Portal de Periódicos da CAPES

HIV's Vagina Travelogue

2007; Cell Press; Volume: 26; Issue: 2 Linguagem: Inglês

10.1016/j.immuni.2007.02.001

1097-4180

César Boggiano, Dan R. Littman,

Reproductive System and Pregnancy

Details of how HIV-1 is transmitted across mucosal barriers remain sparse. In this issue of Immunity, Hladik et al., 2007Hladik F. Sakchalathorn P. Ballweber L. Lentz G. Fialkow M. Eschenbach D. McElrath M.J. Immunity. 2007; 26 (this issue): 257-270Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar describe an organ culture system for imaging HIV-1 interaction with vaginal epithelial T cells and Langerhans cells early after infection. Details of how HIV-1 is transmitted across mucosal barriers remain sparse. In this issue of Immunity, Hladik et al., 2007Hladik F. Sakchalathorn P. Ballweber L. Lentz G. Fialkow M. Eschenbach D. McElrath M.J. Immunity. 2007; 26 (this issue): 257-270Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar describe an organ culture system for imaging HIV-1 interaction with vaginal epithelial T cells and Langerhans cells early after infection. Travelogue: An (illustrated) lecture about places and experiences encountered in the course of travel; hence a film, broadcast, book, etc., about travel; a travel documentary.(Oxford English Dictionary online: http://www.oed.com/) The female genital tract is the primary route for heterosexual transmission of the human immunodeficiency virus (HIV1, referred to in the text as HIV). On the basis of studies with macaques exposed to simian immunodeficiency virus (SIV), it is thought that during male-to-female transmission, virus in semen, either cell-free or cell-associated, penetrates the stratified squamous epithelium of the vagina or the columnar epithelium of the endocervix to infect cells within or below the epithelium (reviewed in Pope and Haase, 2003Pope M. Haase A.T. Nat. Med. 2003; 9: 847-852Crossref PubMed Scopus (291) Google Scholar). This is followed by dissemination of the virus to lymphoid organs, particularly gut-associated lymphoid tissues (GALT), within the first few days after infection (Li et al., 2005Li Q. Duan L. Estes J.D. Ma Z.M. Rourke T. Wang Y. Reilly C. Carlis J. Miller C.J. Haase A.T. Nature. 2005; 434: 1148-1152Crossref PubMed Scopus (790) Google Scholar). Despite intensive efforts to uncover mechanisms by which HIV traverses the mucosal barriers and establishes infection, our understanding of this process remains limited. It is unclear which cells are the first to interact with and to be productively infected with the virus, whether there are environmental factors in the reproductive tract tissues that influence infection, and whether there are local immune-system responses directed at the virus. An understanding of these processes is critical for developing prophylactic microbicides and vaccines. Some clues as to how HIV interacts with mucosal cells in the reproductive tract may come from studies on infection of GALT early after exposure of humans and macaques to HIV or SIV, respectively. Within days after vaginal exposure to SIV, there is massive viral replication and loss of CD4+ memory T cells in the intestinal lamina propria of macaques (Li et al., 2005Li Q. Duan L. Estes J.D. Ma Z.M. Rourke T. Wang Y. Reilly C. Carlis J. Miller C.J. Haase A.T. Nature. 2005; 434: 1148-1152Crossref PubMed Scopus (790) Google Scholar). Similarly, patients who had recently sero-converted were found to have profound depletion of lamina-propria CD4+ T cells (Brenchley et al., 2004Brenchley J.M. Schacker T.W. Ruff L.E. Price D.A. Taylor J.H. Beilman G.J. Nguyen P.L. Khoruts A. Larson M. Haase A.T. Douek D.C. J. Exp. Med. 2004; 200: 749-759Crossref PubMed Scopus (1348) Google Scholar). Moreover, the intestinal lamina propria of patients treated successfully with highly active antiretroviral therapy (HAART) remained depleted of CD4+ T cells despite recovery of circulating CD4+ T cells to normal amounts (Guadalupe et al., 2003Guadalupe M. Reay E. Sankaran S. Prindiville T. Flamm J. McNeil A. Dandekar S. J. Virol. 