Virus receptors and cell tropisms

Journal of Infection (I986) I2, 199-2o3

Virus receptors and cell tropisms C. A. Mims Department of Microbiology, Guy's Hospital Medical School, U.M.D.S. London SEI 9RT Accepted for publication I7 January I986 Recent research on virus receptors has yielded information that not only accounts for the cell tropism of certain viruses but also helps to explain the pathogenesis and immunology of diseases caused by these viruses. By their nature, viruses must gain entrance to host cells in order to replicate. First, they must adhere to the surface of the host cell as a necessary preliminary to entering the cell and being uncoated. This adherence requires binding of viral surface (envelope or capsid) polypeptides to components on the plasma membrane of the host cell, an event which may trigger entry of the virus into the cell. 1 T h e binding site on the cell (virus receptor) is known only for a small number of viruses but is often a specific carbohydrate moiety. A given receptor may be used by more than one virus. Studies done many years ago on Hela cells showed that there were four different families of receptors used by various picornaviruses and adenoviruses. 2 In these experiments an excess of one virus was added to block attachment of other (labelled) viruses using the same receptor, but the interpretation of the results has been questioned2 Receptors, of course, are not displayed on the cell surface for the benefit of infecting viruses. Viruses must make use of whatever molecules are available. Sometimes the receptor molecule will be present on many types of cell but occasionally a virus will have singled out (' chosen') as a receptor a particular molecule that is present on one or two types of cell only. T h e known examples are shown in Table I. Lactic dehydrogenase virus, for instance, which causes a lifelong inapparent infection of mice, attaches to Class II Major Histocompatibility Complex (MHC) antigens (I a antigens) present on a subpopulation of macrophages. 4 Infected cells are destroyed, and since I a + (antigen presenting) cells are essential for the initiation of host immune responses, infected mice show immune dysfunction. Semliki Forest virus was reported to use Class I M H C antigens on human or murine cells as virus receptors, 5 but it is clear that Class I negative cells can also be infected2 Epstein-Barr (EB) virus attaches to the C3d receptor present on B cells 7 and this explains the infection of these cells. Polyclonal activation of infected B cells, together with immune attack on them by the patient's own T cells, accounts for much of the disease. Cells other than B cells may be infected when they are coated with C3d receptors, or when the viral genome is introduced directly into the cell by micromanipulation. Mere binding of virus to a host cell, however, does not ensure productive infection, because this depends on successful completion of a subsequent series oi63-4453/86/o3o199+o5 $o2.oo/o

© x986 The British Society for the Study of Infection

LDV + antibody Dengue + antibody

Vaccinia

Influenza A

Reovirus type 3

Rabies

Lactic dehydrogenase virus (LDV) AIDS-associated virus (HTLV-III/LAV) Epstein-Barr

Virus

Fc receptor Fc receptor

Acetylcholine receptor 2° fl-adrenergic 21 receptor ? Sialic acidcontaining glycoprotein or glycolipid Epidermal growth factor receptor? ~ Macrophage Macrophage

Epidermal cells

Respiratory epithelial ceils (intestinal epithelial cells in birds)

Neurone, T cell in mice

Peripheral nerve

T4 + (helper) T cell (Also macrophage/dendritic cell) B cell (also epithelial cell)

CD4 (T4) C3d receptor

I a + macrophage

Susceptible cell

I a antigen

Receptor

Table I Virus receptors

Infection of I a negative macrophages 9 Enhanced infection of monocytes/ macrophages 23

Epidermal tropism

Depletion of I a + ceils immunosuppression T helper cell depletion, immunosuppression Polyclonal activation B cells; control by uninfected T cells; immunopathology CNS infection initiated via peripheral nerve endings Infection of neurones (encephalitis) and T cells Respiratory replication and pathology (intestinal replication in birds)

