Trends in Microbiology
Volume 17, Issue 3, March 2009, Pages 119-129
Journal home page for Trends in Microbiology

Review
Modulation of the immune system by Kaposi's sarcoma-associated herpesvirus

https://doi.org/10.1016/j.tim.2008.12.001Get rights and content

The most recently identified human herpesvirus is Kaposi's sarcoma-associated herpesvirus (KSHV). It causes Kaposi's sarcoma, a tumour occurring most commonly in untreated AIDS patients and the leading cancer of men in certain parts of Africa. KSHV might also contribute to the pathogenesis of primary effusion lymphoma and multicentric Castleman's disease. The genome of KSHV contains 86 genes, almost a quarter of which encode proteins with either demonstrated or potential immunoregulatory activity. They include homologues of cellular proteins and unique KSHV proteins that can deregulate many aspects of the immune response, including T- and B-cell functions, complement activation, the innate antiviral interferon response and natural killer cell activity. The functions of these proteins and the ways in which they perturb the normal immune response are the subjects of the present review.

Section snippets

Kaposi's sarcoma-associated herpesvirus

Kaposi's sarcoma (KS) is a multifocal malignancy predominantly affecting elderly Mediterranean men, individuals in Africa and patients with immune disorders, including those undergoing organ transplantation or infected with HIV. In all of these clinical categories of KS, the tumour represents aberrant angiogenesis or lymphangiogenesis (i.e. formation of new blood or lymphatic vessels, respectively) through proliferation of Kaposi's sarcoma-associated herpesvirus (KSHV)-infected spindle-shaped

T cells

T cells recognize antigens presented on the surface of cells. Classically, during virus infection, these endogenous antigens are produced as a result of viral replication within permissive cells. The viral proteins are degraded by ubiquitin-dependent proteolysis to yield either individual amino acid residues or short peptides that are transported into the lumen of the endoplasmic reticulum. This process occurs by the peptide transporter associated with antigen presentation (TAP)-1 and TAP-2

Humoral immunity

Secreted immunoglobulins, or antibodies, are produced by activated B lymphocytes. Antibodies can directly neutralise viruses by steric hindrance of receptor-virus ligand interaction or by inducing conformational changes in viral receptor ligands. Other indirect effects of antibodies involve recruitment or activation of innate immune effector mechanisms including antibody-dependent cell cytotoxicity (ADCC), engulfment of antibody-coated (opsonised) virus by phagocytes and complement activation.

IFN

Arguably IFN-α and IFN-β are the most important and certainly the most understood of the IFNs associated with innate immunity to be activated in response to virus infection (Box 2). The assembly of the IFN-enhancesome on the IFN-β promoter initiates gene expression; an essential transcription factor in this process is interferon regulatory factor (IRF)-3 (see Ref. [59]). IRF3 belongs to the mammalian cellular IRF family, which includes other members such as IRF1 and IRF7 that can also

Concluding remarks

As we have seen, the KSHV genome encodes a variety of immune regulatory activities, summarized in Figure 2, Figure 3. Why does KSHV need these activities? A likely explanation is that continuous rounds of lytic KSHV replication might be essential in vivo to maintain the infection (reviewed in Ref. [5]), concomitantly requiring a panoply of immune modulatory functions. Because KSHV infection results in lifelong persistence, it seems that the immunomodulation activities are quite successful.

In

Acknowledgements

We regret many colleagues’ primary research papers that have contributed significantly to the field could not be cited because of space limitations. The authors thank Dr Rachel Colman for helpful comments. Research in D.J.B.’s laboratory is funded by Cancer Research UK and the Medical Research Council. C.A. is supported by MRC grant G0400408, awarded to D.J.B.

Glossary

Episomal
a genetic unit, particularly a bacterial or viral DNA genome, which replicates independently in the host cell. Episomal DNA does not integrate into the cell genome but replicates with the genome. For KSHV, the episome represents the herpesvirus genome in the cell that is circular during latency, but is replicated as linear molecules during production of new progeny.
IFN-enhancesome
enhancesomes modulate the transcriptional activity of genes. They are multicomponent complexes of

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