2003; 77: 11708-11717Crossref PubMed Scopus (663) Google Scholar). There is as yet no explanation for this remarkable finding, although it may be due to irreversible damage incurred by the lamina propria during acute infection, such that T cells can no longer home to the intestine, or to persistence of virus in the face of HAART, perhaps because of unusual properties of the cells in the lamina propria, such as dendritic cells that can harbor virus in vacuolar compartments. Although the cervicovaginal mucosa does not have the density of lymphoid tissues that is found in the gastrointestinal mucosa, both contain an abundant number of effector and memory T cells that are likely to be important in providing protection from breaches in the mucosal barrier. In both tissues, the T cells are in close contact with numerous mucosal dendritic cells (DCs) that are involved in innate responses to commensal and pathogenic microorganisms and that may also have important roles in the dissemination of HIV and also in host responses against the virus. In the murine intestine, DCs are organized in a dense network and often extend processes through epithelial tight junctions to sample the luminal environment. Langerhans cells (LCs), a specialized type of DC found in skin and vaginal epithelium, may function similarly within the stratified epithelium, and may thus provide access for HIV particles to the vaginal epithelium. Transcytosis or any breach in the epithelial barrier may also allow HIV particles to cross the epithelial barrier. The underlying stroma also contains cells known to interact with HIV, such as T cells, macrophages, and DCs. Because it is not feasible to study acute events after heterosexual transmission of HIV in humans, research in this important area has relied on the simian model and also on in vitro infection of organ cultures established with cervicovaginal tissue from human surgical samples. In the vagina, the layers of stratified squamous epithelium and the mucus that they secrete form the outer component of the mucosa and a natural obstacle to infection. Analysis of intact human cervical-tissue organ cultures has shown that HIV can penetrate the stratified epithelium and infect memory CD4+ T cells within several hours, but this process appears to be relatively inefficient, and some investigators have raised the possibility that LCs may have a key role early in infection. Because lymphocytes and LCs exit the epithelium within hours after establishment of organ cultures, it has been difficult to determine whether cells are infected within the epithelium proper or in the submucosal stromal tissue. In this issue of Immunity, Hladik et al., 2007Hladik F. Sakchalathorn P. Ballweber L. Lentz G. Fialkow M. Eschenbach D. McElrath M.J. Immunity. 2007; 26 (this issue): 257-270Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar describe a modified organ culture system that allowed for the separation of the epithelial sheets from the underlying stroma in human vaginal explants. This permitted analysis of cells that were infected exclusively within the epithelium, as well as examination of cells that migrated out of the epithelium into the culture medium. Most of the intraepithelial T cells expressed the surface markers CCR5 and CD45RO, denoting a memory phenotype. The intact epithelial sheets were exposed to HIV particles, whose interaction with resident immune cells was then examined. Through confocal microscopy to detect fluorescently labeled virions interacting with cells in the epithelium, approximately half of the CD4+ T cells were found to have bound virions at 2 hr after infection. A majority of these cells had fluorescent signals on the cytoplasmic side of the plasma membrane, indicating that infection had occurred. Both binding and infection of CD4+ T cells were dependent on CD4 and CCR5, the molecules that make up the viral receptor complex. HIV was also found associated with LCs at this early time point, but the virions were localized in a perinuclear intracellular compartment and replication was undetectable. The uptake of virus by LCs was only partially inhibited by antibodies specific for CD4 and CCR5, both of which are expressed at the surface of LCs. Inhibition of HIV binding to C type lectins by the use of mannan had very little effect, suggesting that molecules such as langerin, which are known to interact with glycans on the envelope glycoprotein of HIV, do not have a major or an exclusive role in viral internalization. This is consistent with the notion that HIV uptake into DCs can occur by multiple means. Virions within LC intracellular compartments were readily observed by electron microscopy for up to 3 days after infection. In contrast, intact virions were found only at the plasma membrane in T cells. The authors did not observe obvious contact between LCs and CD4+ T cells that were undergoing infection at 2 hr. The results therefore suggest that HIV directly infects T cells within the vaginal epithelium and that this process is not dependent on LC-mediated viral uptake or enhancement of infection in trans. This is an important point in light of a growing body of literature suggesting that numerous microorganisms are taken up by dendritic cells and may exploit these specialized antigen-presenting cells by hiding out in their intracellular vesicular compartments (van Kooyk and Geijtenbeek, 2003van Kooyk Y. Geijtenbeek T.B. Nat. Rev. Immunol. 