Viruses are obligate intracellular parasites, relying to a major extent on the host cell for replication. An active replication of the viral genome results in a lytic infection characterized by the release of new progeny virus particles, often upon the lysis of the host cell. Another mode of virus infection is the latent phase, where the virus is ‘quiescent’ (a state in which the virus is not replicating). A combination of these stages, where virus replication involves stages of both silent and productive infection without rapidly killing or even producing excessive damage to the host cells, falls under the umbrella of a persistent infection. Reactivation is the process by which a latent virus switches to a lytic phase of replication. Reactivation may be provoked by a combination of external and/or internal cellular stimuli. Understanding this mechanism is essential in developing future therapeutic agents against viral infection and subsequent disease. This article examines the published literature and current knowledge regarding the viral and cellular proteins that may play a role in viral reactivation. The focus of the article is on those viruses known to cause latent infections, which include herpes simplex virus, varicella zoster virus, Epstein–Barr virus, human cytomegalovirus, human herpesvirus 6, human herpesvirus 7, Kaposi’s sarcoma-associated herpesvirus, JC virus, BK virus, parvovirus and adenovirus.

One of the important questions in the field of virus research is about the balance between latent and lytic cycles of replication. Kaposi's sarcoma-associated herpesvirus (KSHV) remains predominantly in a latent state, with only 1-3% of cells supporting a lytic replication at any time. KSHV glycoprotein B (gB) is expressed not only on the virus envelope but also on the surfaces of the few cells supporting lytic replication. Using co-culture experiments, we determined that expression of KSHV gB on as few as 1-2% of human dermal microvascular endothelial cells resulted in a 10-fold inhibition of expression of ORF50, a viral gene critical for the onset of lytic replication. Also, we demonstrate that such a profound inhibitory effect of gB on the lytic cycle of virus replication is by repressing the ability of Egr-1 (early growth response-1) to bind and activate the ORF50 promoter. In general, virus-encoded late stage structural proteins, such as gB, are said to play major roles in virus entry and egress. The present report provides initial evidence supporting a role for membrane-associated gB expressed in a minimal number of cells to promote virus latency. These findings may have ramifications leading to a better understanding of the role of virusencoded structural proteins not only in KSHV-related diseases but also in other viruses causing latent infections.