Abstract
Oropharyngeal mucosal epithelia of fetuses/neonates/infants and the genital epithelia of adults play a critical role in HIV-1 mother-to-child transmission and sexual transmission of virus, respectively. To study the mechanisms of HIV-1 transmission through mucosal epithelium, we established polarized tonsil, cervical and foreskin epithelial cells. Analysis of HIV-1 transmission through epithelial cells showed that approximately 0.05% of initially inoculated virions transmigrated via epithelium. More than 90% of internalized virions were sequestered in the endosomes of epithelial cells, including multivesicular bodies (MVBs) and vacuoles. Intraepithelial HIV-1 remained infectious for 9 days without viral release. Release of sequestered intraepithelial HIV-1 was induced by the calcium ionophore ionomycin and by cytochalasin D, which increase intracellular calcium and disrupt the cortical actin of epithelial cells, respectively. Cocultivation of epithelial cells containing HIV-1 with activated peripheral blood mononuclear cells and CD4+ T lymphocytes led to the disruption of epithelial cortical actin and spread of virus from epithelial cells to lymphocytes. Treatment of epithelial cells with proinflammatory cytokines tumor necrosis factor-alpha and interferon gamma also induced reorganization of cortical actin and release of virus. Inhibition of MVB formation by small interfering RNA (siRNA)-mediated silencing of its critical protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) expression reduced viral sequestration in epithelial cells and its transmission from epithelial cells to lymphocytes by ~60–70%. Furthermore, inhibition of vacuole formation of epithelial cells by siRNA-inactivated rabankyrin-5 expression also significantly reduced HIV-1 sequestration in epithelial cells and spread of virus from epithelial cells to lymphocytes. Interaction of the intercellular adhesion molecule-1 of epithelial cells with the function-associated antigen-1 of lymphocytes was important for inducing the release of sequestered HIV-1 from epithelial cells and facilitating cell-to-cell spread of virus from epithelial cells to lymphocytes. This mechanism may serve as a pathway of HIV-1 mucosal transmission.
Highlights
Transmission of human immunodeficiency virus-1 (HIV-1) through mucosal epithelium plays a critical role in the initiation of systemic HIV-1 infection and the development of acquired immune deficiency syndrome (AIDS)
The majority of HIV-1 transmissions occur through the mucosal epithelium, the mechanism of initial events of viral spread from epithelia to HIV-1-susceptible CD4+ lymphocytes, macrophages, and Langerhans/dendritic cells is not well understood
In this study we observed that >90% of virions internalized in tonsil, cervical and foreskin epithelial cells did not cross the epithelium but rather were retained in the endosomal compartments for several days
Summary
Transmission of human immunodeficiency virus-1 (HIV-1) through mucosal epithelium plays a critical role in the initiation of systemic HIV-1 infection and the development of acquired immune deficiency syndrome (AIDS). The fetus/infant oropharyngeal mucosal epithelia serve as a portal of entry for HIV-1 mother-to-child transmission (MTCT) [1, 2]. One of the possible pathways of HIV-1 transmission through mucosal epithelium could be viral transcytosis, i.e., transcellular transport of virions by vesicular/endosomal machinary of epithelial cells. Cell-free HIV-1 transcytosis via mucosal epithelial cells is not highly efficient, i.e., 0.01–0.05% of virions from the initial inoculum may translocate across epithelial cells [1, 8, 9]. Very little is known about the specific role of the endosomal/vesicular transport machinery of mucosal epithelium in the regulation of HIV-1 transepithelial transport
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