Elevated elafin/trappin-2 in the female genital tract is associated with protection against HIV acquisition.
OBJECTIVE
Globally, heterosexual intercourse is the primary route of HIV-1 (HIV) transmission. It follows that mechanisms that protect against HIV infection are likely operative at the genital mucosa. In HIV-resistant Kenyan sex workers who are highly exposed to HIV infection yet remain uninfected, protection correlates with HIV-specific immune responses and genetic factors. However, these factors do not entirely explain this model of natural immunity to HIV. We hypothesized that protection may be mediated by innate immune proteins in the genital tract of HIV-resistant sex workers.


METHODS
The genital proteome of mucosal secretions from HIV-resistant women was examined using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Cervical lavage samples were collected from 315 HIV-resistant, HIV-uninfected and HIV-infected commercial sex workers.


RESULTS
Univariate analysis identified a 6 kDa biomarker of HIV resistance in genital secretions from these women. This protein was identified by tandem mass spectrometry as elafin and was found to be overexpressed in HIV-resistant women compared with HIV-uninfected (P = 0.001) and infected (P = 0.002) women. The elevated levels of elafin/trappin-2 in HIV-resistant women were confirmed using ELISA. The prospective association of elevated cervicovaginal elafin/trappin-2 levels with protection from HIV acquisition was then confirmed in an independent cohort of high-risk female sex workers.


CONCLUSIONS
Using a unique proteomics approach in a large scale, cross-sectional cohort study, we identified elafin/trappin-2 as a novel innate immune factor, which is highly associated with resistance. This association was confirmed within an independent, prospective cohort study. Genital tract elafin/trappin-2 levels constitute a natural correlate of HIV protection in humans.
Iqbal
Shehzad M
SM
Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada. shehzad.iqbal@utoronto.ca
Ball
Terry B
TB
Levinson
Pauline
P
Maranan
Lillian
L
Jaoko
Walter
W
Wachihi
Charles
C
Pak
Brian J
BJ
Podust
Vladimir N
VN
Broliden
Kristina
K
Hirbod
Taha
T
Kaul
Rupert
R
Plummer
Francis A
FA
D000328:Adult; D015415:Biomarkers / Q000032:analysis; D015986:Confounding Factors, Epidemiologic; D053492:Elafin / Q000032:analysis*; D005260:Female; D005500:Follow-Up Studies; D005836:Genitalia, Female / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000635:transmission; D015497:HIV-1; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D011446:Prospective Studies; D011477:Sex Work; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods
D015415:Biomarkers; D053492:Elafin; C506806:PI3 protein, human