laura romas (msc . student) burgener lab, university of manitoba, canada
DESCRIPTION
HIV-Exposed Seronegative Men who have Sex with Men overexpress potential antiviral antiproteases in their rectal mucosa. Laura Romas (MSc . Student) Burgener Lab, University of Manitoba, Canada. Why is the rectal mucosa so susceptible to HIV infection?. 1. Thin epithelial layer. - PowerPoint PPT PresentationTRANSCRIPT
www.aids2014.org
HIV-Exposed Seronegative Men who have Sex with Men overexpress potential antiviral antiproteases in their
rectal mucosa
Laura Romas (MSc. Student)Burgener Lab, University of Manitoba, Canada
www.aids2014.org
GALT
Why is the rectal mucosa so susceptible to
HIV infection?
4. Mucosal Fluid?
1. Thin epithelial
layer
2. Many HIV target
cells
3. Easily accessible lymphatic
system
www.aids2014.org
Natural Immunity in HIV Exposed Seronegative (HESN) Individuals
HIV Exposed Seronegative
HIV + Partner
• HESN MSM from the Venhälsan Cohort (est. 2007): – Gay Men`s Health Clinic in
Stockholm, Sweden.– Serodiscordant couples
>5yrs– Men have HIV neutralizing
IgA within their mucosal fluid, but no HIV antibodies in serum
• (Hasselrot et al. AIDS. 2009)
www.aids2014.org
Using Proteomics to Identify Correlates of Protection
P24
PeptidesMucosal FluidHESN vs. Control
(n=23) (n=20)
ID/ Quant Targets
TargetB.
A.
www.aids2014.org
HESN MSM over-express several immune proteins in their mucosal fluid
* 80% power (≥2 fold difference), p<0.05, Benjimani-Hochberg corrected
286 IDs
110 immune proteins
*20 proteins significantly overabunant in HESN
MSM
Intelectin 2α-1-acid glycoprotein 1Antiprotease 1S100A7Antiprotease 2AntirpoteaseS100A9S100A8α -1-acid glycoprotein 1MyeloperoxidaseIg Heavy chainImmunoglobulin ImmunoglobulinImmunoglobulinImmunoglobulinImmunoglobulinImmunoglboulinImmunoglobulinTetraspanin 8
www.aids2014.org
Antiproteases in ImmunityAP
1(L
og2 R
el. A
bund
.)AP
2(L
og2 R
el. A
bund
.)
**p<0.001
www.aids2014.org
Epidemiological Correlations
• Antiprotease expression does not correlate with:– Vial exposure (viral load of HIV+ partner)– Mucosal response to HIV (HIV-neutralizing IgA)– Seminal/microbial exposure from unprotected
intercourse (Frequency of unprotected sex)
www.aids2014.org
AP1 inhibits infection in PBMCs
C. D.
B.A.
P>0.01P>0.01P<0.01
P<0.01
P>0.01P>0.01
P>0.01P>0.01
www.aids2014.org
Conclusions• HESN MSM overexpress antiproteases• AP expression does not correlate with exposure • AP1 show antiviral properties in vitro
– PBMC culture– Maintains cell viability
• Future Directions:– Follow up in colorectal explants (underway)– Antiviral mechanism
• Application:– Increase knowledge of HIV pathogenesis through the
rectum– Guide future microbicide research
www.aids2014.org
Acknowledgements
MentorsAdam Burgener and Blake Ball; Kevin Coombs and Emmanuel Ho Carolina Herrerra (Imperial College of London, Shattock Lab)
University of Manitoba, HIV Research Group, CanadaLindsay Aboud, Melissa Herman, Sue Ramdahin, Kenzie Birse, Max Abou, Derek Stein, Michelle Perner, Jen Butler and Liane Arcinas
National Microbiology Laboratory, CanadaFrank Plummer; Garrett Westmacott, Stuart McCorrister and Patrick Chong
Karolinska Institutet, SwedenKristinal Broliden, Klara Hasselrot, A. Tjerlund, P. Levinson, L. Persson, P. Saberg, G. Bratt, E. Sandstrom
MSM / HESN Participants of the Gay Men’s Health Clinic, Stockholm, SWD.
www.aids2014.org
AP1 inhibits HIV infection in TZM-bl cellsB.
C. D.
A.