Probiotic Supplementation of ARV Treatment during SIV Infection of Pigtail Macaques Results in Enhanced GI Tract CD4+ T Cell Frequency and Immunological Function
Nichole Klatt*1, L Canary1, X Sun2, C Vinton1, M Perkins1, D Hazuda3, J Lifson4, E Haddad2, J Estes4, and J Brenchley1
1Lab of Molecular Microbio and Prgm in Barrier Immunity and Repair, NIAID, NIH, Bethesda, MD, US; 2Vaccine and Gene Therapy Inst, Port St Lucie, FL, US; 3Merck Res Labs, West Point, PA, US; and 4AIDS and Cancer Virus Prgm, SAIC-Frederick, Inc, NCI-Frederick, MD, US
Background: During progressive HIV/SIV infections, damage to the tight epithelial barrier of the gastrointestinal (GI) tract leads to microbial translocation, which contributes to chronic immune activation and disease progression. Furthermore, while ARV treatment in HIV-infected individuals reduces morbidity and mortality compared to untreated individuals these are still increased compared to uninfected individuals. This increased mortality is associated with inflammation and cardiovascular disease, which is associated with persistent microbial translocation. Thus, restoring the immunological and structural barrier of the GI tract may improve the prognosis of ARV-treated, HIV-infected individuals.
Methods: To improve the structural and immunological barrier of the GI tract, we treated chronically SIVmac239-infected pigtail macaques (PTM) with probiotics in combination with ARV treatment, and compared to chronically SIVmac239-infected PTM treated with ARV alone. Combination ARV therapy included 30mg/kg PMPA, 30mg/kg emtricitabine (FTC) (once daily, s.c.), and 120mg L812, 50mg L564 (twice daily, oral) for an average of 162 days.
Results: We found that, compared to PTM treated with ARV alone, animals given probiotics and ARV had enhanced reconstitution of CD4+ T cells in the colon (p = 0.0286). Furthermore, probiotic treatment decreased the activation of CD4+ T cells in the colon as measured by Ki67 (p = 0.0571) but increased the overall functionality of colon CD4+ T cells as measured by multifunctional cytokine production (p = 0.0590). In addition, gene array of colon leukocytes revealed differential transcriptional regulation of the colon immune system, with specific increases in antigen presenting cell (APC) related-genes. Consistent with this, we observed increased functionality of APC, including increased interleukin-23 (IL-23) production (p = 0.0286) in probiotic-treated animals.
Conclusions: Here we demonstrate that combination treatment with ARV and probiotics enhances mucosal immunity. Thus, use of probiotics for HIV-infected individuals may enhance GI health and improve their long-term prognosis.