Family: Retroviridae

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The Retroviridae constitute a large family of viruses that predominantly infect both human and animal vertebrates. They are positive-stranded enveloped RNA viruses that reverse transcribe their RNA into a DNA intermediate during viral replication, hence the name ‘retroviruses’.

their immature capsids at the plasma membrane, as C-type viruses. Members of the Betaretrovirus genus, in contrast, were said to assemble A-type particles (immature capsids) in the cytoplasm which then budded with either a B-type (mouse mammary tumor virus, MMTV) or D-type (Mason-Pfizer monkey virus, MPMV) morphology.

Physicochemical and physical properties

Virion buoyant density is 1.16–1.18 g cm−3 in sucrose. Virion S20,w is approximately 600S in sucrose. Virions are sensitive to heat, detergents, and formaldehyde. The surface glycoproteins may be partially removed by proteolytic enzymes. Virions are relatively resistant to UV light.

Nucleic acid

The virus genome characteristic of members of the subfamily Orthoretrovirinae consists of a dimer of linear, positive sense, ssRNA, each monomer 7–13 kb in size. The RNA constitutes about 2% of the virion dry weight. The monomers are held together by hydrogen bonds. Each monomer of RNA is polyadenylated at the 3′ end and has a cap structure (type 1) at the 5′ end. The purified virion RNA is not infectious. Each monomer is associated with a specific molecule of tRNA that is base-paired to a region (termed the primer binding site) near the 5′ end of the RNA and involves about 18 nt at the 3′ end of the tRNA. Other host-derived RNAs (and small DNA fragments) found in virions are believed to be incidental inclusions. The virus genome characteristic of members of the subfamily Spumaretrovirinae is dsDNA, as reverse transcription is a late step in the viral life cycle of these viruses. The exact structure of the DNA has not been determined.

Proteins

Proteins constitute about 60% of the virion dry weight. There are two envelope proteins: SU (surface) and TM (transmembrane) encoded by the viral env gene. Some members of the subfamily Spumaretrovirinae have a third Env protein, LP (leader peptide). There are 3–6 internal, non-glycosylated structural proteins (encoded by the gag gene). These are, in order from the amino terminus, (1) MA (matrix), (2) in some viruses a protein of undetermined function, (3) CA (capsid protein) and (4) NC (nucleocapsid). The MA protein is often acylated with a myristyl moiety covalently linked to the amino-terminal glycine. Other proteins are a protease (PR, encoded by the pro gene), a reverse transcriptase (RT, encoded by the pol gene) and an integrase (IN, encoded by the pol gene). In some viruses, a dUTPase (DU, role uncertain) is also present. Members of the Spumaretrovirinae encode only a single Gag protein which is cleaved once near the carboxyl-terminus in about half of the proteins. The complex retroviruses in the DeltaretrovirusEpsilonretrovirusLentivirus and Spumavirus genera also encode non-structural proteins. Many of these viruses encode transcriptional transactivators, which are required for expression of the LTR promoters, or proteins required for RNA export from the nucleus.

Lipids

Lipids constitute about 35% of the virion dry weight. They are derived from the plasma membrane of the host cell.

Carbohydrates

Virions are composed of about 3% carbohydrate by weight. This value varies, depending on the virus. At least one (SU), and usually both, envelope proteins are glycosylated. Cellular glycolipids and some glycoproteins are also found in the viral envelope

Genome organization and replication

Virions of members of the subfamily Orthoretrovirinae carry two copies of the RNA genome. Infectious viruses have four main genes coding for the virion proteins in the order: 5′-gagpropolenv-3′. Some retroviruses contain genes encoding non-structural proteins important for the regulation of gene expression and virus replication. Others carry cell-derived sequences that are important in pathogenesis. These cellular sequences are inserted either into a complete retrovirus genome (e.g. some strains of Rous sarcoma virus) or in the form of substitutions for deleted viral sequences (e.g. some isolates of murine sarcoma virus). Such deletions render the virus replication-defective and dependent on non-transforming helper viruses for the production of infectious progeny. In many cases, the cell-derived sequences form a fused gene with a viral structural gene that is then translated into one chimeric protein (e.g. Gag-Onc protein).

Entry into the host cell is mediated by the interaction between the virion SU glycoprotein and specific receptors at the host cell surface, resulting in a fusion of the viral envelope with the plasma membrane, either directly or following endocytosis. Receptors are cell-surface proteins. Many have been identified. For human immunodeficiency virus (HIV), both the CD4 protein, which is an immunoglobulin-like molecule with a single transmembrane region and a chemokine receptor (CCR5 or CXCR4), which spans the membrane seven times, are required for membrane fusion. The receptors for gammaretroviruses are involved in the transport of small molecules and have a complex structure with multiple transmembrane domains. For the avian leukosis viruses (AAVs), four receptors have been identified. That for subgroup A virus is a small protein with a single transmembrane domain that is distantly related to a cell receptor for low-density lipoprotein, that for subgroup B viruses is related to the TNF-receptor family of proteins, that for subgroup C viruses is related to the mammalian butyrophilins, and that for subgroup J viruses is the chicken Na+/H+ exchanger protein.

The process of intracellular uncoating of viral particles is not understood. Subsequent early events are carried out in the context of a nucleoprotein complex derived from the capsid.

