Gut epithelial barrier and systemic inflammation during chronic HIV infection.
OBJECTIVE
Microbial translocation and innate immune action characterize HIV infection. Continued gut mucosal dysfunction during treatment and its relationship to CD4 T-cell recovery has not been well described.


METHODS
A cross-sectional study was performed of antiretroviral therapy (ART)-suppressed (immunologic responders with CD4 > 500 cells/μl and immunologic nonresponders with CD4 < 350 cells/μl), untreated HIV-infected, and seronegative participants consenting to gut biopsies and a blood draw.


METHODS
Neutrophil infiltration as a surrogate response to epithelial breach, colorectal epithelial proliferation as a measure of repair, and mucosal apoptosis by immunohistochemistry were determined in gut biopsies. Plasma markers of monocyte activation (sCD14), immune activation (interleukin-6), and indoleamine 2,3-dioxygenase-1 activity (plasma kynurenine/tryptophanratio) were concurrently measured.


RESULTS
Each HIV-infected group had greater neutrophil infiltration than controls. Similarly, untreated HIV-infected participants and ART-suppressed immunologic responders had increased epithelial proliferation compared with controls, but immunologic nonresponders had no appreciable increase in epithelial proliferation despite elevated neutrophil infiltration. The CD4 T-cell count was positively correlated with epithelial proliferation and was modestly negatively correlated with neutrophil infiltration in ART-suppressed patients. Epithelial proliferation was inversely correlated with mucosal apoptosis, and apoptosis was linked to plasma sCD14 and modestly to kynurenine/tryptophan ratio.


CONCLUSIONS
Neutrophil infiltration and mucosal apoptosis remain abnormally high despite ART. Epithelial proliferation increases in HIV, but may be impaired in immunologic nonresponders. Whether mucosal apoptosis is a cause or consequence of epithelial proliferative defects is unclear, but appears to be associated with systemic inflammation. The impact of ART and interventions targeting the gut epithelial barrier in treated HIV infection warrant further investigation.
aDivision of Gastroenterology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, California bAIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland cDivision of Experimental Medicine, Department of Medicine, UCSF, San Francisco, California dDivision of Gastroenterology, Department of Medicine, University of Washington, Washington eDepartment of Epidemiology and Biostatistics fHIV/AIDS Division, Department of Medicine, UCSF, San Francisco, California, USA.
Ma
M
Somsouk
Jacob D
JD
Estes
Claire
C
Deleage
Richard M
RM
Dunham
Rebecca
R
Albright
John M
JM
Inadomi
Jeffrey N
JN
Martin
Steven G
SG
Deeks
Joseph M
JM
McCune
Peter W
PW
Hunt
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002908:Chronic Disease; D003430:Cross-Sectional Studies; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020556:Neutrophil Infiltration
C576710:IDO1 protein, human; C508600:IL6 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors