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  • Review Article
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Setting the stage: host invasion by HIV

Nature Reviews Immunology volume 8, pages 447–457 (2008)Cite this article

Key Points

  • HIV invasion through the mucosa of the female lower genital tract contributes the largest number of new HIV infections worldwide. The second leading site of viral invasion is the lower male genital tract, followed by invasion via the rectal mucosa in both women and men.

  • Models of explanted human genital tissues have provided new insights into the mechanisms of sexual HIV transmission.

  • Initial attachment of HIV-1 to the mucosa may be aided by cervical mucus and various gp120-binding surface receptors on epithelial cells. HIV-1 penetration into the genital mucosa occurs rapidly after exposure and is possibly enhanced by micro-abrasions or genital ulcer disease.

  • In the human vagina, intraepithelial CD4+ T cells and CD1a+ Langerhans cells are the first cells infected by HIV-1.

  • Vaginal Langerhans cells exhibit a high capacity to endocytose HIV-1 virions. C-type lectins such as dendritic-cell-specific ICAM3-grabbing non-integrin (DC-SIGN; also known as CD209) or langerin (also known as CD207) appear to have little or no role in mediating this infection pathway.

  • Genital CD4+ T cells express high levels of CC-chemokine receptor 5 (CCR5) are rapidly infected by HIV-1 and produce large quantities of viral progeny.

  • In vitro studies have shown that dendritic cells use several pathways to enhance viral propagation to CD4+ T cells for productive infection. Presumably these also occur in the genital mucosa, but direct evidence is lacking.

  • The highly protective effect of circumcision indicates that viral invasion in men occurs predominantly through the inner foreskin, where both CD1a+ Langerhans cells and CD4+ T cells are abundant. The second leading site of viral invasion in the male genital tract is probably the penile urethra.

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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Figure 1: HIV invasion sites.
Figure 2: Pathways of HIV invasion in the mucosa of the vagina and uterine ectocervix.
Figure 3: HIV-1 transcytosis in situ in the vaginal epithelium.
Figure 4: The significance of DC–T-cell interactions for HIV-1 transmission.

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Acknowledgements

We thank L. Ballweber and P. Sakchalathorn for electron microscopy and P. Stegall for editorial assistance. This work was supported by the US National Institutes of Health grants AI51980, HD51455, and the James B. Pendleton Trust.

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Authors and Affiliations

  1. Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Florian Hladik & M. Juliana McElrath

  2. Department of Medicine, University of Washington School of Medicine, Seattle, 98195, Washington, USA

    Florian Hladik & M. Juliana McElrath

  3. Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, 98195, Washington, USA

    Florian Hladik

  4. Department of Global Health and Laboratory Medicine, University of Washington School of Medicine, Seattle, 98195, Washington, USA

    M. Juliana McElrath

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Glossary

Simian–HIV

(SHIV). SHIVs are chimeric viruses that are created by inserting the envelope protein (Env), the transcriptional transactivator (Tat) and the regulator of virion gene expression (Rev) of HIV into the SIVMAC239 clone. Depending on the particular HIV Env protein, these SHIVs have different in vivo characteristics. The SHIV chimeric viruses are best used for testing antibodies specific for HIV in non-human primate models.

Transcytosis

The process of transport of material, including HIV virions, across a cell layer by uptake on one side of the cell into a coated vesicle. The vesicle might then be sorted through the trans-Golgi network and transported to the opposite side of the cell, where its contents are released into the extracelluar space.

Langerhans cell

(LC). A type of dendritic cell that is localized in the squamous epithelial layer of the skin and certain mucosae.

Syndecans

Single transmembrane domain proteins that carry three to five heparan sulphate and chondroitin sulphate chains that allow for interaction with various ligands including residues on the HIV-1 gp 120 protein.

Stromal papillae

Superficial areas of the mucosal stroma that interdigitate with the epithelium.

C-type lectin receptors

A large family of receptors that bind glycosylated ligands and have multiple roles, such as in cell adhesion, endocytosis, natural-killer-cell target recognition and dendritic-cell activation.

R5-tropic HIV-1

An HIV strain that uses CC-chemokine receptor 5 (CCR5) as the co-receptor to gain entry to target cells.

Birbeck granules

Membrane-bound rod- or tennis-racket-shaped structures with a central linear density, found in the cytoplasm of Langerhans cells. Their formation is induced by langerin, an endocytic C-type lectin receptor that is specific to Langerhans cells.

Phagosomes

Vacuolar compartments that confine microorganisms after enforced endocytosis or after phagocytosis. Unless counteracted by a microbial survival strategy, the phagosome matures into a hostile environment that is designed to kill and digest microorganisms.

Cross-presentation

The initiation of a CD8+ T-cell response to an antigen that is not present within antigen-presenting cells (APCs). This exogenous antigen must be taken up by APCs and then re-routed to the MHC-class-I pathway of antigen presentation.

Lamina propria

Connective tissue that underlies the epithelium of the mucosa and contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.

Macropinocytosis

A mechanism of endocytosis in which large droplets of fluid are trapped underneath extensions (ruffles) of the cell surface. Can be exploited by some pathogens as a route for entry into cells.

Exosomes

Small lipid-bilayer vesicles that are released from activated cells. They comprise either plasma membrane or membrane derived from intracellular vesicles.

Filopodia

Slender cytoplasmic projections, which extend from the leading edge of migrating cells.

Cytonemes

Actin-based filopodial-cell extensions.

Nanotubules

Cytonemes that connect blood cells over a distance of several cell diameters and transport membrane proteins, lipids and ions from one of the connected cells to another, thus executing long range intercellular communications.

Glans penis

Sensitive tip of the penis. When the penis is flaccid it is wholly or partially covered by the foreskin, except in men who have been circumcised.

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Hladik, F., McElrath, M. Setting the stage: host invasion by HIV. Nat Rev Immunol 8, 447–457 (2008). https://doi.org/10.1038/nri2302

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