Background: Simian immunodeficiency virus (SIV) causes a rapid and severe depletion of CD4⁺ T cells in the mucosa. The abundance of activated memory CD4⁺ T cells in the mucosa makes this site highly susceptible to initial infection and viral amplification over other lymphoid sites. During ART, CD4⁺ T cells are quickly restored in blood while the restoration in the mucosa is incomplete. To study the effect of SIV and ART on CD4⁺ T-cell restoration in the mucosa, studies have surveyed 1 mucosal compartment as a model for the entire system. However, the diverse array of mucosal cell types and host responses may make this misleading for generalizations. A comparative study to address the differences among mucosal compartments with respect to viral suppression and variants, host response, and CD4⁺ depletion and restoration is therefore warranted.

Methods:  We infected 10 macaques with 1000 TCID₅₀ of SIV_mac251; then treated 1 group of animals with 9-R-2-phosphonomethoxypropyl adenine (PMPA) and emtricitabine (FTC) (n = 5). Infected untreated control animals (n = 10) and uninfected animals were included for comparison (n = 5). We preformed 13-parameter multicolor flow cytometry, immunohistochemistry, and proviral DNA sequencing. Gene expression patterns were assayed by microarray analysis and real time polymerase chain reaction (RT-PCR). Viral loads were determined by RT-PCR.

Results:  The jejunum and colon of uninfected macaques is composed of central memory (CCR7⁺CD28⁺CD27⁺CD95⁺) and effector memory (CCR7^–CD28^–CD27^–CD95⁺) CD4⁺ T cells. The lung was comprised of the T_EM CD4⁺ T-cell subset. The jejunum and lung had no naïve T cells, while the colon had a significant amount due to the high prevalence of Peyers patches.  At 10 weeks post infection, the jejunum was significantly more depleted (2 to 8%) of CD4⁺ T cells then the colon (13 to 18%) or lung (21 to 30%).  By 30 weeks of ART, the restoration was more complete in the lungs (50 to 60%) than the colon (21 to 40%) or jejunum (8 to 35%). Innate gene expression and inflammation were higher in the lungs than the intestines. Viral gene expression and loads were also different in each compartment.

Conclusions:  The mucosal immune system is significantly impacted by SIV infection leading to sustained CD4⁺ T-cell depletion. However, each compartment of the mucosa is affected differently, emphasizing the need to make careful generalizations about the entire system. The unique cell types and close approximation of naïve cells favors restoration of CD4⁺ T cells in the lung and colon over the jejunum.