Article

HIV binding, penetration, and primary infection in human cervicovaginal tissue

Department of Microbiology, University of Minnesota Medical School, MMC 196, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2005; 102(32):11504-9. DOI: 10.1073/pnas.0500848102
Source: PubMed

ABSTRACT We have developed human cervicovaginal organ culture systems to examine the initiating events in HIV transmission after exposure to various sources of HIV infectivity, including semen. Newly infected cells were detected in the cervical submucosa 3-4 days after exposure to a primary HIV isolate. At earlier times, extensive and stable binding occurred when cervical surfaces were exposed to virions or seminal cells. Cervical mucus provided some protection for the endocervical surface, by physically trapping virions and seminal cells. Confocal microscopy combined with 3D surface reconstruction revealed that virions could both bind to the external surface of the cervical epithelium and actually penetrate beneath the epithelial surface. In quantitative assays, pretreatment with a blocking antibody directed against beta1 integrin reduced HIV virion binding. Collectively, these results highlight a continuum of complex interactions that occurs when natural sources of HIV infectivity are deposited onto mucosal surfaces in the female reproductive tract.

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Available from: Diane Maher, Jan 14, 2015
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    • "Furthermore the transformation zone (the interface between the squamous ectocervix and columnar endocervical canal) is thought to be particularly susceptible to HIV infection as it has an enhanced population of CD4+ T cells [55, 67]. Recent studies have highlighted that cervical epithelium can become productively infected and behave as viral reservoirs, which sequester virus and facilitate introduction of virus to leukocytes present in the submucosa [68, 69]. "
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    ABSTRACT: Theconnection between human papillomavirus (HPV) infection and the consequent sequelae which establishes cervical neoplastic transformation and invasive cervical cancer has redefined many aspects of cervical cancer research. However there is still much that we do not know. In particular, the impact of external factors, like seminal fluid in sexually active women, on pathways that regulate cervical inflammation and tumorigenesis, have yet to be fully understood. HPV infection is regarded as the initiating noninflammatory cause of the disease; however emerging evidence points to resident HPV infections as drivers of inflammatory pathways that play important roles in tumorigenesis as well as in the susceptibility to other infections such as human immunodeficiency virus (HIV) infection.Moreover there is emerging evidence to support a role for seminal fluid, in particular, the inflammatory bioactive lipids, and prostaglandins which are present in vast quantities in seminal fluid in regulating pathways that can exacerbate inflammation of the cervix, speed up tumorigenesis, and enhance susceptibility to HIV infection.This review will highlight some of our current knowledge of the role of seminal fluid as a potent driver of inflammatory and tumorigenic pathways in the cervix and will provide some evidence to propose a role for seminal plasma prostaglandins in HIV infection and AIDS-related cancer.
    08/2014; 2014. DOI:10.1155/2014/748740
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    • "Numerous studies using cervical, intestinal and other epithelial cell types have shown that HIV-1 is able to get across an intact epithelial cell layer by transcytosis [6]–[10]. Maher et al used confocal microscopy combined with 3D surface reconstruction to demonstrate that HIV-1 could both bind to the external surface of epithelial cells and actually penetrate beneath the epithelial surface in a cervicovaginal organ tissue culture system [51], which supports the idea that HIV-1 can cross the vaginal epithelial layer through either transcytosis or through the junctions between the epithelial cells. A recent finding has suggested that vaginal epithelial cells may play a bigger role in HIV-1 acquisition than previously believed and argued that the virus is passing between the cells through a diffusive percolation mechanism, penetrating through areas where junctions are absent [52]. "
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    ABSTRACT: While it is accepted that viruses can enter epithelial cells by endocytosis, the lack of an established biological mechanism for the trafficking of infectious virions through vaginal epithelial cells and their release from the plasma membrane has contributed to ongoing controversy about whether endocytosis is a mere artifact of some cell culture systems and whether squamous vaginal epithelial cells are even relevant as it pertains to HIV-1 transmission. In this study, we investigated the intracellular trafficking pathway that HIV-1 exploits to transcytose vaginal epithelial cells. The reduction of endosome tubulation by recycling endosome inhibitors blocked transcytosis of HIV-1 in a cell culture and transwell system. In addition, we demonstrate that although heat-inactivated virus was endocytosed as efficiently as native virus, heat-inactivated virus was trafficked exclusively to the lysosomal pathway for degradation following endocytosis. Lysosomal protease-specific inhibitors blocked the degradation of inactivated virions. Immunofluorescence analysis not only demonstrated that HIV-1 was inside the cells but the different colocalization pattern of native vs. heat inactivated virus with transferrin provided conclusive evidence that HIV-1 uses the recycling pathway to get across vaginal epithelial cells. Altogether, our findings demonstrate the precise intracellular trafficking pathway utilized by HIV-1 in epithelial cells, confirms that HIV-1 transcytosis through vaginal epithelial cells is a biological phenomenon and brings to light the differential intracellular trafficking of native vs heat-inactivated HIV-1 which with further exploration could prove to provide valuable insights that could be used in the prevention of transcytosis/transmission of HIV-1 across the mucosal epithelia.
    PLoS ONE 05/2014; 9(5):e96760. DOI:10.1371/journal.pone.0096760 · 3.23 Impact Factor
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    • "The epithelial surface of the female reproductive tract expresses all the receptors necessary for HIV infection including CD4, CCR5, and CXCR4 [79]. Maher and colleagues have recently shown that HIV virions can bind the external surface of cervical epithelium and penetrate beneath the epithelial surface [80]. Thus, it is plausible that epithelial cells lining the cervico-vaginal interface could be the first cells to come into contact with HIV and might play a role in the replication of the virus and transmission to leukocytes present in the submucosa. "
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    ABSTRACT: Cervical cancer is one of the leading gynaecological malignancies worldwide. It is an infectious disease of the cervix, associated with human papillomavirus infection (HPV), infection with bacterial agents such as Chlamydia trachomatis and Neisseria gonorrhoea as well as human immunodeficiency virus (HIV). Furthermore, it is an AIDS-defining disease with an accelerated mortality in HIV-infected women with cervical cancer. With the introduction of robust vaccination strategies against HPV in the developed world, it is anticipated that the incidence of cervical cancer will decrease in the coming years. However, vaccination has limited benefit for women already infected with high-risk HPV, and alternative therapeutic intervention strategies are needed for these women. Many pathological disorders, including cervical cancer, are characterised by the exacerbated activation and maintenance of inflammatory pathways which are considered to be regulated by infectious agents. In cervical cancer, hyperactivation of these inflammatory pathways and regulation of immune infiltrate into tissues can potentially play a role not only in tumorigenesis but also in HIV infection. In this paper we will discuss the contribution of inflammatory pathways to cervical cancer progression and HIV infection and the role of HIV in cervical cancer progression.
    05/2012; 2012:548150. DOI:10.6064/2012/548150
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