TY - JOUR
T1 - Immune correlates of HIV exposure without infection in foreskins of men from Rakai, Uganda
AU - Prodger, Jessica
AU - Hirbod, T.
AU - Kigozi, G.
AU - Nalugoda, F.
AU - Reynolds, Steven James
AU - Galiwango, R.
AU - Shahabi, K.
AU - Serwadda, D.
AU - Wawer, M. J.
AU - Gray, Ronald H
AU - Kaul, R.
N1 - Funding Information:
We would like to acknowledge STTARR at the Toronto MaRS Discovery District for assistance with CD3 image analysis and Mariethe Ehnlund at the Karolinska Institute for technical assistance. Funding was provided by the Bill and Melinda Gates Foundation, grant number 22006.03, and R01AI087409-01A1, UO1AI51171, and 1UO1AI075115-O1A1 from the National Institutes of Health. The study was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
PY - 2014/5
Y1 - 2014/5
N2 - Human immunodeficiency virus (HIV) susceptibility is heterogenous, with some HIV-exposed but seronegative (HESN) individuals remaining uninfected despite repeated exposure. Previous studies in the cervix have shown that reduced HIV susceptibilitymay bemediated by immune alterations in the genitalmucosa.However, immune correlates ofHIVexposure without infection have not been investigated in the foreskin. We collected sub-preputial swabs and foreskin tissue from HESN (n1/420) and unexposed control (n1/457) men undergoing elective circumcision. Blinded investigators assayed swabs for HIV-neutralizing IgA, innate antimicrobial peptides, and cytokine levels. Functional T-cell subsets fromforeskin tissuewere assessed by flowcytometry.HESNforeskins had elevated a-defensins (3,027 vs. 1,795 pgml1,P1/40.011) and HIV-neutralizing IgA(50.0 vs. 13.5%ofmen,P1/40.019).Foreskin tissue fromHESNmen contained a higherdensityofCD3 T cells (151.9 vs. 69.9 cellsmm2, P1/40.018), but a lower proportion of these was Th17 cells (6.12 vs. 8.04%of CD4 Tcells, P1/40.007), and fewer produced tumor necrosis factor a (TNFa) (34.3 vs. 41.8% of CD4 Tcells, P1/40.037; 36.9 vs. 45.7%of CD8 T cells, P1/40.004). A decrease in the relative abundance of susceptible CD4 T cells and local TNFa production, in combinationwithHIV-neutralizing IgAand a-defensins,may represent a protective immunemilieu at a site ofHIVexposure.
AB - Human immunodeficiency virus (HIV) susceptibility is heterogenous, with some HIV-exposed but seronegative (HESN) individuals remaining uninfected despite repeated exposure. Previous studies in the cervix have shown that reduced HIV susceptibilitymay bemediated by immune alterations in the genitalmucosa.However, immune correlates ofHIVexposure without infection have not been investigated in the foreskin. We collected sub-preputial swabs and foreskin tissue from HESN (n1/420) and unexposed control (n1/457) men undergoing elective circumcision. Blinded investigators assayed swabs for HIV-neutralizing IgA, innate antimicrobial peptides, and cytokine levels. Functional T-cell subsets fromforeskin tissuewere assessed by flowcytometry.HESNforeskins had elevated a-defensins (3,027 vs. 1,795 pgml1,P1/40.011) and HIV-neutralizing IgA(50.0 vs. 13.5%ofmen,P1/40.019).Foreskin tissue fromHESNmen contained a higherdensityofCD3 T cells (151.9 vs. 69.9 cellsmm2, P1/40.018), but a lower proportion of these was Th17 cells (6.12 vs. 8.04%of CD4 Tcells, P1/40.007), and fewer produced tumor necrosis factor a (TNFa) (34.3 vs. 41.8% of CD4 Tcells, P1/40.037; 36.9 vs. 45.7%of CD8 T cells, P1/40.004). A decrease in the relative abundance of susceptible CD4 T cells and local TNFa production, in combinationwithHIV-neutralizing IgAand a-defensins,may represent a protective immunemilieu at a site ofHIVexposure.
UR - http://www.scopus.com/inward/record.url?scp=84897464454&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84897464454&partnerID=8YFLogxK
U2 - 10.1038/mi.2013.83
DO - 10.1038/mi.2013.83
M3 - Article
C2 - 24150258
AN - SCOPUS:84897464454
SN - 1933-0219
VL - 7
SP - 634
EP - 644
JO - Mucosal Immunology
JF - Mucosal Immunology
IS - 3
ER -