Human cytomegalovirus immune evasion strategies

Human cytomegalovirus (HCMV) is a member of the herpes virus family. HCMV is a ubiquitous pathogen, causing severe morbidity and mortality in immunocompromised patients, and is a major factor in congenital birth defects. Most adult individuals become carriers of latent HCMV after an asymptomatic infection, and have antibodies against HCMV proteins (are seropositive).

Experimental studies of HCMV infection has revealed many interesting features and effects of virally encoded genes to enable infected cells to escape immune recognition as well as to be protected from immune effector mechanisms. T cells recognize virus-encoded peptides presented in the context of HLA class I and class II surface molecules. CD4+ T lymphocytes primarily react against HLA class II-viral peptide complexes, whereas CD8+ T lymphocytes react against HLA class I-peptide complexes. NK cells, on the other hand, are usually thought to be more cytotoxic against cells that express lower concentrations of HLA class I molecules. HCMV has developed multiple immune evasion mechanisms to be able to co-exist with its host.

Here, we have investigated the mechanisms of HCMV immune evasion strategies. Several new strategies to avoid specific T cell activation and to resist NK cytotoxicity have been described. Resistance to NK killing is independent on the expression of the virally encoded class I homologue UL18, which has been suggested to be a major candidate for delivering inhibitory signals to NK cells. We have defined a new inhibitory pathway that leads to increased resistance of HCMV infected cells to cytolytic proteins released by activated NK cells. This insensitivity to cytolytic proteins is mediated by the viral protein UL16 and is presumably caused by a redistribution of calreticulin, a protein that has been shown to protect cells from perforin destruction through a membrane stabilization effect.

In addition, we have found that HCMV infected macrophages have a reduced capacity to activate a specific T cell proliferative response, compared to uninfected cells. This, in part, is caused by an abundant viral protein pp65, which mediates an accumulation of HLA-DR to lysosomes and degradation of the HLA-DR a-chain. Interestingly, UL18 interacts directly with immunoreactive T lymphocytes, to limit T cell activation. T cells exposed to HCMV express activation markers, produce lower levels of cytokines, but lack proliferative capacity. These cells do not enter apoptosis and can therefore be described as "anergic". These findings increase the current knowledge of how HCMV can avoid detection and elimination by the host immune system.

List of scientific papers

I. Odeberg J, Cerboni C, Browne H, Karre K, Moller E, Carboni E, Soderberg-Naucler C (2002). Human cytomegalovirus (HCMV) infected endothelial cells and macrophages are less susceptible to NK lysis independently of downregulation of classical HLA class I molecules, or expression of the HCMV class I homologue, UL 18. Scandinavian Journal of Immunology. 55(2): 149-161.

II. Odeberg J, Browne H, Metkar S, Froelich CJ, Branden L, Cosman D, Soderberg-Naucler C (2002). The human cytomegalovirus (HCMV) protein UL 16 mediates increased resistance to cytolytic proteins. [Submitted]

III. Odeberg J, Soderberg-Naucler C (2001). Reduced expression of HLA class II molecules and Iinterleukin-10- and transforming growth factor beta1-independent suppression of T-cell proliferation in human cytomegalovirus-infected macrophage cultures. J Virol. 75(11): 5174-81.
https://pubmed.ncbi.nlm.nih.gov/11333898

IV. Odeberg J, Browne H, Cosman D, Soderberg-Naucler C (2002). The human cytomegalovirus (HCMV) HLA class I homologue UL 18 participates in the induction of anergy in CD4+T cells. [Submitted]