Simian Immunodeficiency Virus Rapidly Penetrates the Cervicovaginal Mucosa after Intravaginal Inoculation and Infects Intraepithelial Dendritic Cells

Abstract

Despite recent insights into mucosal human immunodeficiency virus (HIV) transmission, the route used by primate lentiviruses to traverse the stratified squamous epithelium of mucosal surfaces remains undefined. To determine if dendritic cells (DC) are used by primate lentiviruses to traverse the epithelial barrier of the genital tract, rhesus macaques were intravaginally exposed to cell-free simian immunodeficiency virus SIVmac251. We examined formalin-fixed tissues and HLA-DR ؉ -enriched cell suspensions to identify the cells containing SIV RNA in the genital tract and draining lymph nodes within the first 24 h of infection. Using SIV-specific fluorescent in situ hybridization combined with immunofluorescent antibody labeling of lineagespecific cell markers, numerous SIV RNA ؉ DC were documented in cell suspensions from the vaginal epithelium 18 h after vaginal inoculation. In addition, we determined the minimum time that the SIV inoculum must remain in contact with the genital mucosa for the virus to move from the vaginal lumen into the mucosa. We now show that SIV enters the vaginal mucosa within 60 min of intravaginal exposure, infecting primarily intraepithelial DC and that SIV-infected cells are located in draining lymph nodes within 18 h of intravaginal SIV exposure. The speed with which primate lentiviruses penetrate mucosal surfaces, infect DC, and disseminate to draining lymph nodes poses a serious challenge to HIV vaccine development.

Stimulation of Cell Surface CCR5 and CD40 Molecules by Their Ligands or by HSP70 Up-Regulates APOBEC3G Expression in CD4+ T Cells and Dendritic Cells

“…Furthermore, there are differences both in timing and magnitude of A3G up-regulation in CD4 ϩ T cells and monocyte-derived DC, suggesting that A3G is more readily up-regulated in DC than CD4 ϩ T cells. This finding might be significant in primary cervicovaginal and rectal mucosal transmission of HIV-1 by Langerhans cells and DC that migrate to the regional lymphoid tissue and infect CD4 ϩ T cells (33)(34)(35).…”

Intraepithelial Cell Neutralization of HIV-1 Replication by IgA

“…Several routes of entry have been proposed, including direct transcytosis through epithelial cells, infection of target cells beneath the epithelium via breaks in the lining, transepithelial transport by Langerhans cells, dendritic cells, or M cells, and transcytosis through epithelial tight junctions (1)(2)(3)(4)(5). In addition, epithelial cells derived from colon, uterus, oral cavity, and salivary gland have been reported to support HIV replication (6 -15).…”

“…These findings suggest that in vivo HIV-specific IgA can both exclude HIV from mucosal epithelial cells and prevent transcytosing HIV from spreading to the lamina propria, where abundant T cells and macrophages are potential targets of infection. During transport of IgA through mucosal epithelial cells, after polymeric Ig receptor (pIgR) 4 -mediated endocytosis, IgA Abs may also be able to interact intracellularly with viral proteins to inhibit viral replication. Evidence for such intraepithelial cell neutralization has been demonstrated in vitro with IgA mAbs against Sendai and measles viruses (paramyxoviruses), influenza virus (an orthomyxovirus), and rotavirus (a reovirus) (17)(18)(19)(20)(21)(22)37), but not yet with Abs to HIV (a retrovirus).…”

Influência do uso de anticoncepcionais hormonais orais sobre o número de células de Langerhans em mulheres com captura híbrida negativa para papilomavírus humano

“…O estudo dos efeitos dos contraceptivos hormonais sobre o número de CLs do epitélio do trato genital feminino tornou-se de fundamental importância, com trabalhos relatando a infecção intraepitelial das CLs pelo vírus de imunodeficiência dos macacos 20 . Diversos trabalhos referem também diminuição do número de CLs nas infecções por HPV e aumento das mesmas em presença de NIC 21 .…”