OBJECTIVE(S): Dual HIV-1 utilizes cellular CCR5 and CXCR4 coreceptors to enter host cells. Recent studies indicate that the ability of these viruses to use both coreceptors varies significantly in cell lines expressing CXCR4 or CCR5; however, it is not clear whether differences in coreceptor mediated infection in vitro reflect infection of primary cells in vivo. METHODS: We evaluated coreceptor usage of dual envelope clones from patient viruses using a single-cycle pseudovirus assay conducted in cell lines and a replication-competent assay performed using peripheral blood mononuclear cells. Dual envelope clones were selected and classified into three groups, R5>X4, R5 approximately X4, and X4>R5, based on their ability to mediate entry by using CXCR4 and CCR5 in a pseudovirus assay. RESULTS: We observed a high degree of concordance between measurements of coreceptor-mediated entry in pseudovirus and peripheral blood mononuclear cell assays. R5>X4 viruses were efficiently inhibited by a CCR5 antagonist, but not a CXCR4 antagonist, whereas X4>R5 viruses were efficiently inhibited by a CXCR4 antagonist, but not a CCR5 antagonist. R5 approximately X4 viruses were not inhibited, or only partially inhibited, by either a CCR5 or a CXCR4 antagonist alone. CONCLUSIONS: These observations indicate that measurements of coreceptor use determined using pseudoviruses and coreceptor-expressing cell lines are generally concordant with the results obtained using replication-competent assays and peripheral blood mononuclear cell. This suggests that a considerable fraction of dual viruses preferentially infect either CCR5 or CXCR4 target cells in vivo. The clinical implications of preferential coreceptor utilization by dual viruses, that is, HIV-1 pathogenesis and response to coreceptor antagonists, require additional studies.
OBJECTIVE(S): Dual HIV-1 utilizes cellular CCR5 and CXCR4 coreceptors to enter host cells. Recent studies indicate that the ability of these viruses to use both coreceptors varies significantly in cell lines expressing CXCR4 or CCR5; however, it is not clear whether differences in coreceptor mediated infection in vitro reflect infection of primary cells in vivo. METHODS: We evaluated coreceptor usage of dual envelope clones from patient viruses using a single-cycle pseudovirus assay conducted in cell lines and a replication-competent assay performed using peripheral blood mononuclear cells. Dual envelope clones were selected and classified into three groups, R5>X4, R5 approximately X4, and X4>R5, based on their ability to mediate entry by using CXCR4 and CCR5 in a pseudovirus assay. RESULTS: We observed a high degree of concordance between measurements of coreceptor-mediated entry in pseudovirus and peripheral blood mononuclear cell assays. R5>X4 viruses were efficiently inhibited by a CCR5 antagonist, but not a CXCR4 antagonist, whereas X4>R5 viruses were efficiently inhibited by a CXCR4 antagonist, but not a CCR5 antagonist. R5 approximately X4 viruses were not inhibited, or only partially inhibited, by either a CCR5 or a CXCR4 antagonist alone. CONCLUSIONS: These observations indicate that measurements of coreceptor use determined using pseudoviruses and coreceptor-expressing cell lines are generally concordant with the results obtained using replication-competent assays and peripheral blood mononuclear cell. This suggests that a considerable fraction of dual viruses preferentially infect either CCR5 or CXCR4 target cells in vivo. The clinical implications of preferential coreceptor utilization by dual viruses, that is, HIV-1 pathogenesis and response to coreceptor antagonists, require additional studies.
Authors: Timothy J Henrich; Paul J McLaren; Suhas S P Rao; Nina H Lin; Emily Hanhauser; Francoise Giguel; Roy M Gulick; Heather Ribaudo; Paul I W de Bakker; Daniel R Kuritzkes Journal: Open Forum Infect Dis Date: 2014-05-22 Impact factor: 3.835