Control of human immunodeficiency virus replication by the tat, rev, nef and protease genes ! Jonathan Karn MRC Laboratoty of ‘Molecular Biology, Cambridge, UK Immediately after infection, human immunodeficiency virus directs the synthesis of three regulatory proteins tat, rev and nef that together allow the synthesis of the structural proteins of the virus after a delay of several hours. Viral mRNA production is controlled by the tat gene, which appears to stimulate elongation by RNA poly?nerase II, and the rev gene, which allows the accumulation of unspliced.,or partially spliced mRNAs in the cytoplasm. The nef gene is dispensible for virus growth but may limit virus spread by downregulating the levels of cellular surface proteins such as the CD4 receptor. Virus maturation also depends critically on the protease gene which allows the orderly rearrangement of the viral core structures in newly budded virions as well as the vpu and vif genes which allow efficient production of mature envelope glycoprotein. Current Opinion in Immunology 1991, 3:526-536 Introduction The discovery that acquiredimmune deficiency syndrome (AIDS)was caused by the human immunodeficiency virus @IN) stimulated an intensive research effort into the molecularbiology of retroviruses. It soon became appar- ent that HIV is not only structurallymore complicated than the oncogenic retroviruses, but also that it uses no- vel genetic control mechanisms. Perhaps the greatest sur- prise to emerge was the discovety that the regulationof HIV gene expression is achieved by tbe binding of viral regulatory proteins to speciiic RNA target sequences, and is not mediatedby DNA binding proteins, as was the case in all retrovirusesstudied previously.Tbis review is in- tended to highlight major advances in our understanding of HIV obtained over the past year, and to draw atten- tion to some unresolved problems that are the focus of current research. Cenetic structure Tbe HIV genome is tightlycompressed (Fig. 1). At least 30 Merent mRNA transcripts are produced by splicing using the six splice acceptors and two splice donor se- quences [1*,2*]. The structural proteins encoded by HIV are chemically similarto tbose of the C-type retroviruses and like them are encoded as polyproteins by the gag (group antigen), pol (polymerase) and eno (envelope) genes. Cleavage of the polyprotelnsby the vlral protease or cellularenzymes generates eight functionalvition pro- teins. In additionto these structural genes, HlVl als0 car- ries genes for three regulatory proteins, rw (regulator of virion protein), kat ( trunsactivator) and nef(negative regulatory factor); and two proteins involved in virusmat- uration, oif(virIon infectivhy factor) and vpu (viral pro- tein IJ). Tbe upr (viral protein R) gene encodes a low copy number virion component. In the closely related viruses HIV-2 and simian immunodeficiency virus (SIV) vpr is replakd by vpx (viral protein X), a unique virion protein. Transcription of the HIV genome is characterized by a progressive shift from me synthesis of the short mul- tiply spliced mRNAs, which encode the viral regulatoty proteins tat, rev and nef, towards production of larger mRNAs that encode env and other HIV proteins such as vpu, vlf and vpr [3*]. Only late in infection does mRNA production switch to full leng&, unspliced transcripts. These act both as the virion RNA and the mRNA for the gag-pol polyprotein. This complex pattem of gene ex- pression is controlled entirely by the viral trawactiva- tor proteins tat and rev. Control of the HIV life-cycle, however,is not restrIctedto transcriptional control alone. Virus assembly and morphogenesis require the viralpro- tease, virus maturation is iniluenced by vpu, and virus ac- tivity is aikcted by vif. Abbreviations AIDS-acquired immune detìciency syndrome; HlV-human immunodeficiency virus; LTR-long terminal repeat; RRE-rev-responsive element; SlV--simian immunodeficiency virus; TAR-trans-activation-responsive region. 526 @ Current Biology Ud ISSN095297915