Figure 1 Genome structure of a C-type retrovirus (MLV), a tax-type' retrovirus (HTLV-I), a lentivirus (HIV-1) and a foamy virus (HFV). Structural genes are represented by open boxes, auxiliary (regulatory) genes by hatched boxes. The three compartments of the LTR (U3, R, U5) are indicated by different patterns.

retroviruses assemble viral particles with mature core structures inside the cell. Retroviral core particles can be released from the cell in the absence of envelope glycoproteins or coated in envelope proteins from some other viruses. This feature allows the packaging of envelope-deficient virus mutants into the envelope proteins of another retrovirus and has been exploited in the construction of retroviral vectors targeted at cells expressing particular receptors.

The env gene encodes two proteins which are derived from a common precursor protein. One of them extends through the lipid membrane of the envelope and is therefore referred to as TM (transmembrane) protein. It anchors the second envelope protein, termed SU (surface protein) to the virion membrane. This anchorage is mostly mediated by noncovalent bonds, although in the case of some C-type retroviruses a proportion of the SU protein is covalently linked to the TM protein by disulfide bonds. In the case of tissue culture-adapted strains of human immunodeficiency virus type 1 (HIV-1) the interaction between the SU and TM proteins is weak and these viruses therefore shed their SU proteins easily.

The SU proteins mediate the attachment of virions to their target cells by binding the virion to the cellular receptor. Several retroviral receptors have been identified so far. The CD4 glycoprotein serves as the primary receptor for primate lentiviruses, including HIV-1 and HIV-2 (Table 1). HIV-1 and HIV-2 require additional 'coreceptors' to gain entry into cells, and recently several chemokine receptors (mainly CCR5, CXCR4, CCR3, CCR2b) have been shown to play this role. Binding to CD4 induces conformational changes in the HIV envelope protein complex which can then interact efficiently with one of these chemokine receptors. Sequence variation in several regions of the HIV SU protein determines the tropism of individual isolates, presumably by influencing the choice of coreceptor. For 'non human1 retroviruses, the cellular receptors have been identified for ecotropic and amphotropic MLV, for Gibbon ape leukemia virus (Gal.V), for bovine leukosis virus (BLV), and for avian leukosis virus (ALV). All are membrane glycoproteins. As for HIV, the different tropism, due to the use of different receptors, of ecotropic and amphotropic MLV is determined by minor sequence variation in an N-terminal domain of the SU protein. Although this is not completely resolved, it seems as if in most instances retroviruses enter the cell by fusing with the cell surface membrane. This is in contrast to some other envelope RNA viruses, e.g. influenza, which require the lower pH of endosomes to trigger the fusion event with internal (endosomal) membranes. The sequence responsible for the fusion ('fusion domain') is located at the N-terminus of the TM protein and is most likely hidden within the tri- or tetrameric envelope protein complex, until the fusion event is triggered by contact with the cellular receptor.

Characteristic features of individual groups of retroviruses

MMTV has a long U3 region in its LTR which, unusually, contains a protein-encoding region. This protein, mis (minor lymphocyte stimulating), has properties of a superantigen and stimulates B cells. Some retroviruses carry oncogenes in their genomes (see under Neoplasia). An example of this is Rous sarcoma virus (RSV) which carries the src oncogene between env and the 3' LTR.

The primate T lymphotropic viruses (HTLV-I, II, STLV) and bovine leukemia virus (BLV), as well as primate lentiviruses (HIV-1/2, SIVmac, SIVAGM, SIVMN, SIVSM) possess an extensive genomic region downstream of their envelope gene (Figure 1). In addition, the lentivirus group is characterized by a 'central region' between their pol and env genes (Figure 1). Both regions contain genes coding for control proteins which regulate viral transcription, processing of viral RNAs or maturation of viral particles. These control regions are translated from subgenomic, multiply spliced RNAs. Their mode of action can only be briefly summarized here.