Consequence

¢3

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of events. Thus, lactic dehydrogenase virus does not cause productive infection in mouse dendritic cells (I a positive), in I a-positive B cell lines, or in mouse L cells expressing I a antigens after transfection with I A or I E (Class II) genes. 8 Also, the existence of a given receptor does not necessarily mean that a cell lacking this receptor cannot be infected. Thus, EB virus infects epithelial cells both in vitro and in vivo and these cells do not have C3d receptors. Presumably there are alternative receptors or alternative modes of entry into epithelial cells. Conceivably infected B lymphocytes transmit infection to epithelial cells by direct contact. In the case of lactic dehydrogenase virus, it has been shown that when virus is complexed with non-neutralising antibody the Fc portion of the antibody will bind the complex to macrophages bearing Fc receptors, and these cells, even when they lack the I a receptor for the virus, can thus be infected. ° Again, in vitro studies make it clear that rabies virus can infect cells which do not carry the acetylcholine receptor. 1°, 11 T h e receptor for the AIDS-associated virus ( H T L V - I I I / L A V ) appears to be the CD4 (T4) antigen or closely related component present on T helper cells, as identified by the monoclonal antibody O K T 4 .12 Hence T helper cells are infected and ultimately deleted, and the T helper deficit to a large extent accounts for the immune deficit in A I D S patients. T helper cells are more susceptible, in the sense that they produce more virus, when they are immunologically activated. There is electron microscopical evidence that antigen-presenting cell types (follicular dendritic cells, macrophages) are also infected, 13 and it is possible that this is because they can express low levels of CD4. A recent report suggests that in the early stages the immune deficit is due to defects in antigen presentation or recognition rather than to defective function of T helper cells, because the latter cells respond normally to mitogenic stimulation. 14 Neural cells also appear to be infected by A I D S associated virus, l° giving rise to encephalopathy and dementia. T h e y do not express the CD4 antigen, and either possess different receptors for the virus or possibly are infected by direct contact with infected CD4 + cells which have migrated into the brain. T h e importance of these studies on virus receptors is not only that they may account for cell tropisms, but also, when the target cell is a vital one and is killed or functionally inactivated, this can account for the disease itself. It is possible that other virus receptors may turn out to be important host cell components, such as receptors for hormones or growth factors. It is not out of the question that a given virus could have two different receptors, enabling it to infect different types of cell at key stages in pathogenesis. T h e list in Table I will certainly be expanded. T h e work on virus receptors which happen to be immunologically important molecules leads to the following suggestions about the interaction of viruses with the immune system. Invasion of cells of the immune system can be looked upon teleologically as a virus strategy, as far as persistent infections (or infections with a long incubation period) are concerned. I f the virus can interfere with immune function and switch off or delay immune responses directed against itself, then persistence is made easier and there is time for a lengthy incubation period to be completed. In the example of lactic dehydrogenase virus in mice, invasion of immunologically important cells is associated

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with failure to eliminate the virus. Immunosuppression is demonstrable but is not severe enough to cause disease'by increasing susceptibility to infection with other micro-organisms. Mice remain well in spite of lifelong persistence of the infection. This can be compared to infection with the A I D S-associated virus which also invades cells of the immune system and causes immunosuppression. As with lactic dehydrogenase virus in mice, this can be regarded as a viral strategy in so far as it is associated with almost complete failure to produce neutralising antibodies, 16 and the virus persists in the body. With AIDS-associated virus, however, the immuno-suppression, looked upon as a viral strategy, appears to have overshot the mark, as it were. It is much more severe, or possibly is made more severe by the additional infections (CMV, etc.) that occur, and the disease A I D S is a result of this. I have discussed virus receptors as determinants of cell susceptibility, but there are other factors accounting for infection of certain cell types in vivo. Many years ago it was shown that in mice infected with vaccinia virus, hepatic cells were not normally involved because circulating virus was taken up by Kupffer cells and failed to reach hepatic cells. 17 Hepatic cells became infected when virus was introduced directly into them following injection up the bile duct. Perhaps there are other examples where infection is restricted to a specific type of cell in v i v o merely because the virus fails to encounter other types of cell which may also be susceptible. For instance, influenza A virus infects respiratory epithelial cells in mammals, and this was one of the first viruses to have its receptor identified (see Table I). Yet in birds, closely related influenza A viruses infect intestinal epithelial cells and are shed in large amounts in faeces. Could it be that human influenza virus, if it were more resistant to acid pH and was given the chance, would infect intestinal epithelial cells in man? In ferrets, the urogenital tract has been shown to support the growth of influenza virus experimentally. 16 Conceivably the virus could develop the ability to infect urethral cells in man if it were given the opportunity, perhaps causing a new type of viral urethritis. Sexually transmitted infections are doing very well and look as if they have a great future in our species. Although this concept may be only a fantasy, it has to be pointed out that influenza virus can undergo rapid adaptive change, and regular encounters with urethral cells would select any virus variants capable of replicating in these ceils. T h e same may be said of other human viruses. T h e adenoviruses, for instance, are known to be a versatile group, and include types that infect epithelium in the conjunctiva, bladder, nasopharynx, lung and intestine. Some of them have already given signs that they have the ability to infect male and female genital tracts. ~9 New human virus infections may be caused not only by viruses acquired from animals, but also by old human viruses that have learnt new tricks. References

