Setting the stage: host invasion by HIV - PubMed (original) (raw)

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Setting the stage: host invasion by HIV

Florian Hladik et al. Nat Rev Immunol. 2008 Jun.

Abstract

For more than two decades, HIV has infected millions of people worldwide each year through mucosal transmission. Our knowledge of how HIV secures a foothold at both the molecular and cellular levels has been expanded by recent investigations that have applied new technologies and used improved techniques to isolate ex vivo human tissue and generate in vitro cellular models, as well as more relevant in vivo animal challenge systems. Here, we review the current concepts of the immediate events that follow viral exposure at genital mucosal sites where most documented transmissions occur. Furthermore, we discuss the gaps in our knowledge that are relevant to future studies, which will shape strategies for effective HIV prevention.

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Figures

Figure 1

Figure 1. HIV invasion sites

HIV mucosal invasion sites of the lower genital tract, the rectum, and the upper intestinal tract. In women, viral invasion occurs mostly through the non-keratinized squamous epithelium of the vagina and ectocervix, as well as through the single-layer columnar epithelium of the endocervix. The endocervical canal is filled with mucus, providing a barrier against ascent of pathogens. However, ovulation is accompanied by hydration and alkalinization of the mucus plug, possibly decreasing its barrier function. Infection in women can also ensue when HIV-1 invades the single-layer columnar epithelium of the rectum following receptive anal intercourse. In men, viral invasion occurs most frequently through the inner foreskin and the penile urethra as a consequence of penile–vaginal or penile–anal intercourse. Thinly stratified columnar epithelial cells line most of the urethra except for the fossa navicularis near the external meatus (exit hole), which is covered by non-keratinized squamous epithelium. The glans penis and the outer foreskin are protected by keratinized squamous epithelium, which provides a strong mechanical barrier against HIV invasion. By contrast, a thin and poorly keratinized squamous epithelium covers the inner foreskin, rendering this site vulnerable to HIV invasion. Men are also infected by viral invasion through the rectum. In fact, receptive anal intercourse carries the highest per exposure probability of infection among all mucosal transmission sites. The upper gastrointestinal (tract, lined by non-keratinized squamous epithelium in the oropharynx and the esophagus, and by single layer columnar epithelium in the stomach and the small intestine, is another site of mucosal HIV invasion. In adults, transmission in the upper gastrointestinal tract occurs following contact with HIV-containing semen during fellatio, but the efficiency of this route is low. In infants, HIV invasion in the upper gastrointestinal tract occurs after exposure to or ingestion of infected maternal blood and genital secretions during birth as well as infected milk during breast feeding.

Figure 2

Figure 2. Pathways of HIV invasion in the mucosa of the vagina and uterine ectocervix, part A

The human vagina and ectocervix are covered by non-keratinized squamous epithelium. Shearing during sexual intercourse can lead to physical abrasions of the epithelium, in particular in microanatomical regions where the stromal papillae, enriched with stromal DCs, reach close to the luminal surface of the mucosa. Depicted are two stromal papillae containing arterioles, venules and lymphatic vessels. The stromal papilla on the right signifies the afferent arm shuttling blood cells to the mucosa. Monocytic precursor cells differentiate upon arrival either into macrophages or dendritic cells (DCs), and DCs may differentiate further into subsets. Three stromal DC subsets have been identified in human skin, distinguished by BDCA-1, CD1 and CD14 expression patterns, but their presence and susceptibility to HIV have not been determined in the mucosa. An abrasion of the outer epithelium exposes the stromal papilla tip (left), as well as several epithelial cells located close to or within the basal layer. Infected donor cells and free virions may migrate along such an abrasion, as shown here, and directly contact various target cells in the mucosal epithelium and stroma. Resident mucosal leukocytes such as DCs and T cells tend to cluster in these regions (see Figure 3e), creating susceptible foci for infection. Possible pathways for HIV penetration are depicted on the left side of the illustration and are indicated by letters. Characteristic phenotypic cell receptors and receptors relevant for HIV binding and infection are shown on the top of the figure. a. Trapping of free HIV virions or HIV-infected donor cells in mucus covering the mucosa. b. Attachment of HIV-infected donor cells to the luminal surface of the mucosa and secretion of virions upon contact. c. Penetration of virions into gaps between epithelial cells. d. Capture of penetrating virions by Langerhans cells (LCs) residing within the epithelium, which extend processes toward the vaginal lumen. e. Internalization of virions into endocytic compartments of LCs. f. Fusion of HIV with the surface of intraepithelial CD4+ T cells, followed by productive infection. g. Transcytosis of virions through epithelial cells located close to or within the basal layer of the squamous epithelium (Figure 3a–c). h. Productive infection of basal epithelial cells. i. Internalization of virions into endocytic compartments of basal epithelial cells. j. Immigration of infected donor cells along physical abrasions of the epithelium into the mucosal stroma, where they are taken up by lymphatic or venous microvessels and transported to local lymph nodes or the blood circulation. k. Immigration of free virions along microabrasions into the stroma, where they can make direct contact with stromal DCs. l. Productive infection of stromal DCs by HIV. m. Internalization of virions into endocytic compartments of stromal DCs. n. Passage of virus from stromal DCs to CD4+ T cells across an infectious synapse (see also Figure 4). o. Massive productive infection of mucosal CD4+ T cells activated by contact with antigen-presenting DCs. p. Productive infection of resting mucosal CD4+ memory T cells. q. Binding of HIV and possibly productive infection of stromal macrophages. r. Emigration of productively infected CD4+ T cells and DCs into the submucosa and the draining lymphatic and venous microvessels. T cells may derive from the epithelium or the stroma. Likewise, emigrating DCs may originate from intraepithelial LCs or stromal DCs. DCs and T cells often form conjugates, and HIV may accumulate between the two cells along an infectious synapse. DCs carry virions in endocytic compartments and some are also productively infected, but it remains unclear at which differentiation stage this occurs.

