Background:  Previous studies have shown that CD4⁺ T cell depletion in simian immunodeficiency virus (SIV) is more rapid and dramatic at mucosal sites where viral replication is higher than in peripheral blood. Among these sites, the oral mucosa is particularly susceptible to secondary infection and pathogenesis. While research has been focused on treatment strategies to combat opportunistic microbial invasions, the molecular character of host response and mechanisms that lead to pathogenesis of the local environment remain poorly understood. To determine the characteristics and kinetics of the manifestation of pathologies in the oral cavity, we have investigated changes in T-cell homeostasis, morphology, and host gene expression in the oropharynx during SIV infection in treated and untreated macaques.

Methods:  Colony-bred rhesus macaques from the California National Primate Research Center were intravenously infected with SIV_mac251. Animals receiving ART began receiving therapy (PMPA and emtricitabine [FTC]) at 1 week post-infection. Oropharyngeal tissue samples were obtained at the indicated stage of SIV infection. Oropharyngeal morphology was assessed following H&E staining. T-cell subsets were measured by flow cytometry. Fluorescence-based immunohistochemistry was used to directly assess the quantities of CD4⁺ and CD8⁺ T cells in oropharynx fresh frozen tissue sections. Host and SIV specific gene expression was monitored by DNA microarray analysis.

Results:  We found that SIV was actively replicating in the oropharynx in the primary acute stage of infection, as well as in chronic stage in animals not receiving ART. CD4⁺ T cells were depleted and innate and adaptive immune responses appeared hyper-activated in the absence of therapy. After 30 weeks of therapy, we detected decreased expression of cytotoxicity and inflammatory response-associated genes. Although innate response factors were, in general, normalized in the presence of ART, expression of beta defensins remained repressed. Genes regulating tissue and muscle growth and muscular functions were dramatically down-regulated in both primary and chronic stage infection.

Conclusions:  We conclude that SIV is rapidly disseminated to mucosal sites, including the oropharynx, early in primary acute infection and that ongoing viral replication and hyper-activated host immune responses may rapidly lead to pathological tissue damage, disruption of function in the oropharyngeal compartment, and susceptibility to secondary infection.