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As detailed in Chapter 17, Part IV, hallmarks of herpesvirus infections are an initial acute infection followed by apparent recovery where viral genomes are maintained in the absence of infectious virus production in specific tissue. Latency is characterized by episodic reactivation (recrudescence) with ensuing (usually) milder symptoms of the original acute infection. Example viruses include herpes simplex virus (HSV), Epstein–Barr virus (EBV), and varicella zoster virus (VZV).

In a latent infection, the viral genome is maintained in a specific cell type and does not actively replicate. HSV maintains latent infections in sensory neurons, whereas EBV maintains itself in B lymphocytes. Latent infections often require the expression of specific virus genes that function to ensure the survival of the viral genome or to mediate the reactivation process.

Reactivation requires active participation of the host. Immunity, which normally shields the body against re‐infection, must temporarily decline. Such a decline can be triggered by the host's reaction to physical or psychological stress. HSV reactivation often correlates with a host stressed by fatigue or anxiety. VZV reactivation leads to shingles, a very painful recrudescence throughout the sensory nerve net serving as the site of the latent virus. Unlike HSV reactivation, VZV reactivation results in destruction of the nerve ganglia and is associated with a generalized decline in immunity associated with aging.

Effective immunity is vital for controlling and maintaining herpesvirus latency and localizing its sites of replication. Newborns not protected by maternal immunity are subject to profound disseminated HSV infections of their central nervous system (CNS; see the “Viral Infections of Nerve Tissue” section) if they encounter the virus, for instance by infection from a mother carrying a primary acute infection. Disseminated human cytomegalovirus (CMV) infections are a major cause of death in individuals undergoing immunosuppressive treatment to facilitate organ transplants. Furthermore, CMV infections of the eye are a leading cause of blindness in patients with advanced immune deficiencies due to infection by HIV. Also, primary CMV infection of a pregnant woman is a leading cause of neurological abnormalities in developing fetuses.