Herpesviruses: HHV-4

HHV-4 has a dual cell tropism for human B-lymphocytes (generally non-productive infection) and epithelial cells (productive infection) (Epstein-Barr virus entry. J Virol. 2007 81: 7825-7832). There is no suitable animal host, but replication/latency has been studied extensively in transformed human cell lines. HHV-4 is widespread worldwide, with ~75% of UK adults infected (lifelong!):

The usual outcome of infection is polyclonal B-cell activation and benign proliferation, which may be sub-clinical or produce infectious mononucleosis (glandular fever):

Disease:	Comments:
Infectious mononucleosis ("glandular fever")	Primary infection, self limiting. Occurs in ~50% of primary infections of adolescents and young adults.
Burkitt's lymphoma	HHV-4 found as latent infection in 97% of endemic, 15-85% of sporadic and 30-40% of AIDS-linked Burkitt's lymphoma cases.
Hodgkin's disease	Sporadic lymphoma; latent HHV-4 found in ~50% of cases.
B-lymphoproliferative disease	Lymphoproliferative disease/lymphomas, almost exclusively in the immunocompromised host, especially post-transplant (as a result of immunosuppressive drug therapy) and in AIDS. Might occur in primary infection or persistent infection.
X-linked lymphoproliferative syndrome	Rare genetic immune dysfunction results in fatal primary infection (see below).
Nasopharyngeal carcinoma	Malignant squamous epithelial tumour of the nasopharynx; cells contain latent virus.
Oral hairy leukoplakia	Viral replication in the superficial layers of tongue epithelium results in a benign lesion, almost exclusively in HIV-positive individuals.

There is a well-established relationship between HHV-4 and oncogenesis - Burkitts lymphoma and nasopharyngeal carcinoma. Infection is also associated with B cell lymphomas in immunosuppressed patients, certain T cell lymphomas, and Hodgkin's disease. The complete nucleotide sequence (~172kbp) contains many internal repeats.

HHV-4 is a powerful transforming agent for normal resting human B lymphocytes in vitro, resulting in the outgrowth of HHV-4-immortalized lymphoblastoid cell lines (LCL). HHV-4 gene expression in LCL is restricted to about nine of the approximately 100 genes encoded by the virus, and since LCL are largely non-permissive for virus production, the HHV-4 genes expressed in LCL are defined as latent genes. Six of the latent genes encode the nuclear antigens:

EBNA-1, EBNA-2, EBNA-3A, EBNA-3C and LMP-1 are essential for HHV-4-induced transformation of B cells, while EBNA-LP and LMP-2A enhance the transformation efficiency. The process of cellular transformation by HHV-4 is not completely understood. In HHV-4-associated malignancies, not all of the transforming proteins are expressed: in Burkitt's lymphoma, only EBNA-1 is regularly detected, while in nasopharyngeal carcinoma, EBNA-1 is the only protein invariably expressed but many tumours also express LMP-1 and LMP-2. A number of reasons may be put forward to explain these observations:

X-linked lymphoproliferative syndrome (XLP) is a rare condition usually seen in males where on initial infection with HHV-4 (usually around the age of 2-3) results in a hyperimmune response, sometimes causing a fatal form of glandular fever and sometimes cancer of the lymph nodes. Death by the age of 40 is inevitable. XLP is an inherited defect due to a faulty gene on the X chromosome. Females have two X chromosomes, so if one copy is faulty, the other can usually compensate. But males have just one X chromosome and one Y. There is no backup X, hence the predominance of the disease in males. The gene responsible (SH2D1A or SAP) causes a failure in the communication between the cells of the immune system. A protein known as SLAM ("signalling lymphocyte activation molecule") stimulates activity and proliferation of cells in the immune system. SLAM is found on the surface of both B and T cells, effectively coupling them together. When this happens, it signals changes inside the cells that cause them to become active and to develop and proliferate. SAP ("SLAM-associated protein") is produced by T cells, and is an inhibitor of SLAM. This is the gene which is defective in XLP. HHV-4 first infects the throat but shortly afterwards invades the B cells, and triggers them to multiply, partly by increasing the number of SLAM proteins on the surface. Without functional SAP protein, the body is unable to control the B-cell proliferation triggered by infection. T cells recognize the EBV-infected B cells as foreign and instigate a massive inflammatory response (J.Sayos et al. Nature 395: 462-469, 1998).

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Epstein-Barr Virus (EBV/HHV-4)