Abstract
Vpr is an HIV-1 accessory protein that plays numerous roles during viral replication, and some of which are cell type dependent. To test the hypothesis that HIV-1 tropism extends beyond the envelope into the vpr gene, studies were performed to identify the associations between coreceptor usage and Vpr variation in HIV-1-infected patients. Colinear HIV-1 Env-V3 and Vpr amino acid sequences were obtained from the LANL HIV-1 sequence database and from well-suppressed patients in the Drexel/Temple Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. Genotypic classification of Env-V3 sequences as X4 (CXCR4-utilizing) or R5 (CCR5-utilizing) was used to group colinear Vpr sequences. To reveal the sequences associated with a specific coreceptor usage genotype, Vpr amino acid sequences were assessed for amino acid diversity and Jensen-Shannon divergence between the two groups. Five amino acid alphabets were used to comprehensively examine the impact of amino acid substitutions involving side chains with similar physiochemical properties. Positions 36, 37, 41, 89, and 96 of Vpr were characterized by statistically significant divergence across multiple alphabets when X4 and R5 sequence groups were compared. In addition, consensus amino acid switches were found at positions 37 and 41 in comparisons of the R5 and X4 sequence populations. These results suggest an evolutionary link between Vpr and gp120 in HIV-1-infected patients.
Highlights
HIV-1 entry proceeds via direct interaction between the viral envelope glycoprotein 120 and the host cell CD4 receptor molecule, as well as one of two coreceptor molecules, CCR5 or CXCR4 [1]
Patients enrolled in the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort were recruited from the Partnership Comprehensive Care Practice of the Division of Infectious Diseases and HIV Medicine in the Department of Medicine at Drexel University College of Medicine (Philadelphia, Pennsylvania, USA) and the Center for Clinical and Translational Medicine in the Institute for Molecular Medicine and Infectious Disease
Sequences of clinical origin were derived from blood samples collected from HIV-1-infected patients in the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort [11, 16,17,18, 28, 29]
Summary
HIV-1 entry proceeds via direct interaction between the viral envelope glycoprotein (gp) 120 and the host cell CD4 receptor molecule, as well as one of two coreceptor molecules, CCR5 or CXCR4 [1]. As conformational changes within the V3 loop occur upon the binding of gp120 with CD4, it is possible that the coreceptor usage-associated amino acid residues within other. Patients with HIV-1 infections that are not well suppressed by effective antiretroviral therapy will experience some form of coreceptor switch, in which CXCR4-utilizing (X4) viruses gradually emerge from a predominantly CCR5-utilizing (R5) swarm due to the accumulation of amino acid changes within the V3 loop, at amino acid positions 11 and 25. Coreceptor utilization prediction algorithms can be effectively used to classify Env-V3 sequences computationally, as previously reviewed [6]
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