Control mechanisms of virus replication in naturally SIVsmm infected mangabeys and experimentally infected macaques

As a close cousin to Asian macaques, the African sooty mangabey monkey, a s pecies naturally infected with SIV without ever developing disease, represe nts an intriguing and thought provoking model for the study of lentiviral i nfection and disease development. Pursuant to our previous findings that do cumented the presence of high frequencies of CD8(+-)T-cells capable of inhi biting lentiviral replication in vitro via a soluble factor, the potential contribution of beta-chemokines and their receptor was evaluated in samples from sooty mangabeys and disease susceptible macaques. Both mangabey and R hesus macaque PBMC were found to secrete comparable levels of MIP-1(alpha), MIP-1(beta) and RANTES after stimulation in vitro. Constitutive expression of CCR-5 appeared lower in mangabey PBMC but the vast majority of T-cells from mangabeys or macaques were found to express CCR-5 after in vitro activ ation. Sequence analysis of macaque and mangabey MIP-1(alpha) and RANTES sh owed complete homology to the human counterpart. MIP-1(beta) on the other h and while highly conserved among both monkey species, showed only 93% homol ogy to human MIP-1(beta). In addition, CCR-5, CCR-2b and CXCR-4 presented n o consistent differences between rhesus and mangabey sequences. Thus, based on current data, differences in disease susceptibility between macaques an d mangabeys do not appear to rely on differences in chemokine pathways. How ever, analyses of the ontogeny of CD8(+) T-cell-mediated inhibition of SIV replication showed that macaque PBMC acquire this function shortly after in fection, and show a progressive loss thereafter, correlated with progressio n towards disease. Mangabeys, on the other hand, appear to acquire the CD8( +) T-cell inhibitory function long before any evidence of seroconversion to SIV and maintain this function for the lifetime of the animal. In vitro an alyses of induction of the CD8(+) inhibitory function showed that rhesus CD 8(+) T-cells have the potential to secrete the inhibitory factor(s) prior t o SIV infection. (C) 1999 Elsevier Science B.V. All rights reserved.