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Abstract
Trappin-2: discovery of a novel inhibitor of HIV highly elevated in HIV-resistant sex workers
S. Iqbal1, T. Ball1, Z. Ao1, L. Maranan1, J. Rutherford1, C. Wachihi2, B. Pak3, V. Podust3, X.-j. Yao1, F. Plummer1
1University of Manitoba, Medical Microbiology, Winnipeg, Canada, 2University of Nairobi, Medical Microbiology, Nairobi, Kenya, 3Ciphergen Biosystems, Fremont, United States
Background: The HIV pandemic currently afflicts 40 million people world-wide and recently shifted its predominance, showing a higher prevalence of infection in women than men. As such, a call for a preventative microbicide was put forth as a means of protecting women from infection. In Nairobi, Kenya a group of HIV-resistant women have been identified who, despite repeated exposure, remain uninfected. Importantly, this resistance shows association with specific immune responses that protect them from infection. As most HIV transmission is through heterosexual contact, the initial site of infection in the body is the genital mucosa. Therefore, we hypothesized that the HIV-resistant women have a unique immune phenotype within their genital mucosa that confers protection from infection with HIV.
Methods: We employed a proteomics approach to characterize the mucosal proteins found within genital tract lavage samples from HIV-resistant women and compared them to HIV-uninfected and infected women. Using surface enhanced laser desorption ionization-time of flight (SELDI-TOF) mass spectrometry (MS), we identified protein peaks of interest (or ‘biomarkers’) that were highly associated with the HIV-resistant group. We purified and identified one such biomarker using tandem MS and subsequently tested it for anti-HIV activity using in vitro assay systems.
Results: A 6 kDa biomarker of HIV-resistance was elevated when compared to the HIV-uninfected (p<0.001) and HIV-infected (p<0.000001) study groups and subsequently identified as Trappin-2. We confirmed the over expression of Trappin-2 in HIV-resistant individuals by ELISA. Further, we show that Trappin-2 is a potent inhibitor of HIV.
Conclusions: We have identified a previously uncharacterized inhibitor of HIV using a novel proteomics approach. Importantly, elevated expression of this protein is highly associated with natural immunity to HIV infection in a HIV-resistance cohort. As such, this protein may make an ideal candidate for a component of a preventative microbicide.
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