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Background:  To compare coreceptor use and macrophage tropism of sequential SIV_sm reisolates in relation to the severity of SIV_sm infection, following intravenous or intrarectal inoculation of cynomolgus macaques.

Methods:</s>  Cynomolgus macaques were infected with SIV_sm (sooty mangabey origin) either by the intravenous or intrarectal route. The monkeys were monitored for general clinical status. Samples for virus isolation, and number of circulating CD4⁺ cells were collected at regular intervals after infection. The animals were kept until development of symptoms of AIDS when they were euthanized. Co-receptor use of sequential reisolates was tested in the GHOST(3) cell lines, expressing the CD4 receptor and one of the chemokine receptors CCR3, CCR5, CXCR4, CXCR6 (former STRL33/BONZO/TYMSTR), or the orphan receptor BOB/GPR15. Macrophage tropism was determined in human monocyte derived macrophages (hMDM)

Results:  Out of 30 monkeys, 16 developed immunodeficiency. The animals were divided into three groups based on disease progression, CD4 decline, time of death and, viral load. These three groups were simian AIDS (SAIDS), slow progressor (SP) and nonprogressor (NP) monkeys.The main co-receptor used by the reisolates was CCR5. In general, early reisolates from all 3 groups were multitropic, using CCR5, CXCR6 and BOB. In contrast, the ability to use many different receptors decreased over time in the slow progressor and especially the nonprogressor group. Interestingly one of the monkeys in the SAIDS group yielded a dualtropic X4X6 isolate, which used the CXCR4 receptor with high efficiency. The inoculum virus and the early reisolates could infect hMDM and established a productive infection. Reisolates from monkeys that developed AIDS or showed slow progression maintained the ability to infect hMDM throughout the follow up 1 to 5 years. Reisolates obtained late in the course of infection from nonprogressing monkeys with the most stable CD4 counts infected macrophages inefficiently or not at all.

Conclusions:  The results indicate a relationship between disease progression and macrophage tropism in SIVsm infection. That macrophage tropism is maintained during progressive disease, but lost in nonprogression, suggests an important role for macrophages in SIV pathogenesis.

Keywords: Macrophage tropism; Simian immunodeficiency virus; Coreceptor use