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Control mechanisms of virus replication in naturally SIVsmm infected mangabeys and experimentally infected macaques
F Villinger1, G T Brice, A Mayne
1Winship Cancer, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. fvillin@emory.edu
Abstract:
As a close cousin to Asian macaques, the African sooty mangabey monkey, a species naturally infected with SIV without ever developing disease, represents an intriguing and thought provoking model for the study of lentiviral infection and disease development. Pursuant to our previous findings that documented the presence of high frequencies of CD8+ T-cells capable of inhibiting 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 Rhesus macaque PBMC were found to secrete comparable levels of MIP-1alpha, MIP-1beta 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 activation. Sequence analysis of macaque and mangabey MIP-1alpha and RANTES showed complete homology to the human counterpart. MIP-1beta on the other hand while highly conserved among both monkey species, showed only 93% homology to human MIP-1beta. In addition, CCR-5, CCR-2b and CXCR-4 presented no consistent differences between rhesus and mangabey sequences. Thus, based on current data, differences in disease susceptibility between macaques and mangabeys do not appear to rely on differences in chemokine pathways. However, analyses of the ontogeny of CD8+ T-cell-mediated inhibition of SIV replication showed that macaque PBMC acquire this function shortly after infection, and show a progressive loss thereafter, correlated with progression 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 analyses of induction of the CD8+ inhibitory function showed that rhesus CD8+ T-cells have the potential to secrete the inhibitory factor(s) prior to SIV infection.
Insights
Sooty mangabeys control SIV infection lifelong via CD8+ T-cells, unlike macaques. This study investigated chemokine pathways and T-cell function in SIV resistance, finding differences in T-cell function, not chemokines, explain disease resistance.
Area of Science:
- Immunology
- Virology
- Primatology
Background:
- Sooty mangabeys are naturally infected with SIV but do not develop disease, making them a valuable model for lentiviral infection studies.
- Previous research indicated high frequencies of CD8+ T-cells inhibiting lentiviral replication in vitro via soluble factors in sooty mangabeys.
- Understanding the role of beta-chemokines and their receptors in SIV resistance is crucial for identifying mechanisms of disease control.
Purpose of the Study:
- To evaluate the potential contribution of beta-chemokines and their receptors in SIV-resistant sooty mangabeys compared to disease-susceptible macaques.
- To investigate the ontogeny and maintenance of CD8+ T-cell-mediated inhibition of SIV replication in both species.
Main Methods:
- Quantification of beta-chemokines (MIP-1alpha, MIP-1beta, RANTES) secreted by PBMC (peripheral blood mononuclear cells) from sooty mangabeys and macaques after in vitro stimulation.
- Analysis of CCR-5 expression on T-cells and sequence analysis of key chemokine genes (MIP-1alpha, RANTES, MIP-1beta, CCR-5, CCR-2b, CXCR-4).
- Assessment of the timing and persistence of CD8+ T-cell inhibitory function against SIV replication in relation to infection and disease progression.
Main Results:
- Comparable levels of MIP-1alpha, MIP-1beta, and RANTES were secreted by both species' PBMC.
- While constitutive CCR-5 expression was lower in mangabeys, T-cells from both species expressed CCR-5 after activation.
- Sequence analyses revealed high homology for most chemokines and receptors between species and to human counterparts, except for MIP-1beta.
- Crucially, sooty mangabeys acquired CD8+ T-cell inhibitory function long before seroconversion and maintained it lifelong, whereas macaques acquired it post-infection with subsequent loss.
Conclusions:
- Differences in disease susceptibility between macaques and sooty mangabeys do not appear to be primarily due to variations in chemokine pathways.
- The lifelong maintenance of CD8+ T-cell-mediated SIV inhibition in sooty mangabeys is a key factor in their natural resistance to lentiviral disease.
- Rhesus macaque CD8+ T-cells possess the intrinsic potential to secrete inhibitory factors prior to SIV infection, suggesting regulatory mechanisms influence long-term control.