2003; 3: 697-709Crossref PubMed Scopus (727) Google Scholar). It has been known for some time that DCs are relatively resistant to infection with HIV, yet they potently enhance infection of CD4+ T lymphocytes in trans (Cameron et al., 1992Cameron P.U. Freudenthal P.S. Barker J.M. Gezelter S. Inaba K. Steinman R.M. Science. 1992; 257: 383-387Crossref PubMed Scopus (540) Google Scholar). The significance of this process has yet to be demonstrated for HIV infection in vivo, and the mechanism for this enhancement has been the subject of considerable debate. Initial studies showed that virus-particle uptake by endocytic mechanisms is necessary for DCs to enhance infection of T cells, and this finding was supported by subsequent publications suggesting that virus is transmitted from multivesicular bodies in DCs to conjugated T cells across an “infectious synapse” (McDonald et al., 2003McDonald D. Wu L. Bohks S.M. KewalRamani V.N. Unutmaz D. Hope T.J. Science. 2003; 300: 1295-1297Crossref PubMed Scopus (561) Google Scholar). Consistent with such an interpretation, fluorescently labeled HIV was found to localize preferentially toward the cell-cell interface in conjugates of T cells and LCs that had emigrated from vaginal explants at 60 hr of culture (Hladik et al., 2007Hladik F. Sakchalathorn P. Ballweber L. Lentz G. Fialkow M. Eschenbach D. McElrath M.J. Immunity. 2007; 26 (this issue): 257-270Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar). Thus, HIV that persists in vacuolar compartments in LCs may be involved in infecting CD4+ T cells at later time points after exposure of the vaginal epithelium (Figure 1). However, this interpretation has been challenged by a recent finding that only virions bound to the surface of DCs are transmitted in trans to activated T cells, which suggested that viral particles within DC intracellular compartments are not competent to be released and infect T cells (Cavrois et al., 2007Cavrois M. Neidleman J. Kreisberg J.F. Greene W.C. PLoS Pathog. 2007; 3: e4Crossref PubMed Scopus (117) Google Scholar). If this is correct, then the virions observed by Hladek et al. in LCs after infection of vaginal epithelial explants may represent a dead-end by-product of infection (Figure 1). Recent studies have demonstrated that DCs have mechanisms that control acidification of endosomal compartments, ensuring that antigen taken up for cross-presentation to T cells is not degraded (Savina et al., 2006Savina A. Jancic C. Hugues S. Guermonprez P. Vargas P. Moura I.C. Lennon-Dumenil A.M. Seabra M.C. Raposo G. Amigorena S. Cell. 2006; 126: 205-218Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar). The presence of intact HIV particles within membrane-delimited compartments may reflect this unique property of DCs, but additional studies are warranted to determine the fate and infectious competence of these virions, particularly in vivo in infected patients. The elegant imaging studies of Hladik et al. highlight the potential importance of memory T cells and LCs as the first targets of HIV infection in the human vagina. The observation by electron microscopy of intracellular intact virions several days after infection in emigrated LCs, coupled with the finding of viral particles in LC:T cell conjugates, is consistent with the possibility that LCs catalyze CD4+ T cell infection and/or promote transport of infectious particles to draining lymphoid organs. It therefore remains possible that the success of the virus in establishing a systemic infection depends on its early interaction with vaginal epithelial LCs, particularly when the amount of virus reaching the intraepithelial microenvironment is limited. Continued development of organ culture systems that closely mimic the in vivo environment will be essential for better understanding the earliest steps in HIV transmission. Initial Events in Establishing Vaginal Entry and Infection by Human Immunodeficiency Virus Type-1Hladik et al.ImmunityFebruary 23, 2007In BriefUnderstanding the initial events in the establishment of vaginal human immunodeficiency virus type-1 (HIV-1) entry and infection has been hampered by the lack of appropriate experimental models. Here, we show in an ex vivo human organ culture system that upon contact in situ, HIV-1 rapidly penetrated both intraepithelial vaginal Langerhans and CD4+ T cells. HIV-1 entered CD4+ T cells almost exclusively by CD4 and CCR5 receptor-mediated direct fusion, without requiring passage from Langerhans cells, and overt productive infection ensued. Full-Text PDF Open Access