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HIV-Exposed Seronegative Men who have Sex with Men overexpress potential antiviral antiproteases in their rectal mucosa
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Reported by Jules Levin
20th International AIDS Conference, July 20-25, 2014, Melbourne
Presented by Laura Romas (Canada).
L. Romas1, K. Hasselrot2, S. Ramdahin1, G. Westmacott3, F. Plummer3, T.B. Ball1,3, K. Broliden2, A. Burgener1,3
1University of Manitoba, Medical Microbiology and Infectious Disease, Winnipeg, Canada, 2Karolinska Institutet, Medicine, Stockholm, Sweden, 3Public Health Agency of Canada, Winnipeg, Canada
Webcast: http://pag.aids2014.org/flash.aspx?pid=1259
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Program Abstract
Background: HIV-Exposed Seronegative (HESN) individuals have shown altered mucosal immune responses in cervical, salivary and foreskin secretions associated with reduced HIV-susceptibility; however, this has not been investigated in rectal mucosa. This is the first comprehensive proteomic study defining mucosal immune differences in the rectal secretions of HESN MSM. These differences may contribute to a natural reduced susceptibility to HIV-1 in this population.
Methods: Rectal lavage from HESN MSM (n=25) and non-exposed healthy controls (n=14) from the Venhalsan clinic, Sweden, were analysed by label-free tandem mass spectrometry. Identification of proteins, differential expression analysis and pathway analysis were performed. Several differentially expressed proteins were screened for HIV-neutralizing activity in PBMC culture in the presence of
R- and X-tropic HIV lab strains (Bal and 3B, respectively). HIV replication in vitro was quantified by p24 ELISA.
Results: Of the 289 identified, all 25 deferentially expressed proteins were overabundant in HESN MSM (p< 0.05), and had functions related to acute phase response, antimicrobial defense and Ig-mediated immunity. These proteins did not show a significant correlation (p>0.05) with clinical variables (frequency oral/anal sex, HIV-neutralizing IgA, and VL of HIV+ partner). Pathway analysis linked overabundant proteins to the canonical pathway "Role of IL-17 in Psoriasis" (p=3.6x10-6, 3 proteins), which is critical in gut epithelial maintenance and production of antimicrobial and inflammatory proteins. Notably, 2 peptides were overabundant in HESN MSM and demonstrated antiviral activity in vitro. Neutralization assays showed that "peptide 1" reduced HIV-Bal infection by 50% and "peptide 2" reduced HIV-3B infection by 20% in PBMC culture at physiologically relevant concentrations. The ability of these factors to limit HIV infection supports our hypothesis that these overexpressed factors contribute to mucosal immunity against HIV in HESN MSM.
Conclusions: HESN MSM overexpress proteins important in immunity and may contribute to reduced susceptibility to HIV at the rectal mucosa. This may be a result of HIV-exposure or genetic differences. Our findings overlap with previous studies of showing an overabundance of antiviral factors in the cervical secretions of HESN women, supporting further study into their roles in HIV infection. This this knowledge is critical for the design of safe, effective HIV-prevention technologies for MSM.
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