Transactivating genes (tat, tax) The primate T lymphotropic viruses (PTLVs) and BLV as well as the primate lentiviruses (HIV-1, HIV 2, SIVs) produce nuclear activating proteins which act by enhancing transcription from the viral LTR. The Tat of primate lentiviruses acts by binding directly to the nascent viral RNA at a region termed tar (for tat responsive) which is localized in the R region of the viral LTR and promotes transcription. PTLV and BLV Tax achieve their effect through interaction with cellular transcription factors of the CREB, NFkB, SRF families. By binding to these transcription factors Tax also affects the expression of cellular genes: it enhances the expression of the genes for interleukin 2 (IL-2), the IL-2 receptor a chain, granulocyte-macrophage colony-stimulating factor GM-GSF, c-fos and others and suppresses the gene for (3-polymerase, a cellular DNA repair enzyme. The activation of some of these cellular genes is thought to be important for the transforming properties of HTLV-I and the inhibition of ^-polymerase may contribute to DNA damage and subsequent chromosomal aberrations commonly found in adult T cell leukemia/lymphoma, the malignancy associated with HTLV-I. So far, the effects of this kind have never been observed for the lentiviral tat protein.

Genes affecting RNA processing (rev, rex) Rev (primate lentiviruses) and Rex (HTLV-I/II, STLV, BLV) have a common mode of action and facilitate the export from the nucleus of unspliced viral RNA. They thus increase the generation of full-length genomic RNA (encoding Gag/Pol proteins), as well as singly spliced RNA (encoding Env), at the expense of multiply spliced RNAs which code for control proteins.

Other control proteins The Net" protein of primate lentiviruses, encoded between the second exons of tat and rev and the 3' LTR (in some cases partially overlapping with the latter) is important for efficient replication in vivo, but its function is poorly understood. Vif, found in all primate lentiviruses, is encoded upstream of the first Tat exon and required for the infectivity of cell-free virions. Vpu is only present in the HIV-1 genome and may play a role in the release of virus particles from infected cells. Vpx is found in HIV-2 as well as nonhuman primate lentiviruses and Vpr in HIV-1, HIV-2, SIVnu„ SIVsm. Vpx plays a role during the nuclear import of the pre-integration complex. Vpr of HIV-1 and SIVA(lM is important for nuclear import and induces cell cycle arrest, whereas in HIV-2 these functions are split, and Vpr only causes cell cycle arrest.

Foamy viruses, the third major subfamily of retroviruses, also have a set of open reading frames downstream of the env gene, termed bel genes. The Bel-1 protein also serves as a transcriptional trans-activator.

Retroviral antigens

All major structural proteins encoded by the gag, pol and env genes elicit antibody production and, in some cases, also a T cell response. Antibodies to gag proteins show some cross-reactivity among diverse retroviruses such as all strains of avian leukosis virus or gibbon leukemia virus and all murine C-type viruses - hence the designation gag for group-specific antigen. In contrast, antibodies to envelope antigens are more specific. Virus-neutralizing antibodies are directed against envelope antigens - both linear and conformational epitopes have been shown to be 'neutralizing' epitopes in HIV, HTLV-I and BLV. The variable regions of the HIV envelope protein, in particular V1/V2 and V3, as well as its (conformational) CD-4-binding site and a region in the TM protein, are targets for neutralizing antibodies. In contrast to laboratory strains of HIV-1 which have been adapted to grow in established T cell lines, 'primary' HIV-1 strains are more resistant to antibody-mediated neutralization. Neutralizing antibodies to HTLV-I cross-neutralize all HTLV-I variants, but not (or much less efficiently) HTLV-II. The nonstructural regulatory proteins of HIV-1/2 and HTLV-I/II are also immunogenic although in patient sera antibodies to these antigens are found much less frequently than antibodies to structural proteins.

A cytotoxic T cell response to structural proteins has also been demonstrated for some retroviruses, e.g. HIV-1, HTLV-I, friend leukemia virus. In HIV-1 infection cytotoxic T cells are thought to limit viral replication during the early disease stages and to protect against primary infection. Immunization attempts against retroviral disease have been successful for feline leukemia virus and experiments with srvimu. in macaques suggest that immunization with viral structural proteins may confer limited protection against infection. However, in the macaque model efficient protection against SIV infection has only been achieved using attenuated viruses from which some auxiliary genes (e.g. nef) had been deleted, but the mechanism of protection is still unclear.

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