Resolución de problemas

Both human (Beersma e t a l , 1993; Warren et a l, 1994) and murine CMV (Del Val et a l ,

1989) cause MHC class I downregulation, due to a failure of class I molecules to leave the ER. In the case of human CMV, early evidence of MHC class I downregulation was given by Barnes & Grundy, who demonstrated a dramatic reduction in the cell surface level of class I molecules on infected cells (Barnes and Grundy, 1992). Since then several CMV genes have been shown to be responsible for that effect. Experiments using a series of CMV deletion mutants identified a 7 kb region, encoding 10 genes, that is required for class I downregulation in CMV-infected cells (Hengel et a l , 1996; Jones et a l , 1995). Three of the genes encoded in this region, US2, US3 and USl 1, were able to reduce class I expression at the cell surface when expressed individually (Ahn et al, 1996; Jones et a l ,

1996; Wiertz et a l , 1996a). The US2 and US 11 gene products decrease the surface

expression of MHC class I molecules by causing a rapid translocation of newly synthesised class I heavy chains from the ER to the cytosol where they are exposed to proteases and proteosomes and degraded. In the case of the US2 gene product, it has been shown to be capable of relocating the nascent ER class I chain back into the cytosol (Wiertz

et al, 1996b). The US3 protein destabilises the maturation and transport to the cell surface

of class I heavy chains. The US3 gene product forms a complex with p^^^-^ssociated class

I heavy chain, which then accumulates in the ER. Thus, class I molecules are retained but not degraded during the immediate early period of the infection (Ahn et al., 1996; Jones et

al., 1996). The mechanism of class I downregulation used by the US6 gene product is to

bind directly to the TAP complex, and thereby inhibiting peptide translocation from the cytosol to the ER lumen (Hengel et al., 1996; Lehner et al, 1997).

The observation that even though the 72 kd immediate early protein from CMV is abundantly expressed in the immediate early phase of the infection, it is relatively poorly recognised by CMV-specific T cells, led to the identification of another mechanism of evasion of the T cell response. As demonstrated in a vaccinia virus expression system, recognition of the 72 kd immediate early protein by CMV-specific CTLs was selectively abrogated by the co-expression of pp65, a protein which possesses an associated kinase activity (Gilbert et a l, 1996). The interpretation of this finding was that the phosphorylation of the 72 kd substrate by pp65 would limit the access of the 72 kd protein to the class I processing machinery.

Although interference with class I cell surface expression would seem a simple way for any virus to escape immune surveillance, the down regulation of class I molecules could potentially lead to improved recognition by NK cells (Karre et al., 1986). An increasing amount of evidence suggests that NK cells recognise and destroy cells that no longer express MHC class I molecules, the 'missing self hypothesis' (Ljunggren and Karre,

1990). Therefore, any virus infected cell that has reduced or lost the expression of MHC class I molecules in order to avoid CTL attack could be susceptible to attack by NK cells.

Interestingly, CMV seems to have evolved an extra strategy to avoid being recognised by the host’s immune system. The CMV UL18 gene encodes a protein with homology to the

class I heavy chain (Beck and Barrell, 1988; Browne et a l, 1990) which binds to and

is also able to bind peptides (Fahnestock et al, 1995). In one study, cells transfected with

UL18 became resistant to NK cell lysis (Reybum et a l, 1997). However, this finding has recently been disputed (Leong et a l, 1998), and the function of UL18 awaits further

clarification. The reason why CMV might have to have had to acquire these complementary strategies in order to avoid immune recognition, might be because of its prolonged replication period, which means that the virus has an extended exposure to immune recognition and attack.

7.5

Pathogenicity o f CMV infection

There are several chnical situations in which individuals are incapable of mounting an effective immune response to certain viruses. In these type of situations CMV infections represent an important cause of severe and sometimes fatal disease. Before transplantation became a common procedure, congenital infection of the immunologically immature foetus was the most important clinical manifestation of CMV infection in humans (Weller, 1971). However, since the emergence of solid organ and bone marrow transplantation, which require long-term immunosuppression to prevent allograft rejection or graft-versus host disease, CMV infection has been associated with a high incidence of morbidity and mortality (Drew et a l, 1984; Riddell and Greenberg, 1995a; Rubin et a l , 1985). The appearance of the acquired immunodeficiency syndrome (AIDS) generated an additional population of immunocompromised patients at high risk from CMV disease.

The pathology of CMV disease in general can be caused by two different mechanisms, the first one being direct viral damage of infected cells, which is common in severely immunocompromised hosts, such as AIDS patients or in congenital infection, where the

absence of an immune response allows high levels of viral replication and systemic disease. The second mechanism, involves pathology caused by the host immune response, and may be a contributory factor in the development of conditions associated with CMV infection in allogeneic transplant recipients (Grundy, 1993).