Comparative studies on mucosal and intravenous transmission of simian immunodeficiency virus (SIVsm): evolution of coreceptor use varies with pathogenic outcome

Abstract

Coreceptor usage of isolates from 30 cynomolgus macaques infected intrarectally (n=22) or intravenously (n=8) with simian immunodeficiency virus of sooty mangabey origin (SIVsm) was evaluated in U87.CD4 and GHOST(3) cell lines. Based on progression rate, the animals were divided into progressors (18 animals), slow progressors (five animals) and long-term non-progressors (seven animals). There was no difference in how many or which coreceptors were used according to route of infection. All isolates but one used CCR5 for cell entry, and CCR5 was also the major coreceptor in 70 out of 105 isolates tested. In general, early isolates were multitropic, using CCR5, CXCR6 and/or gpr15. Interestingly, CXCR4-using viruses could be isolated on human peripheral blood mononuclear cells (PBMCs), but not on cynomolgus macaque PBMCs, suggesting that human PBMCs select for variants with CXCR4 use. Even though CXCR4-using SIV isolates have been reported rarely, we could recover CXCR4-using viruses from 13 monkeys. CXCR4 use either appeared early during the acute phase of infection and disappeared later or only appeared late in infection during immunodeficiency. Surprisingly, one late isolate from a progressor monkey did not use CCR5 at all and used the CXCR4 receptor with high efficiency. The ability to use many different receptors decreased over time in long-term non-progressor monkeys, whilst the majority of progressor monkeys showed broadening of coreceptor use, stable coreceptor use or fluctuation between the different coreceptor-usage patterns. The results indicate that, in the infected host, evolution of SIV coreceptor usage occurs, involving changes in the mode of coreceptor use.