Fig. 13.31 The genomic organization of HIV. like all retroviruses, HiV-1 has an Rna genome flanked by long terminal repeats (ltRs) involved in viral integration and in regulation of transcription of the viral genome. the genome can be read in three frames, and several of the viral genes overlap in different reading frames. this allows the virus to encode many proteins in a small genome. the three main protein products—Gag, Pol, and env—are synthesized by all infectious retroviruses. the known functions of the different genes and their products are listed. the products of gag, pol, and env are known to be present in the mature viral particle, together with the viral Rna. the mRnas for tat, Rev, and nef proteins are produced by splicing of viral transcripts, so their genes are split in the viral genome. in the case of nef, only one exon, shown in yellow, is translated.
Gene product/function Group-speciÿc antigen gag pol env tat rev vif Polymerase Envelope Transactivator Regulator of viral expression Viral infectivity vpr Viral protein R vpu Viral protein U nef Negative-regulation factor Gene pol env tat LTR LTR gag Core proteins and matrix proteins Reverse transcriptase, protease, and integrase enzymes Transmembrane glycoproteins. gp120 binds CD4 and CCR5; gp41 is required for virus fusion and internalization Positive regulator of transcription Allows export of unspliced and partially spliced transcripts from nucleus Affects particle infectivity Transport of DNA to nucleus. Augments virion production. Cell-cycle arrest Promotes intracellular degradation of CD4 and enhances release of virus from cell membrane Augments viral replication in vivo and in vitro. Decreases CD4, MHC class I and II expression nefrev tat rev vif vpr vpu host cells would be shortlived. Thus, longlived latency of HIV is primarily a consequence of the tropism of the virus for CD4 T cells. The combined features of tropism for CD4 T cells and activationdependent transcription of the provirus are central to the pathogenesis of HIV and its characteristic progressive depletion of CD4 T cells that leads to AIDS.
13-27 Activated CD4 T cells are the major source of HIV replication.
HIV provirus requires activation of the host cell to complete its replication cycle and produce infectious virions that can infect other cells. This is due to a requirement for transactivation of proviral gene expression by transcription factors of the host cell. Two host transcription factors can initiate transcription of the viral genome: NFκB and NFAT. Both of these factors require cellular activation for their translocation to the nucleus, where they bind DNA and induce gene transcription (see Sections 714 and 716). While NFκB is expressed in all of the immune cells infected by HIV, NFAT is primarily activated in CD4 T cells, enabling transactivation of the provirus by an additional factor in this cell host. This, coupled with the fact that CD4 T cells are longlived and abundant in immune tissues, contributes to CD4 T cells being the major cellular source for HIV replication. Here we consider the mechanism by which transcription of the HIV provirus is regulated in CD4 T cells.