title: Comprehensive proteomic study identifies serpin and cystatin antiproteases as novel correlates of HIV-1 resistance in the cervicovaginal mucosa of female sex workers.
abstract: Not all individuals exposed to HIV-1 become infected, and evidence from HIV-1 highly exposed seronegative women (HIV-1-resistant) suggests that mucosal factors in the female genital tract, the first site of contact for the virus, are playing a role. To better understand factors mediating protection from HIV-1, we performed a large clinical study using the tools of systems biology to fully characterize the cervicovaginal mucosa proteome in HIV-1-resistant women. Cervicovaginal lavage fluid was collected from 293 HIV-1-resistant, uninfected, and infected sex workers and analyzed by 2D-LC LTQ-FT-MS. Of the more than 360 unique proteins identified, 41 were differentially abundant (>3-fold cutoff) in HIV-1-resistant women. The majority of over-abundant proteins were antiproteases (>40%), some with described anti-inflammatory and anti-HIV-1 activity. Quantification of specific anti-HIV-1 antiproteases Serpin A1, Serpin A3, and Cystatin B and an epithelial antiprotease A2ML1 found them to be significantly over-abundant in HIV-1-resistant women (p = 0.004; p = 0.046; p = 0.0003; and p = 0.04, respectively). Expression levels were not correlated to sexual practices or other epidemiological factors. Mucosal antiprotease levels correlated with pro-inflammatory cytokine concentration (p = <0.0001), but independently of pro-inflammatory cytokine levels in HIV-1-resistant women including TNF-alpha, IL-1 alpha, IL-1 beta, IL-6, and IL-8. This comprehensive systems biology approach identifies mucosal serpins and cystatins as novel correlates of HIV-1-resistance. This represents the first study characterizing these factors in the female genital tract.
authors.affiliation: Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada. burgener@cc.umanitoba.ca
authors.forename: A
authors.initials: A
authors.lastname: Burgener
authors.forename: S
authors.initials: S
authors.lastname: Rahman
authors.forename: R
authors.initials: R
authors.lastname: Ahmad
authors.forename: J
authors.initials: J
authors.lastname: Lajoie
authors.forename: S
authors.initials: S
authors.lastname: Ramdahin
authors.forename: C
authors.initials: C
authors.lastname: Mesa
authors.forename: S
authors.initials: S
authors.lastname: Brunet
authors.forename: C
authors.initials: C
authors.lastname: Wachihi
authors.forename: J
authors.initials: J
authors.lastname: Kimani
authors.forename: K
authors.initials: K
authors.lastname: Fowke
authors.forename: S
authors.initials: S
authors.lastname: Carr
authors.forename: F
authors.initials: F
authors.lastname: Plummer
authors.forename: T B
authors.initials: TB
authors.lastname: Ball
mesh_terms: D000328:Adult; D002584:Cervix Uteri / Q000378:metabolism; D055313:Cystatin B / Q000235:genetics / Q000378:metabolism*; D060467:Disease Resistance / Q000235:genetics*; D005260:Female; D005836:Genitalia, Female / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism; D010641:Phenotype; D040901:Proteomics; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D060386:Sex Workers; D014621:Vagina / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000235:genetics / Q000378:metabolism
chemical_list: C510358:A2ML1 protein, human; C524994:CSTB protein, human; C516148:SERPINA3 protein, human; D015843:Serpins; D000515:alpha 1-Antitrypsin; D000511:alpha-Macroglobulins; D055313:Cystatin B