Herpesvirus

About Human Herpesviruses Human herpesviruses are large, enveloped double-stranded DNA viruses in the order Herpesvirales and family Orthoherpesviridae. Their virions contain a linear DNA genome packaged within a T=16 icosahedral capsid, surrounded by a protein-rich tegument and a host-derived lipid envelope bearing multiple viral glycoproteins. The overall particle is spherical to pleomorphic and is typically approximately 150–200 nm in diameter. Nine herpesviruses are recognized as human pathogens: herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human herpesvirus 6A, human herpesvirus 6B, human herpesvirus 7, and Kaposi sarcoma-associated herpesvirus (KSHV). These viruses are distributed among the subfamilies Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. After attachment and fusion, the capsid and associated tegument proteins enter the cytoplasm and are transported toward the nucleus. Viral DNA is delivered through a nuclear pore, where transcription, DNA replication, capsid assembly, and genome packaging occur. Newly formed nucleocapsids undergo nuclear egress, acquire additional tegument, and receive their final envelope during maturation through intracellular membranes.

Generalized structure of an enveloped human herpesvirus virion.

A defining biological feature of human herpesviruses is their ability to establish lifelong latent infection. Alphaherpesviruses persist mainly in sensory or autonomic neurons, betaherpesviruses establish latency in cells of the myeloid lineage and other tissues, and gammaherpesviruses persist primarily in lymphocytes. Periodic reactivation can lead to renewed viral replication, disease, and transmission.

Herpesvirus entry uses a conserved membrane-fusion apparatus centered on glycoprotein B (gB) and the gH/gL heterodimer, together with virus-specific receptor-binding proteins. In HSV-1 and HSV-2, receptor engagement by gD activates the gH/gL-gB fusion machinery. In EBV, the gH/gL/gp42 complex binds HLA class II and supports B-cell entry, whereas epithelial-cell entry uses gH/gL and gB without gp42 as the B-cell receptor-binding component. HCMV employs the gH/gL/gO trimer and the gH/gL/UL128/UL130/UL131A pentamer, which contribute differently to entry and cell tropism.

Human herpesviruses are associated with a broad spectrum of disease, including oral and genital lesions, chickenpox, shingles, infectious mononucleosis, congenital infection, encephalitis, transplant-associated disease, and virus-associated malignancies such as Burkitt lymphoma, nasopharyngeal carcinoma, certain Hodgkin lymphomas, primary effusion lymphoma, and Kaposi sarcoma.

Orthoherpesvirus genomes are linear double-stranded DNA molecules of approximately 125–241 kbp and generally encode about 70–170 proteins. Their architectures vary among genera and commonly contain unique sequence regions flanked or interrupted by terminal and internal repeats. Approximately 43 genes are inherited from an ancestral orthoherpesvirus and form a conserved core involved in DNA replication, capsid construction, genome packaging, nuclear egress, virion assembly, and membrane fusion.

Viral gene expression follows a regulated kinetic cascade. Immediate-early proteins initiate and control the lytic program, early proteins support DNA replication and nucleotide metabolism, and late genes mainly encode structural components of the capsid, tegument, and envelope. Virus-specific genes additionally regulate host range, cell tropism, immune evasion, latency, reactivation, cell survival, and pathogenesis.

The table below summarizes major conserved protein groups and important virus-specific entry complexes. Gene names differ among herpesvirus species, so functional groups are used where a single universal gene designation would be misleading.