Retroviridae

The Retroviridae is a very large family of complexly constructed, enveloped, RNA viruses with numerous animal-specific species (pathogenic to birds and mammals) as well as 2 major human pathogenic genera - Deltavirus and Lentivirus - with their species HTLV 1, HTLV 2 as well as HIV 1, HIV 2. The "Xenotropic murine leukemia virus-related virus", which belongs to the genus Gammaretrovirus, was first described in 2006 as a novel human pathogen in tissue samples from men with prostate cancer. Its pathogenic significance remains to be elucidated.

Retroviridae virions are spherical enveloped viral particles with a size of 80-100 nm in diameter. The glycoprotein surface projections are about 8 nm long. The inner core is formed by the viral nucleocapsid. The apparently spherical nucleocapsid (nucleoid) is eccentric in members of the genus Betaretrovirus, concentric in members of the genera Alpharetrovirus, Gammaretrovirus, Deltaretrovirus, and Spumavirus, and rod- or frustoconical in members of the genus Lentivirus. The virions of the Retroviridae are sensitive to heat, detergents, and formaldehyde. The surface glycoproteins can be partially removed by proteolytic enzymes. The virions are relatively resistant to UV light.

The currently valid taxonomy by the International Committee on Taxonomy of Viruses (ICTV) shows the family of Retroviridae (Retroviruses) in the order Orthovirales with 2 subfamilies and 11 genera:

Subfamily: Orthoretroviruses (Orthoretrovirinae)

Genera:

• Alpharetrovirus
• Betaretrovirus (with species Human mammary tumor virus)
• Gammaretrovirus
• Deltaretrovirus (with species Primate T-lymphotropic virus 1 (HTLV-1), Primate T-lymphotropic virus 2 (HTLV-2))
• Epsilon retrovirus
• Lentivirus (with species HIV-1, HIV-2, SIV, BIV, FIV)
• Subfamily: Foamy- or Spumaretroviruses (Spumaretrovirinae)

5 species of retroviruses are known to be human pathogens:

In the genus Deltavirus:

• Human T-lymphotropic virus 1 (HTLV-1)
• Human T-lymphotropic virus 2 (HTLV-2)

In the genus Lentivirus:

• Human immunodeficiency virus-1 (HIV-1)
• Human immunodeficiency virus type II (HIV-2)

In the genus Gammaretrovirus

• Xenotropic murine leukemia virus-related virus (XMRV)

Structure of the virus:

The viral genome, which is characteristic of members of the subfamily Orthoretrovirinae, consists of a dimer of linear, positive-sense ssRNA, each monomer being 7-13 kb in size. The RNA makes up about 2 % of the dry weight of the virion. The monomers are held together by hydrogen bonds. Each RNA monomer is polyadenylated at the 3′-end and has a cap structure at the 5′-end and is associated with a specific tRNA molecule that is base-paired to a region (called the primer binding site) near the 5′-end of the RNA and comprises about 18 nt at the 3′-end of the tRNA.

Proteins: Proteins make up about 60 % of the dry weight of the virion. The glycoprotein env (gp160 - note: env stands for envelope), which is responsible for adsorption, is found IN the envelope. This consists of the attached SU protein (gp 120/surface - binding to the cellular CD4 receptor) and the TM protein (gp 41/transmembrane - fusogenic capacity). Both proteins are encoded by the viral env gene (envelope gene). Some members of the subfamily Spumaretrovirinae have a third env protein. Furthermore, there are 3-6 internal, non-glycosylated structural proteins (encoded by the gag gene).

M (matrix protein): The M protein (p17) is often acylated with a myristyl residue covalently linked to the amino-terminal glycine. It is attached below the envelope like a net. The envelope encloses the capsid, which in lentiviruses is formed conically by the capsid protein CA(p24). The capsid also contains 3 enzymes that are important for replication and maturation: reverse transcriptase/RNAse (TR/NASE -p66/51-), integrase (INT . p35-), protease (PROT - p9-). Other proteins present in the virion are the accessory protein or the capsid-interacting protein p16. The complex retroviruses of the genera Deltaretrovirus, Epsilonretrovirus, Lentivirus and Spumavirus also encode non-structural proteins. Many of these viruses also encode transcriptional transactivators required for LTR promoter expression or proteins required for RNA export from the nucleus.

Lipids: Lipids make up about 35 % of the dry weight of the virion. They are extracted from the plasma membrane of the host cell.