I. DimmockNJ. Initial stages in infectionwith animal viruses, jr Gen Virol I982 ; 59: 1--22. 2. Lonberg-Holm K, Crowell RL, Philipson L. Unrelated animal viruses share receptors. Nature r976; 259: 679--68I. 3. Spier RE, Murdin A, Whittle CJ. The attachment of the Foot-and-Mouth Disease virus Asia I Iran I/73 to BHK. suspensioncells does not require virus specificcell receptors.Arch Virol i983; 77: 97-Io8.

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4. Inada T, Mims CA. Mouse I a antigens are receptors for lactate dehydrogenase virus. Nature 1984; 309: 59--61. 5. Helenius A, Morein B, Fries E et al. Human (HLA-A and HLA-B) and murine (H-2K and H-2D) histocompatibility antigens are cell surface receptors for Semliki Forest virus. Proe Natl Acad Sci U S A 1979; 75:3846-385 o. 6. Oldstone MBA, Tishon A, Dutko FJ, Kennedy SI. Holland JJ, Lampert P.W. Does the major histocompatibility complex serve as a specific receptor for Semliki Forest virus? J Virol 198o; 34: 256-265. 7. Fingeroth JD, Weiss JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Aead Sci U S A 1984; 81 : 45IO-4514. 8. Inada T, Mims CA. Unpublished observations. 9. Inada T, Mims CA. Ia antigens and Fc receptors of mouse peritoneal macrophages as determinants ofsusceptibil.ity to lactic dehydrogenase virus.J Gen Viro11985; 66: 1469-I477. lO. Lentz TL, Burrage TG, Smith AL, Crick J, Tignor GH. Is the acetylcholine receptor a rabies virus receptor? Science 1982; 215: 182. I I. Reagan KJ, Wunrler WH. Rabies virus interaction with various cell lines is independent of the acetylcholine receptor. Arch Virol 1985; 84: 277-282. 12. Dalgleish AG, Beverley PCL, Clapham PR, Crawford DH, Greaves MF, Weiss RA. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 1984; 312: 763-767. 13. Armstrong JA. Research developments in AIDS. M e d J Australia 1984; 141 : 556-557. 14. Lane HC, Depper JM, Greene WC, Whalen G, Waldmann" TA, Fauci AS. Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. New E n g I J Med 1985; 313: 7915. Shaw GM, Hayer ME, Hahn BH et al. H T L V - I I I infection in brains of children and adults with AIDS encephalopathy. Science 1985; 227: 177-182. 16. Weiss RA, Clapham PR, Cheingsong-Popov R et al. Neutralisation of human T lymphotropic virus type I I I by sera of AIDS and AIDS-risk patients. Nature 1985; 316: 69. 17. Mims CA. Aspects of the pathogenesis of virus diseases. Bact Rev 1964; 28: 30. 18. Toms GL, Rosztoczy I, Smith H. The localisations of influenza virus, minimal infectious dose determination and single cycle kinetic studies on organ cultures of respiratory and other ferret tissues. Br J Exp Pathol 1974; 55: 116-129. 19. Harnett GB, Newnham WA. Isolation of adenovirus type 19 from the male and female genital tracts. Br J Vener Dis 1981; 57: 55-57. 20. Burrage TC, Tignor GH, Smith AL. Rabies virus binding at neuromuscular junctions. Virus Res 1985; 2: 273-279. 21. Co MS, Gaulton GN, Fields BN, Green MI. Isolation and biochemical characterisation of the mammalian reovirus type 3 cell-surface receptor. Proc Natl Acad Sci U S A 1985 ; 82: 1494-1498. 22. Eppstein DA, Marsh YV, Schreiber AB, Newman SR, Todaro GJ, Nestor JJ. Epidermal growth factor receptor occupancy inhibits vaccinia virus infection. Nature 1985; 318: 663-665. 23. Peiris JSM, Porterfield JS. Antibody-mediated enhancement of flavivirus replication in macrophage-like cell lines. Nature 1979; 282 : 509-51 I.