Fig. 3. Schematic diagram of the productive (lytic) replication of herpes simplex virus type 1 (HSV-1) in a susceptible mammalian cell. 1. The virion attaches to the plasma membrane at specific receptor sites. Virion adsorption (penetration) occurs by fusion of the envelope of the virion with the plasma membrane of the cell. The envelope is, therefore, lost and remains a part of the plasma membrane. 2. The naked nucleocapsid enters the cytoplasm and is transported along cytoskeletal elements to a nuclear pore of the nuclear membrane. At least two of the tegument proteins are released from the virion. One shuts off host protein synthesis and the other (VP16) is transported to the nucleus to serve as a transinducing regulatory protein. 3. The viral deoxyribonucleic acid (DNA) is released from the capsid and enters the nucleus where it becomes circularized. The empty capsid remains at the nuclear pore. 4. The transinducing regulatory protein, VP16, induces the transcription of the immediate-early genes to yield immediate-early messenger ribonucleic acids (mRNAs). These transcripts are transported to the cytoplasm where they are translated to immediate-early proteins using cellular ribosomes. These proteins induce the transcription of early genes with transport of early mRNAs to the cytoplasm where they are translated to early proteins that are involved in DNA synthesis. DNA synthesis occurs by a rolling circle mechanism that yields concatamers of viral DNA. The early gene products induce transcription of the late genes that yields late proteins, which serve as structural proteins of the virus. 5. The capsid proteins are assembled into complex icosahedral capsid structures that are packaged with viral DNA cleaved from the rolling DNA concatamers to yield mature nucleocapsids. Following glycosylation events in the cytoplasm, viral glycoproteins are inserted into all cellular membranes including the inner nuclear membrane where tegument proteins also accumulate. The nucleocapsid acquires an envelope as it passes through the altered inner nuclear membrane and leaves the nucleus. 6. The enveloped virus travels through the endoplasmic reticulum and Golgi apparatus and exits the cell to become a resident of the extracellular space or infect contiguous cells by fusion. (Liesegang TJ: Biology and molecular aspects of herpes simplex and varicella-zoster virus infections. Ophthalmology 99:781, 1992)