Carbohydrates: Virions consist of about 3 % by weight of carbohydrates. This value varies depending on the virus. Usually both envelope proteins (gp120/gp41) are glycosylated.

Genome organization and replication: The viruses of the members of the subfamily Orthoretrovirinae carry two copies of the RNA genome (gRNA). They form nucleocapsids with the protein NC (p7). Infectious viruses have four main genes that code for the virion proteins in the order: 5′-gag-pro-pol-env-3′. Some retroviruses contain genes coding for non-structural proteins that are important for the regulation of gene expression and viral replication. Others carry cell-derived sequences that are important for pathogenesis. In many cases, the cell-derived sequences form a fused gene with a viral structural gene, which is then translated into a chimeric protein (e.g. Gag-Onc protein).

Replication:

Entry into the host cell is mediated by the interaction between the virion SU glycoprotein (gp160) and specific receptors on the host cell surface. Numerous "entry receptors" have been identified. For the human immunodeficiency virus (HIV), both CD4 (an immunoglobulin-like molecule with a single transmembrane region) and the chemokine receptors CCR5 and CXCR4 are required for membrane fusion. The interaction of ligand and receptor results in fusion of the viral envelope with the plasma membrane. The capsid is released into the cytoplasm.

Although the viral genome is of positive polarity, it is not used for direct translation at the ribosomes. Instead, it serves as a template for the reverse transcriptase (RT) contained in the capsid. The RT makes a double-stranded DNA copy of the RNA. In its final form, the linear dsDNA derived from the viral ssRNA genome contains long terminal repeats (LTRs) consisting of unique sequences from the 3′ (U3) and 5′ (U5) ends of the viral RNA, flanking a repeated sequence (R) located near both ends of the RNA. The process of reverse transcription is characterized by a high recombination frequency resulting from the transfer of RT from one template RNA to another. The mechanism of reverse transcription enables high recombination rates and genetic diversity for many of the retroviruses. The synthesized DNA copy is then transported through the nuclear pore into the cell nucleus in the form of the so-called "preintegration complex". The integrase contained in the preintegration complex ensures the integration of the viral DNA into the genome of the host. This state is referred to as a provirus. In this form, the virus can persist latently in a dormant cell for a very long time. When the host cell is activated, the cellular RNA polymerase begins to transcribe the proviral DNA. The resulting mRNAs code for accessory proteins (Hof H et al. 2019).

After translation, the nucleocapsids assemble with capsule proteins, enzymes and other accessory proteins. Capsid formation occurs due to the activity of the viral protease. In human pathogenic species, the capsids are assembled at the plasma membrane (in the majority of genera) and released from the cell by a budding process. Budding appears to occur preferentially at specialized membrane microdomains, so-called lipid rafts. Polyprotein processing of the internal proteins occurs simultaneously with or immediately after maturation of the virions. During retrovirus maturation, cleavage of the structural precursor Gag polyprotein by the viral protease induces architectural restructuring of the viral particle from an immature to a mature, infectious form (Pornillos O et al. 2019).

Antigenic properties: The 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 can also be shared between members of different serogroups within a given genus. There is evidence of weak cross-reactivity between members of different genera. Epitopes that trigger T cell responses are found on many structural proteins. Antigenic properties are not used in the classification of members of the Retroviridae family.

Biological properties:

Retroviruses are widely distributed as exogenous infectious agents of vertebrates. Endogenous proviruses, which have arisen at some point through infection of germline cells, are inherited according to Mendelian rules. They are widespread in vertebrates and can account for 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 after activation, either by replication in a manner indistinguishable from exogenous viruses or after recombination with replication-competent viruses.

Retroviruses are associated with a variety of diseases. These include: malignancies, including certain leukemias, lymphomas, sarcomas, and other tumors of mesodermal origin; breast carcinomas and carcinomas of the liver, lung, and kidney; immunodeficiencies (such as AIDS); autoimmune diseases; lower motor neuron diseases; and various acute diseases involving tissue damage. Some retroviruses appear to be nonpathogenic. Retroviruses are transmitted horizontally 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.

The human pathogenic retroviruses are so closely related to those of other primates that the two groups are often grouped together under the name primate retroviruses. It is assumed that the human retroviruses arose by transmission of simian retroviruses to humans. For HTLV 1(Human T-cell leukemia virus 1/2) and HTLV 2, this transmission probably occurred thousands of years ago. For HIV 1 (human immunodeficiency virus 1/ 2) and HIV 2, it probably did not occur until the 20th century.

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