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Immunology and Cell Biology (2014) 92, 735–736; doi:10.1038/icb.2014.66; published online 26 August 2014

Beyond HIV envelope: host derived hitchhikers that limit HIV entry

Blocking of HIV entry through CD44–hyaluronic acid interactions

Stuart Turville1

1Laboratory of HIV Biology, Immunovirology and Pathogenesis Program, The Kirby Institute, University of New South Wales, Kensington, NSW, Australia

Correspondence: Stuart Turville, E-mail:

We often naively observe HIV as an entity that primarily utilizes its viral glycoprotein in the first-line contacts with cells or tissue. However, since the early pioneering work of Arthur et al.1 along with studies by Orentas and Hildreth,2 this has made us appreciate that many other cell-derived proteins in addition to HIV glycoproteins occupy the limiting space of the viral membrane. Indeed these latter cell-derived proteins can be in significantly higher abundance to the envelope glycoprotein.1 While investigators have ingeniously used this feature for capturing and/or purifying HIV virions3 or used their presence for determining their cellular source,4 their role in the virion is often perceived as that of unavoidable passengers during viral egress from the plasma membrane.

In this issue of ICB, Li et al.5 present data that highlight the role of the cell-derived protein CD44 and how it influences HIV entry into arguably the major HIV cellular targets, primary CD4 T cells. It also gives us a timely reminder of how producing HIV can be simply influenced by the choice of producer cell. Indeed if that latter cell is not derived from the in vivo targets that HIV infects, the subsequent dynamics of the viral progeny may not be representative of that which occurs in vivo. One of the major proteins captured by HIV when infecting CD4 T cells and macrophages is the CD44 receptor. Thus, Li et al.5 have turned their attention to this receptor and how it influences HIV spread. Through the use of producer cell lines that do not express CD44, Li et al. use this as a foundation and control to produce HIV with and without CD44 on its surface. Using this approach they focus their study on the major ligand for CD44, hyaluronic acid (HA), and how it influences infection in cell lines and primary CD4 T cells. Curiously HA is a major constituent of the extracellular matrix of the human mucosa and is broken down by the action of the enzyme Hyaluronidase. This breakdown of HA is believed to be key in many fundamental immunological processes, with high-molecular-weight HA engagement and low-molecular-weight HA having anti- and pro-inflammatory responses, respectively.6 In addition, inflammatory responses are exacerbated in CD44 knockout mice. Thus, it is no surprise that the CD44 HA interaction has been observed to regulate T-cell recruitment in addition to various inflammatory processes.

Through the dissection of the CD44–HA interaction between virions and primary CD4 T cells, several key observations are made by Li et al.5 The first is that extracellular HA can inhibit HIV infection in a dose-dependent manner only with virions that carry CD44. The latter was potentially related to the ability of HA to block protein kinase C alpha, yet the mechanistic role of why this would impact HIV infection is unclear. Following on from the ability of soluble HA to block was its actual role in the infection process of CD4 T cells. It is herein that they demonstrate the role of the enzyme hyaluronidase and its ability to not only cleave HA from the surface of CD4 T cells, but also increase HIV binding and subsequent infection in the process (Figure 1). Thus, in a physiological setting, any condition that would lead to the stripping back of HA by the increase of hyaluronidase would potentially result in an increase of CD4 T-cell substrates that HIV can infect. Interestingly, human semen is enriched in hyaluronidase, as this enzyme is needed by sperm to digest the hyaluronan in the corona radiata.7 Thus, it is no surprise that HA and hyaluronidase are increased as a consequence of sexual intercourse. Whether the presence of hyaluronidase in semen increases the ability of HIV to infect mucosal T cells is not yet known, but may be yet another factor in addition to amyloid fibrils8 that can significantly increase the ability of HIV to seed the T cells of the genital tract.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

The role of the CD44 on the limiting viral membrane. (a) (Left) Active viral egress from an infected CD4 T cell. Alongside HIV trimers (dark blue) are host-derived receptors (light blue) that are also incorporated into the viral membrane. (Right) The hypothetical interaction of the host cell-derived receptor CD44 with the ligand hyaluronic acid that limits the subsequent infection of a permissive neighboring cell expressing CD4 and the relevant chemokine receptors. (b) The role of surface expressed hyaluronic acid and its impact on HIV infection of a CD4 T cell. Note that CD44 on the left panel limits HIV infection by hyaluronic acid engagement. In the right panel the digestion of hyaluronic acid by the enzyme hyaluronidase limits the impact of CD44 binding and thus favours HIV envelope binding to CD4 and the relevant chemokine receptors to allow increased viral entry/infection.

Full figure and legend (134K)

Clearly more information is needed on the relative roles of HA and hyaluronidase in the context of the genital mucosa and HIV infection. In addition, it is unknown how HA affects infection of other cell types that line the epithelium (Langerhans cells and macrophages). If digestion of HA is an event that promotes HIV infection, fortunately HIV microbicides that inhibit hyaluronidase do exist, including poly (sodium 4-styrene sulfonate) (T-PSS) gel formulations9 and Vivagel (Starpharma; unpublished observations). Naturally, given hyaluronidase is needed for conception, these latter microbicides are also potent contraceptives.10,11

To conclude, the role of cellular receptors acquired within HIV’s membrane are largely unknown. Fortunately this current contribution by Li et al. gives an active role to one receptor that is acquired by HIV and makes us appreciate the complex surface that the virus carries in addition to its own envelope. It also reminds us that many other receptors and their roles are presently unknown. Are they passive? Do they aid infection or even tropism? Are viruses derived from macrophages with a separate repertoire of receptors equivalent to viruses that passage through CD4 T cells? Fortunately this study can act as a primer for these future studies, where we can further appreciate the role of other cellular receptors that hitch a ride with the virus during the final stages of egress.



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