Gammaherpesvirinae is a subfamily of viruses in the order Herpesvirales, in the family Herpesviridae. Viruses in Gammaherpesvirinae are distinguished by reproducing at a more variable rate than other subfamilies of Herpesviridae. Mammals serve as natural hosts. There are currently 32 species in this subfamily, divided among 4 genera. Diseases associated with this subfamily include: HHV-4: infectious mononucleosis. HHV-8: kaposi's sarcoma.

Introduction

Herpesviruses represent a group of double-stranded DNA viruses distributed widely within the animal kingdom. The family Herpesviridae, which contains eight viruses that infect humans, is the most extensively studied group within this order and comprises three subfamilies, namely Alphaherpesvirinae, Betaherpesvirinae and Gammaherpesvirinae. Gammaherpesviruses belong to four separate genera: the well-established genera Lymphocryptovirus and Rhadinovirus and the more recently defined genera Macavirus and Percavirus.

Gammaherpesviruses are of primary interest due to the two human viruses, EBV and KSHV and the diseases they cause.The gammaherpesviruses replicate and persist in lymphoid cells but some are capable of undergoing lytic replication in epithelial or fibroblast cells. Gammaherpesviruses may be a cause of chronic fibrotic lung diseases in humans and in animals.

These viruses can be subdivided into two genera: lymphocryptoviruses (gamma-1) and rhadinoviruses (gamma-2). The lymphocryptoviruses (gamma-1) include Epstein-Barr virus (EBV) or Human herpesvirus 4, Lymphocryptovirus of rhesus monkeys and Herpesvirus papio of baboons, whereas the rhadinoviruses (gamma-2) include Herpesvirus saimiri (HVS), Kaposi's sarcoma-associated herpesvirus (KSHV) or Human herpesvirus 8, Rhesus monkey rhadinovirus (RRV), Equine herpesvirus 2 and Murid herpesvirus 68 (an important model system for the study of gammaherpesviruses with tractable genetics). The gammaherpesviruses, including HVS, EBV, KSHV, and RRV, are capable of establishing latent infection in lymphocytes.

Within this genus there are a number of unclassified viruses including cynomys herpesvirus 1 (CynGHV-1) Elephantid herpesvirus 3, Elephantid herpesvirus 4, Elephantid herpesvirus 5, Procavid herpesvirus 1, Trichechid herpesvirus 1.

Taxonomy

Group: dsDNA

Order: Herpesvirales

Structure

Viruses in Gammaherpesvirinae are enveloped, with icosahedral, spherical to pleomorphic, and round geometries, and T=16 symmetry. The diameter is around 150-200 nm. Genomes are linear and non-segmented, around 180kb in length.

Genus Structure Symmetry Capsid Genomic Arrangement Genomic Segmentation
Macavirus Spherical Pleomorphic T=16 Enveloped Linear Monopartite
Percavirus Spherical Pleomorphic T=16 Enveloped Linear Monopartite
Lymphocryptovirus Spherical Pleomorphic T=16 Enveloped Linear Monopartite
Rhadinovirus Spherical Pleomorphic T=16 Enveloped Linear Monopartite
Virus Life cycle

The main stages in the lifecycle of Gamma herpes virus are namely
• Virus attachment and entry
• Viral DNA injection through nuclear pore complex (NPC) into nucleus
• Assembly of nucleocapsids and encapsidation of viral genome
• Primary envelopment, invaginations of nuclear membrane(s) and nuclear egress
• Tegumentation and secondary envelopment in the cytoplasm
• Egress and extracellularvirions release

Genus Host Details Tissue Tropism Entry Details Release Details Replication Site Assembly Site Transmission
Macavirus Mammals T-lymphocytes Glycoprotiens Budding Nucleus Nucleus Nasal and ocular secretion
Percavirus Mammals B-lymphocytes Glycoprotiens Budding Nucleus Nucleus Sex; saliva
Lymphocryptovirus Humans; mammals B-lymphocytes Glycoprotiens Budding Nucleus Nucleus Saliva
Rhadinovirus Humans; mammals B-lymphocytes Glycoprotiens Budding Nucleus Nucleus Sex; saliva
Lytic Cycle

The lytic cycle of the gammaherpesviruses is initiated only on rare occasions (Oehmig et al., 2004). Therefore, the least contribution to pathogenicity has to be expected from this stage. The ORFs expressed during that stage are further divided into immediate-early, early, and late. Promoter activation mediated by these proteins has also a strong effect on DNA synthesis from the origins of lytic DNA replication. As a result, virions are generated and released from the productively infected cells.

Growth De-regulating genes of Gammaherpesvirus

Herpesviruses have large genomes containing a wide array of genes. Although the first ORF in these gammaherpesviruses have oncogenic potential, other viral genes may also play a role in viral transformation. A striking feature of the four gammaherpesviruses is that they contain distinct ORFs involved in lymphocyte signaling events. At the left end of each viral genome are located ORFs encoding distinct transforming proteins.The Gammaherpes viral genes are capable of modulating cellular signals such that cell proliferation and viral replication occur at the appropriate times in the viral life cycle.

Immune evasion strategies

Viruses that establish lifelong latent infections must ensure that the viral genome is maintained within the latently infected cell throughout the life of the host, yet at the same time must also be capable of avoiding elimination by the immune surveillance system especially must avoid being detected by host CD8+ cytotoxic T lymphocytes (CTLs). The gamma-herpesviruses are characteristically latent in lymphocytes and drive the proliferation that requires the expression of latent viral antigens. The majority of gammaherpesviruses encode a specific protein that is critical for maintenance of the viral genome within latently infected cells termed the genome maintenance protein (GMP). GMPs are DNA-binding proteins that ensures that, as the host cell progresses through mitosis, the viral episomes are partitioned to daughter cells. This provides continuous existence of the viral genome within the host cells.

Vaccines

Attenuated virus mutants represent a promising approach towards gamma-herpesvirus infection control. Surprisingly, latency-deficient and, therefore, apathogenic MHV-68 mutants are found to be highly effective vaccines against these viruses. Research in this area is almost exclusively performed using MHV68 as KSHV and EBV (the major human pathogens of this family) do not productively infect model organisms typically used for this type of experimentation.


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