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

California Regional Primate Research Center, School of Medicine, University of California, Davis 95616, USA.
Journal of Virology (Impact Factor: 4.44). 08/2000; 74(13):6087-95. DOI: 10.1128/JVI.74.13.6087-6095.2000
Source: PubMed


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 lineage-specific 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.

Download full-text


Available from: Christopher James Miller
  • Source
    • "CD8 TRM have been targeted in the quest to develop a vaccine against HIV because CTLs are thought to be most important for killing virally infected cells. Non-human primate models reveal that the simian immunodeficiency virus (SIV) establishes a small founder population of infected cells in the local tissue after infection (65, 66). This founder population serves as an expanding source of virus that contributes to virus dissemination (66), and presents an opportunity for total elimination of mucosal viral infections during a narrow window of time early after infection. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tissue-resident memory T cells (TRM) comprise a newly defined subset, which comprises a major component of lymphocyte populations in diverse peripheral tissue sites, including mucosal tissues, barrier surfaces, and in other non-lymphoid and lymphoid sites in humans and mice. Many studies have focused on the role of CD8 TRM in protection; however, there is now accumulating evidence that CD4 TRM predominate in tissue sites, and are integral for in situ protective immunity, particularly in mucosal sites. New evidence suggests that mucosal CD4 TRM populations differentiate at tissue sites following the recruitment of effector T cells by local inflammation or infection. The resulting TRM populations are enriched in T-cell specificities associated with the inducing pathogen/antigen. This compartmentalization of memory T cells at specific tissue sites may provide an optimal design for future vaccination strategies. In addition, emerging evidence suggests that CD4 TRM may also play a role in immunoregulation and immunopathology, and therefore, targeting TRM may be a viable therapeutic approach to treat inflammatory diseases in mucosal sites. This review will summarize our current understanding of CD4 TRM in diverse tissues, with an emphasis on their role in protective immunity and the mechanisms by which these populations are established and maintained in diverse mucosal sites.
    Full-text · Article · Jul 2014 · Frontiers in Immunology
  • Source
    • "The laboratory-adapted env clones BaL and IIIB in pcDNA3.1 were described previously (Hu et al., 2000; Huang et al., 2012). MWS2 env was cloned from semen of a man who was known to have vaginal intercourse with a HIV-1 acutely infected woman (Hu et al., 2005), while CH811 env was cloned from a blood sample isolated from a Chinese patient as described previously (Hu et al., 2000). The T/F env clones were kindly provided by the Centre for HIV/AIDS Vaccine Immunology (CHAVI) (Hu et al., 2010; Keele et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The C-type lectin receptors (CLRs) expressed on dendritic cells (DCs), in particular DC-SIGN and DCIR, likely play an important role in HIV-1 early infection. Here, we systematically compared the capture and transfer capability of DC-SIGN and DCIR using a wide range of HIV-1 isolates. Our results indicated that DC-SIGN plays a stronger role than DCIR in DC-mediated HIV-1 capture and transfer. This was further strengthened by the data from transient and stable transfectants, showing that DC-SIGN had better capability, compared with DCIR in HIV-1 capture and transfer. Following constructing and analyzing a series of soluble DC-SIGN and DCIR truncates and chimeras, we demonstrated that the neck domain, but not the CRD, renders DC-SIGN higher binding affinity to gp120 likely via the formation of tetramerization. Our findings provide insights into CLR-mediated HIV-1 capture and transfer, highlighting potential targets for intervention strategies against gp120-CLR interactions.
    Full-text · Article · Jun 2014 · Virology
    • "Lactobacilli found in the vagina acidify at a rate of ∼0.5 pH units/h, which is consistent with lactobacilli being responsible for re-acidifying the vagina within several hours of coitus, following neutralization by semen.28 While the time required for HIV to infect target cells after introduction in the vagina is unknown, a study where rhesus macaques were vaginally infected with a high inoculum of simian immunodeficiency virus (SIV) reveals that cell-free virus penetrates the cervicovaginal epithelium and infects epithelial dendritic cells within 60 min of exposure.59 However, macaques are sparsely colonized with lactobacilli and have low levels of lactic acid, and consequently rarely have acidic vaginas.31 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives When Lactobacillus spp. dominate the vaginal microbiota of women of reproductive age they acidify the vagina to pH <4.0 by producing ∼1% lactic acid in a nearly racemic mixture of d- and l-isomers. We determined the HIV virucidal activity of racemic lactic acid, and its d- and l-isomers, compared with acetic acid and acidity alone (by the addition of HCl). Methods HIV-1 and HIV-2 were transiently treated with acids in the absence or presence of human genital secretions at 37°C for different time intervals, then immediately neutralized and residual infectivity determined in the TZM-bl reporter cell line. Results l-lactic acid at 0.3% (w/w) was 17-fold more potent than d-lactic acid in inactivating HIVBa-L. Complete inactivation of different HIV-1 subtypes and HIV-2 was achieved with ≥0.4% (w/w) l-lactic acid. At a typical vaginal pH of 3.8, l-lactic acid at 1% (w/w) more potently and rapidly inactivated HIVBa-L and HIV-1 transmitter/founder strains compared with 1% (w/w) acetic acid and with acidity alone, all adjusted to pH 3.8. A final concentration of 1% (w/w) l-lactic acid maximally inactivated HIVBa-L in the presence of cervicovaginal secretions and seminal plasma. The anti-HIV activity of l-lactic acid was pH dependent, being abrogated at neutral pH, indicating that its virucidal activity is mediated by protonated lactic acid and not the lactate anion. Conclusions l-lactic acid at physiological concentrations demonstrates potent HIV virucidal activity distinct from acidity alone and greater than acetic acid, suggesting a protective role in the sexual transmission of HIV.
    No preview · Article · May 2013 · Journal of Antimicrobial Chemotherapy
Show more