IL-21 and probiotic therapy improve Th17 frequencies, microbial translocation, and microbiome in ARV-treated, SIV-infected macaques.
Increased mortality in antiretroviral (ARV)-treated, HIV-infected individuals has been attributed to persistent immune dysfunction, in part due to abnormalities at the gastrointestinal barrier. In particular, the poor reconstitution of gastrointestinal Th17 cells correlates with residual translocation of dysbiotic, immunostimulatory microflora across a compromised intestinal epithelial barrier. We have previously demonstrated that oral probiotics promote increased intestinal CD4(+) T-cell reconstitution during ARV treatment in a non-human primate model of HIV infection; however, essential mucosal T-cell subsets, such as Th17 cells, had limited recovery. Here, we sought to promote Th17 cell recovery by administering interleukin (IL)-21 to a limited number of ARV-treated, probiotic-supplemented, Simian Immunodeficiency Virus (SIV)-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs are associated with enhanced polyfunctional Th17 expansion and reduced markers of microbial translocation and dysbiosis as compared with infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared with controls, and was independent of increased immune activation or loss of viral suppression. We propose that combining ARVs with therapeutics aimed at restoring intestinal stasis may significantly improve disease prognosis of ARV-treated, HIV-infected individuals.
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
A M
AM
Ortiz
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.|Department of Biological Sciences, University of the Sciences, Philadelphia, Pennsylvania, USA.
Z A
ZA
Klase
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
S R
SR
DiNapoli
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, California, USA.
I
I
Vujkovic-Cvijin
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
K
K
Carmack
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
M R
MR
Perkins
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
N
N
Calantone
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
C L
CL
Vinton
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
N E
NE
Riddick
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
J
J
Gallagher
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.|Department of Pharmaceutics, Washington National Primate Research Center, University of Washington, Seattle, Washington, USA.
N R
NR
Klatt
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, California, USA.
J M
JM
McCune
AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
J D
JD
Estes
Division of Microbiology and Immunology, Yerkes National Primate Research Center, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
M
M
Paiardini
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
J M
JM
Brenchley
D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D018988:Bacterial Translocation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D064806:Dysbiosis / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology; D000068679:Emtricitabine / Q000494:pharmacology; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000276:immunology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology; D018928:Immunity, Mucosal / Q000187:drug effects; D007378:Interleukins / Q000494:pharmacology*; D008254:Macaca nemestrina; D019936:Probiotics / Q000494:pharmacology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D000068698:Tenofovir / Q000494:pharmacology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology; D000098546:Interleukin-21
D044966:Anti-Retroviral Agents; D007378:Interleukins; D000068698:Tenofovir; D000068679:Emtricitabine; D000098546:Interleukin-21