Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease

Retrovirus structure and replication. (a) Genome organization. The RNA and DNA forms of a generalized retrovirus genome are shown with conserved features. R, repeated region at termini of RNA genome; U5 and U3, unique elements close to the 5′ and 3′ ends, respectively, of the RNA genome; PBS, primer binding site used for initiation of reverse transcription; Ψ, encapsidation signal; PPT, polypurine tract. All infectious retroviruses have at least one splice donor (SD) and one splice acceptor (SA) site used for expression of a spliced transcript encoding env; some retroviruses have additional splice sites. During reverse transcription, the LTR is formed, which contains gene promoter and enhancer elements. At least four genes are present in all infectious retroviruses, gag, pro, pol, and env. Retroviral proteins are synthesized as large polyprotein precursors and later cleaved into the mature viral proteins matrix (MA), capsid (CA), nucleocapsid (NC), protease (PR), reverse transcriptase (RT), and integrase (IN) and into-the-surface (SU) and transmembrane (TM) glycoproteins. Specific retroviruses encode additional proteins with specialized functions in the viral life cycle or pathogenesis. (b) Comparison of proviral structures of MLV and HTLV-1 showing arrangement of ORFs for viral genes. (Panels a and b are adapted from reference 345 with permission from Elsevier.) (c) Structure of a generalized retrovirus particle indicating virus capsid containing two copies of the RNA genome associated with NC protein, viral enzymes, and a cellular tRNA molecule. The capsid is contained within the viral lipid envelope, which is associated with the envelope glycoproteins. (d) Replication. Retroviruses infect their target cells by adsorption to one or more specific cell surface receptors. Binding leads to conformational changes in the envelope and receptor molecules that trigger fusion of the viral and cell membranes. Depending on the specific virus, this may occur at the plasma membrane or within endosomes following endocytosis. Fusion releases the viral core into the cytoplasm (uncoating), and reverse transcription is initiated, during which the single-stranded RNA genome is converted into a double-stranded DNA form. This DNA subsequently becomes integrated into the chromosomal DNA of the cell to form the provirus. The expression of viral genes and proteins requires the host cellular machinery for transcription and translation, although some retroviruses also encode proteins that can regulate these processes. The cellular specificity of expression is dependent on enhancer elements located in the LTR. Assembly of retroviral capsids occurs either in the cytoplasm prior to budding (betaretroviruses and spumaviruses) or at the plasma membrane concomitant with budding (all other retroviral genera). Once released, the retroviral protease is activated, and the viral polyproteins become cleaved into their mature forms. This maturation step is required for infectivity.