Kaposi’s sarcoma-associated virus mounts novel attack on immune system

Abstract

Herpesviruses are well known for their complex strategies for evading the immune response, which enable them to produce persistent infections. However, the approach of Kaposi’s sarcoma-associated herpesvirus (KSHV) is unprecedented. ‘It is not escaping in the sense of hiding or of altering itself so it cannot be recognized,’ comments immunologist Frances Gotch (Imperial College School of Medicine, London, UK). ‘It actually is still capable of being recognized, but it is hijacking that very part of the immune system involved in its recognition – an extremely clever mechanism.’Intracellular viruses can be detected by the immune system because class I major histocompatibility complex (MHC) molecules continually deliver fragments of viral proteins to the cell surface, where they are detected by cytotoxic T lymphocytes (CTLs). As a result, CTLs kill the infected target cells. Herpesviruses encode many proteins that downregulate MHC-I expression. So does KSHV. But, while other herpesvirus proteins affect the synthesis, translocation or assembly of class I chains, the K3 and K5 proteins of KSHV accelerate endocytosis of MHC-I molecules that have made it to the surface of infected cells.Two research teams, at the University of California in San Francisco (CA, USA) and at Harvard Medical School (Southborough and Charleston, MA, USA), reached this conclusion after having done a ‘phenomenal amount of work’, as John Wilkinson, a KSHV specialist in Gotch’s lab, puts it. Both groups showed that K3 and K5 do not affect MHC-I maturation or egress from the endoplasmic reticulum (ER) (pulse-chase experiments and endo H digestion) but accelerate the internalization of surface MHC-I chains (immunofluor-escence-based endocytosis assays)1xKaposi’s sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Coscoy, L. and Ganem, D. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 8051–8056Crossref | PubMed | Scopus (319)See all References, 2xDownregulation of major histocompatibility complex class I molecules by Kaposi’s sarcoma-associated herpesvirus K3 and K5 proteins. Ishido, S. et al. J. Virol. 2000; 74: 5300–5309Crossref | PubMed | Scopus (319)See all References. Don Ganem’s laboratory in California conducted further studies to support the endocytosis hypothesis, such as experiments in K5-expressing cells in which the endocytic pathway was blocked by dominant-negative dynamin mutants; they also demonstrated that internalized chains undergo lysosomal degradation.Exactly how endocytosis of MHC-I is achieved remains a puzzle. Both groups confirmed the localization of K3 and K5 in the ER, that is, in a compartment with no link to the cell surface (Fig. 1Fig. 1). The team led by Jae Jung at Harvard demonstrated that K5 targets the transmembrane domain of class I chains, a result that has now been confirmed by Ganem’s team. Jung’s lab is currently investigating how rearrangements of the cytoskeleton are involved in the regulation of class I internalization. ‘At this stage, we cannot say much about how endocytosis is upregulated,’ concludes Ganem, ‘but our results suggest that there is a whole form of endocytic regulation that is different from those that have been described in the past.’Figure 1MHC-I molecules (a) and the viral protein K3 (b) are not colocalized in the same compartment of HeLa cells, as demonstrated by indirect immunofluorescence and confocal microscopy (c). Green staining indicates MHC-I expression and red staining indicates expression of haemagglutinin-tagged K3. Images kindly provided by Laurent Coscoy and Don Ganem.View Large Image | Download PowerPoint SlideKSHV has been identified only recently and is linked strongly to the development of Kaposi’s sarcoma (KS), a cancer that develops in connective tissues, including cartilage, bone and blood vessels. In the past 20 years, most cases of KS have developed in association with HIV infection; about one in four homosexual or bisexual men with AIDS will develop KS during their illness. The condition is believed to cause, or contribute to, death in up to 30% of AIDS cases.Although the two studies described above provide no direct clues to the understanding of how infection predisposes to KS, they underline the fact that the immune system is very important in the control of KSHV and that the virus has equipped itself with devices to evade it. Both Ganem and Jung have new evidence that K5 not only ‘hijacks’ MHC-I chains, but that it also targets other molecules involved in lymphocyte signaling, thereby affecting the responses not only of CTLs, but also of other immune effectors as well. Even though those devices turn out to be imperfect and most infections remain subclinical, the virus poses a real threat to immunodeficient people.