Identification of Differentially Expressed Proteins in the Cervical Mucosa of HIV-1-Resistant Sex Workers

Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.
Journal of Proteome Research (Impact Factor: 4.25). 09/2008; 7(10):4446-54. DOI: 10.1021/pr800406r
Source: PubMed


Novel tools are necessary to understand mechanisms of altered susceptibility to HIV-1 infection in women of the Pumwani Sex Worker cohort, Kenya. In this cohort, more than 140 of the 2000 participants have been characterized to be relatively resistant to HIV-1 infection. Given that sexual transmission of HIV-1 occurs through mucosal surfaces such as that in the cervicovaginal environment, our hypothesis is that innate immune factors in the genital tract may play a role in HIV-1 infection resistance. Understanding this mechanism may help develop microbicides and/or vaccines against HIV-1. A quantitative proteomics technique (2D-DIGE: two-dimensional difference in-gel electrophoresis) was used to examine cervical mucosa of HIV-1 resistant women ( n = 10) for biomarkers of HIV-1 resistance. Over 15 proteins were found to be differentially expressed between HIV-1-resistant women and control groups ( n = 29), some which show a greater than 8-fold change. HIV-1-resistant women overexpressed several antiproteases, including those from the serpin B family, and also cystatin A, a known anti-HIV-1 factor. Immunoblotting for a selection of the identified proteins confirmed the DIGE volume differences. Validation of these results on a larger sample of individuals will provide further evidence these biomarkers are associated with HIV-1 resistance and could help aid in the development of effective microbicides against HIV-1.


Available from: Terry Blake Ball
  • Source
    • "There is a group of HIV-exposed, seronegative (HESN) women in Kenya that have been studied for many years for clues to the mechanism of their resistance to HIV-1 [10]. It is believed that the answer lies within their cervicovaginal mucosa and their innate immune system [11]. Compared to controls, these HESN women are described as having a “quiescent” innate immune phenotype [12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Years of extensive research have yielded much knowledge in many aspects of HIV-1 infection, treatments, and education. However, without a vaccine, the number of people infected worldwide continues to grow. The partial success of the Thai RV144 vaccine trial provides hope that a method of protection is indeed possible. Understanding the mechanism behind the protection is critical if we hope to achieve our goal of inhibiting new infections of HIV-1. We hypothesize that the Fc of IgG binding protein (Fcgbp) is associated with the protection observed in the RV144 vaccine trial. It has the ability to trap viral-antibody complexes in the mucosa by binding the Fc of IgG to Fcgbp. This property could be used in the form of a microbicide containing antibodies to a variety of HIV-1 epitopes to prevent sexual transmission of HIV-1. The aim of this paper is to stimulate further research into Fcgbp and its role in innate immunity.
    The Open AIDS Journal 09/2014; 8(1):21-4. DOI:10.2174/1874613601408010021
  • Source
    • " 1990s ) no ARVs were available in Côte d ' Ivoire . Therefore , this group was expected to be enriched for HIV resistance factors because the individuals were exposed to HIV for a long time in the absence of HIV infection . ( 3 ) An HIV - positive group of the same cohort of female sex workers ( HIV ) was included as an additional control group ( Burgener et al . , 2008 ; Jennes et al . , 2004 ; Marmor et al . , 2006 ; Kulkarni et al . , 2003 ; Iqbal et al . , 2009 ) ."
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV-exposed seronegative individuals (HESNs) are persons who possess in vivo resistance against HIV. Using iTRAQ, we compared protein abundance profiles from cervicovaginal fluid (CVF) samples obtained from HESNs with samples from low-risk seronegative and from seropositive persons. Serpin A5 and myeloblastin were up- and downregulated, respectively. We hypothesize that a balance between the downregulation of serine proteinases and the upregulation of their inhibitors may contribute to HIV-resistance Figure optionsDownload full-size imageDownload high-quality image (155 K)Download as PowerPoint slide
    Virology 06/2014; s 458–459(1):11–21. DOI:10.1016/j.virol.2014.04.015 · 3.32 Impact Factor
  • Source
    • "To identify putative factors involved in mediating resistance against infection, a proteomics approach was applied to screen for differences in CVL proteins between HESN and high-risk HIV-negative CSW from the Pumwani cohort. These comparisons revealed that HESN overexpressed several antiproteases, including members of the serpin A family, cystatin B, Elafin and A2ML1 [40,41]. In line with these observations, Elafin has been identified as a correlate of protection in HESN [42]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aberrant immune activation is a strong correlate of HIV disease progression, but little is known about how immune activation alters susceptibility to HIV infection. Susceptibility to HIV infection varies between individuals, but the immunological determinants of HIV transmission are not well understood. Here, we present evidence from studies of HIV transmission in the context of clinical trials and HIV-exposed seronegative (HESN) cohorts that implicates elevated immune activation as a risk factor for acquiring HIV. We propose a model of protection from infection based on a phenotype of low baseline immune activation referred to as immune quiescence. Immune quiescence is evidenced by reduced expression of T cell activation markers, low levels of generalized gene transcription and low levels of proinflammatory cytokine and chemokine production in the periphery and genital mucosa of HESN. Since HIV preferentially replicates in activated CD4+ T cells, immune quiescence may protect against infection by limiting HIV target cell availability. Although the determinants of immune quiescence are unclear, several potential factors have been identified that may be involved in driving this phenotype. HESN were shown to have elevated proportions of regulatory T cells (Tregs), which are known to suppress T cell activation. Likewise, proteins involved in controlling inflammation in the genital tract have been found to be elevated in HESN. Furthermore, expression of interferon regulatory factor 1 (IRF-1) is reduced in HESN as a consequence of genetic polymorphisms and differential epigenetic regulation. Since IRF-1 is an important regulator of immune responses, it may play a role in maintaining immune quiescence. Based on this model, we propose a novel avenue for HIV prevention targeted based on reducing host mucosal immune activation.
    Retrovirology 11/2013; 10(1):141. DOI:10.1186/1742-4690-10-141 · 4.19 Impact Factor
Show more