Figure 3

Figure 3. Pathways of HIV invasion in the mucosa of the vagina and uterine ectocervix, part B

A–C. Likely HIV transcytosis in a vaginal epithelial cell in situ located one layer above the basal cell layer. Virions can be seen in the cytoplasm on both sides of the nucleus. Desmosomes and keratin fibers identify the cell as epithelial.

Figure 4

Figure 4. Significance of DC–T-cell interactions for HIV-1 transmission

A. Pathways of HIV-1 passage between dendritic cells (DCs) and T cells. DCs can store HIV-1 in three forms for eventual infection of CD4+ T cells. (1) Endocytosed intact virions. Endocytic entry via C-type lectins such as DC-specific ICAM3-grabbing non-integrin (DC-SIGN, CD209) directs HIV to early and late endosomes. From there it enters multivesicular bodies and remains intact, or traffics to lysosomes where it is degraded. (2) Integrated provirus. Entry of HIV-1 by CD4- and co-receptor-mediated fusion leads to productive infection of DCs. (3) Surface-bound intact virions. Binding and trapping of intact virions on the cell surface can also occur by C-type lectins such as DC-SIGN. Passage of HIV-1 from DCs to CD4+ T cell occurs most effectively across an infectious synapse, formed by concentration of HIV-1 on the DC side and of HIV receptors such as CD4 and CC-chemokine receptor 5 (CCR5) on the T cell side. HIV is released into the infectious synapse either by exocytosis of stored virions from multivesicular bodies (MVBs) or by budding of newly formed virions following active viral replication. Surface bound virions may also accumulate at the infectious synapse. Migration of HIV toward the T cell may be further enhanced by “surfing” of virions along the outer surface of filopodia or cytonemes that are extended from the T cell toward the DC. Coupling of virions with exosomes as they are being released from MVBs may also increase their infectivity. Exosome-associated virions are likely to be transmitted to CD4+ T cells through membrane binding and fusion, either within the infectious synapse or over longer distances. In parallel to transmission of virus from the DC to the CD4+ T cell, the DC also presents antigenic peptides through MHC class II molecules to the T-cell receptor CD3. During peptide recognition, additional receptor–ligand pairs that are important for T-cell stimulation accumulate in this region and form an immunological synapse. Signals delivered through the immunological synapse lead to T-cell activation, which ultimately causes transcription factors such as nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NFAT) to translocate into the nucleus of the T cell. There, they bind to the enhancer region of the viral long terminal repeat (LTR) and activate viral gene transcription, driving HIV-1 replication. B–D. Example of infectious synapse formation between DCs and T cells in the human vagina (taken from Hladik F. et al.69). HIV-1 buds from the surface of the productively infected DC toward the contact zone between the DC and the two T cells. Viral budding is also seen along other areas of the DC surface. The DC contains the typical veiled nucleus as well as multiple large mitochondria, and one large cytoplasmic process is formed at the top right. C–D. The two contact zones with the lymphocytes are further magnified, displaying virus budding from the DC into the infectious synapse.

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