For members of the subfamily Orthoretrovirinae, replication starts with reverse transcription (by RT) of virion RNA into cDNA using the 3′ end of the tRNA as a primer for synthesis of a negative sense cDNA transcript. The initial short product (to the 5′ end of the genome) transfers and primes further cDNA synthesis from the 3′ end of the genome by virtue of duplicated sequences at the ends of the viral RNA. cDNA synthesis involves the concomitant digestion of the viral RNA (RNase H activity of the RT protein). A product of this hydrolysis serves to prime positive sense cDNA synthesis on the negative sense DNA copies. In its final form, the linear dsDNA derived from the viral ssRNA genome contains long terminal repeats (LTRs) composed of unique sequences from the 3′ (U3) and 5′ (U5) ends of the viral RNA flanking a repeated sequence (R) found near both ends of the RNA. The process of reverse transcription is characterized by a high frequency of recombination due to the transfer of the RT from one template RNA to the other. Reverse transcription is thought to follow the same pathway in members of the subfamily Spumaretrovirinae, but the timing is different as it occurs during viral assembly and/or release from the cell. The mechanism of reverse transcription allows for high rates of recombination and genetic diversity for many of the retroviruses. The high rate of genetic variation in vivo can lead to the formation of a quasispecies consisting of a large number of genetically diverse virions.

Retroviral DNA becomes integrated into the chromosomal DNA of the host, to form a provirus, by a mechanism involving the viral IN protein. The ends of the virus DNA are joined to cell DNA, involving the removal of two bases from the ends of the linear viral DNA and generating a short duplication of cell sequences at the integration site. Virus DNA can integrate at many sites in the cellular genome. However, once integrated, a sequence is apparently incapable of further transposition within the same cell. The map of the integrated provirus is co-linear with that of non-integrated viral DNA. Integration appears to be a prerequisite for virus replication. Different retroviruses can show distinct preferences in integration site selection, with HIV-1 tending to insert within gene sequences whereas murine leukemia viruses (MLV) prefer regions near the start of transcribed genes.

The integrated provirus is transcribed by cellular RNA polymerase II into virion RNA and mRNA species in response to transcriptional signals in the viral LTRs. In some genera, transcription is also regulated by virus-encoded transactivators. There are several classes of mRNA depending on the virus and its genetic map. An mRNA comprising the whole genome serves for translation of the gagpro and pol genes (positioned in the 5′-half of the RNA). This results in the formation of polyprotein precursors that are cleaved to yield the structural proteins, PR, RT and IN, respectively. A smaller mRNA consisting of the 5′ end of the genome spliced to sequences from the 3′ end of the genome, and including the env gene and the U3 and R regions, is translated into the precursor of the envelope proteins. In viruses that contain additional genes, other forms of spliced mRNA are also made; all these spliced mRNAs share a common sequence at their 5′ ends. Members of the subfamily Spumaretrovirinae are unique in that they make use of an internal promoter (IP), which is located in the env gene upstream of the accessory reading frames, for transcription of these distal genes. Most primary translation products in retrovirus infections are polyproteins that require proteolytic cleavage before becoming functional. The gagpro, and pol gene products are generally produced from a nested set of primary translation products. For pro and pol, translation involves bypassing translational termination signals by ribosomal frameshifting or by readthrough at the Gag-Pro and/or the Pro-Pol boundaries. Members of the subfamily Spumaretrovirinae synthesize Pol protein from its own mRNA rather than as a Gag-Pol fusion protein.

The retroviral genomic RNA contains sequences of varying lengths, usually located near the 5′ end between U3 and gag, which comprise a packaging signal (Ψ). Ψ is required for efficient encapsidation of the genome into particles, and is generally not present on the subgenomic mRNAs, a notable exception being the alpharetroviruses. In the case of the spumaviruses, Ψ does not appear to be in the 5′ end of the genome. In all cases, Ψ activity is not defined by the primary sequence, but by a complex folded structure.

Capsids assemble either at the plasma membrane (for a majority of the genera), or as intracytoplasmic particles (for members of the genera Betaretrovirus and Spumavirus) and are released from the cell by a process of budding. Budding appears to occur preferentially at specialized membrane microdomains known as lipid rafts. Virions of the spumaviruses and deltaretroviruses are highly cell-associated. Polyprotein processing of the internal proteins occurs concomitant with or just subsequent to the maturation of virions of members of the subfamily Orthoretrovirinae.

Antigenic properties

Virion proteins contain type-specific and group-specific determinants. Some type-specific determinants of the envelope glycoproteins are involved in antibody-mediated virus neutralization. Group-specific determinants are shared by members of a serogroup and may be shared between members of different serogroups within a particular genus. There is evidence for weak cross-reactivities between members of different genera. Epitopes that elicit T-cell responses are found on many of the structural proteins. Antigenic properties are not used in the classification of members of the family Retroviridae.

Biological properties

Retroviruses are widely distributed as exogenous infectious agents of vertebrates. Endogenous proviruses that have resulted at some time from infection of germline cells are inherited as Mendelian genes. They occur widely among vertebrates and can constitute up to 10% of genomic DNA. The vast majority have suffered inactivating mutations and cannot produce infectious virus. A few can exert significant biological effects following activation, either by replication in a manner indistinguishable from exogenous viruses or following recombination with the replication-competent virus.

Retroviruses are associated with a variety of diseases. These include malignancies, including certain leukemias, lymphomas, sarcomas and other tumors of mesodermal origin; mammary carcinomas and carcinomas of liver, lung, and kidney; immunodeficiencies (such as AIDS); autoimmune diseases; lower motor neuron diseases; and several acute diseases involving tissue damage. Some retroviruses appear to be non-pathogenic. Transmission of retroviruses is horizontal via a number of routes, including blood, saliva, sexual contact, etc., and via direct infection of the developing embryo, or via milk or perinatal routes. Endogenous retroviruses are transmitted vertically by inheritance of proviruses.

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