In article <814992394.8666 at akemi.demon.co.uk>,
Julian Brown <julian at akemi.demon.co.uk> wrote:
>Can someone explain how it is that the herpes viruses evade the immune
>system? I realise they integrate themselves into the genome and are
>able to remain dormant. But why is it that once they reactivate the
>immune system isn't able to clobber the multiplying viruses? If the
>virus has been dealt with in a primary infection one might expect the
>the immune system to be able to prevent secondary outbreaks. Why
Well, now you've touched on a subject near and dear to my heart. But
first I should clarify a couple of points. First, herpesviruses do not
integrate into the genome - the maintain themselves extrachromasomally.
Secondly, not all herpesviruses remain fully dormant - for example,
Epstein-Barr virus expresses several proteins even during its latency.
The other important point is that the different herpesvirus all seem to
use different mechanisms to evade the immune system. The best-understood
virus is herpes simplex, but its mechanisms seem quite different from
EBV, and human and mouse cytomegaloviruses are not only different from
herpes simplex, but from each other as well.
Starting with HSV: There are multiple mechanisms which target various
aspects of the immune system. HSV expresses receptors for both the Fc
region of antibodies, and for the C3b component of the complement
cascade. It's believed that these help reduce antibody-mediated cellular
cytotoxicity, complement-mediated lysis of infected cells, and perhaps
also increase resistance of the viral particle.
Of course the main antiviral activity isn't antibody, but rather cellular
immunity, mainly CD8(+) lymphocytes. The most important mechanism here is
a viral protein called ICP47, which binds to the TAP (transporters
associated with antigen processing) and thereby block MHC class
I-restricted antigen processing. This seems remarkably effective, as in
humans there are very few CD8(+) HSV-specific CTL - most cytotoxic
lymphocytes are of the CD4(+) phenotype, which is otherwise unusual.
It's also possible that HSV can evade natural killer cell activity - HSV
can infect NK cells through cell-to-cell spread quite efficiently and
rapidly inactivate the NK cell lytic activity. It's not clear how
important this is in vivo.
There may be other activities as well, but this is a start.
In the case of other herpesviruses, EBV does a bunch of things, including
secreting a viral protein homologous to IL-10 which modulates the immune
response in several ways. There's also recent evidence that something is
screwy about the overall cell-mediated immune response to EBV - but it's
not clear how. Also, one of the major latency proteins of EBV (EBNA-1)
contains a stretch of Gly-Gly-Ala repeats which seem to specifically
block presentation of proteins containing that sequence.
Cytomegaloviruses also block antigen presentation through MHC class I.
Human CMV inhibits transport of the MHC from the ER to the cell surface,
which mouse CMV causes rapid degradation of the MHC I proteins. The
viral proteins involved in the latter have recently been identified; the
mechanism is not yet known (or at least not yet published). The HCMV
proteins have also been recently identified and again the mechanism(s)
are not known. There seems to be redundancy in at least the MCMV and
probably the HCMV as well.
As far as other herpesviruses are concerned, there are yet more immune
evasion strategies. Most are poorly understood but potentially
interesting and useful.
There's an essay on viral immune evasion on the WWW at
http://www.eps.lshtm.ac.uk/~npanjwan/eiv.html ... it lists further
references and reviews. In case you can't get that, here are a few
relevant references - drop me a note if you want more, I've got a million
There are reviews in -
York IA, Johnson DC. 1995. Inhibition of humoral and cellular immune
recognition by herpes simplex viruses. IN: Viroceptors, Virokines, and
Related Immune Modulators Encoded by DNA Viruses. Ed. G. McFadden.
Austin: R.G. Landes Co., pp. 89-110
Dubin G, Fishman NO, Eisenberg RJ, Cohen GH, Friedman HM. 1992. The role
of herpes simplex virus glycoproteins in immune evasion. Curr. Top.
Microbiol. Immunol. 179: 111-20
Some articles -
Hill A, Jugovic P, York I, Russ G, Bennink J, Yewdell J, Ploegh H, Johnson
D. 1995. Herpes simplex virus turns off the TAP to evade host immunity.
York IA, Roop C, Andrews DW, Riddell SR, Graham FL, Johnson DC. 1994. A
cytosolic herpes simplex virus protein inhibits antigen presentation to
CD8+ T lymphocytes. Cell 77: 525-35
York IA, Johnson DC. 1993. Direct contact with herpes simplex
virus-infected cells results in inhibition of lymphokine-activated killer
cells because of cell-to-cell spread of virus. J. Infect. Dis.
Ian York (iayork at panix.com)
Dana-Farber Cancer Institute, 44 Binney St., Boston MA 02115
Phone (617)-632-3921 Fax (617)-632-2627