the location of the sequence in sequence space and of relating this location to the CD4+ T-cell count of the patient. We support previous findings that the usage of CCR5 is correlated with relatively high sequence conservation whereas CXCR4-tropic viruses spread over larger regions in sequence space. The incorrectly predicted sequences are mostly located in regions in which their phenotype represents the minority or in close vicinity of regions dominated by the opposite phenotype. Nevertheless, the location of the sequence in sequence space can be used to improve the accuracy of the prediction of the coreceptor usage. Sequences from patients with high CD4+ T-cell counts are relatively highly conserved as compared to those of immunosuppressed patients. Our study thus supports hypotheses of an association of immune system depletion with an increase in V3 loop sequence variability and with the escape of the viral sequence to distant parts of the sequence space.
Highlights
IntroductionThe initial contact between the viral envelope glycoprotein gp120 and the cellular receptor CD4 is followed by a second interaction between gp120 and one of the cellular coreceptors: CCR5 or CXCR4 [2,3]
Host cell entry of human immunodeficiency virus type 1 (HIV-1) is mediated by viral membrane-bound proteins [1]
It has been shown that viruses binding to CCR5 are almost exclusively present during the early asymptomatic stage of the infection whereas CXCR4-binding viruses may emerge in later phases of the infection and are associated with a CD4+ T-cell decline and progression towards AIDS [4]
Summary
The initial contact between the viral envelope glycoprotein gp120 and the cellular receptor CD4 is followed by a second interaction between gp120 and one of the cellular coreceptors: CCR5 or CXCR4 [2,3]. It has been shown that viruses binding to CCR5 are almost exclusively present during the early asymptomatic stage of the infection whereas CXCR4-binding viruses may emerge in later phases of the infection and are associated with a CD4+ T-cell decline and progression towards AIDS [4]. The question whether the emergence of CXCR4 and SI virus is a cause of advanced progression towards CD4+ T-cell depletion and the rise of AIDS symptoms or appears as a result of these phenomena (or both), as well as the evolutionary reasons for the development of these variants remain largely unresolved
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