Modulation of the immune system by Kaposi’s sarcoma-associated herpesvirus
Kaposi’s sarcoma (KS) is a multifocal tumour only found in a few groups of people, including elderly Mediterranean men, individuals in Africa and patients with immune disorders. The tumours arise from the formation of new blood or lymphatic vessels (angiogenesis or lymphangiogenesis) due to the proliferation of endothelial cells. In 1994 Chang and Moore identified a new virus, Kaposi’s sarcoma-associated herpesvirus (KSHV) as the cause of these tumours.
Unlike other herpesviruses, the seroprevalence of KSHV is not ubiquitous, perhaps only 5% in those countries with low KSHV rates such as the USA and Northern Europe). Like all herpesviruses, KSHV infection persists for the life of the host and can enter either of two states: latency or lytic reactivation. In latency, the minimum number of viral genes is expressed to maintain the virus genome in dividing cells, evading immune detection. Lytic reactivation occurs when the virus re-enters productive replication to generate new progeny, lysing the host cell in the process. And like all herpesviruses KSHV likes to mess with the immune system of its host. The KSHV genome contains 86 genes, almost a quarter of which encode proteins with immunoregulatory activities such as T- and B-cell function, complement activation, the innate antiviral interferon response and natural killer cell activity. Many of these gene are homologues of cellular proteins.
- The KSHV proteins MIR1 and MIR2 ubiquitinate the cytoplasmic tail of MHC-I which triggers endocytosis and proteasomal degradation. This protects KSHV-infected cells from NK-mediated lysis. MIR2 can also down-regulate other components of the immune synapse, ICAM (CD54) and PECAM (CD31) by the same mechanism.
- The KSHV vOX2 protein causes the cellular CD200 receptor to deliver an inhibitory signal to granulocytes, although the mechanism by which this acts is not yet well defined.
- The KCP protein is present on the surface of KSHV virions and infected cells and protects them from complement attack by accelerating the decay of the classical pathway C3 convertase enzyme complex.
- The K15 protein activates MAP kinases and this affects immune function.
- KSHV encodes a family of 12 miRNAs. These regulate both B- and T-cell function.
- The K1 protein reduces the presence of B cell receptors on the surface of B cells and interferes with the production of cytokines, and inhibits apoptosis.
- The MIR2 protein down-regulates tetherin, which is involved in normal B-cell differentiation.
- Three KSHV chemokine homologues (vCCL1–3) have affinity for chemokine receptors (CCRs) and this affects T-cell responses.
- KSHV proteins inhibit interferon pathways.
Since KSHV infection results in lifelong persistence of the virus, these immunomodulation activities are clearly successful in preventing its elimination by the immune system. Many questions about KSHV infection remain unanswered, but we have learned valuable lessons about the normal function of the immune system through studying this virus.
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Related:
- MicrobiologyBytes: Human Herpesvirus 8 (HHV-8/KSHV)
- Cellular Genes Targeted by KSHV MicroRNAs
- Herpesviruses – not all bad?
Tags: Biology, Health, HIV/AIDS, Immunology, Medicine, Microbiology, Podcast, Science, Video, Virology
