Structure of retroviral proviruses. (a) Infectious retroviruses have at least three genes: gag, which encodes the structural proteins of the viral core; pol, which encodes the viral enzymes, including reverse transcriptase; and env, which encodes the surface glycoproteins of the viral envelope. Viral protein expression is controlled by promoter and enhancer elements and polyadenylation signals in the long terminal repeats (LTRs), which are generated during reverse transcription. Other regulatory elements are also present in the viral genome, including splice donor (SD) and acceptor (SA) sites (for env expression) and a primer-binding site (PBS) for a specific tRNA molecule used to initiate reverse transcription. The tRNA specificity varies among different retroviruses and has been used to classify endogenous retroviruses in the human genome. (b) Human endogenous retroviruses (HERVs) have a similar structure to the proviruses of infectious retroviruses but typically contain many inactivating mutations including point mutations (dark bands), frameshifts and deletions (particularly in env). Frequently, the entire central portion has been lost by homologous recombination, leaving behind a 'solitary LTR'. Although almost all HERVs are defective, the LTRs may still be active, and transcription of HERVs is common particularly in fetal tissue and in inflammatory disease and cancer. In a few cases, coding competence has been retained for env even when adjacent viral genes are heavily mutated, suggesting that selective pressures have maintained these open reading frames because they serve a cellular function.