Retrovirus and Retroviridae Viruses - Essay Example

Retroviridae Introduction Retroviridae is a large family of enveloped RNA viruses categorized under group-4 RNA viruses and which have common structure, composition and replicative properties (Table-1). The viruses included in this family are known as retroviruses. They are named for the action of a unique viral-encoded enzyme called reverse transcriptase (Coombs, Medscape). The hallmark of these viruses is the method of replication. Reverse transcription of the virion RNA into linear double-stranded DNA occurs and this DNA is integrated into the host cell genome. These viruses are obligate intracellular parasites whose replication depends absolutely on their hosts. Classification Retroviruses are subdivided into seven groups. The division is based on the evolutionary relatedness. Each subdivision has a taxonomic rank of a genus (Coffin, NCBI): 1. Avian sarcoma and leukosis viral group 2. Mammalian B-type viral group 3. Murine leukemia-related viral group 4. Human T-cell leukemia–bovine leukemia viral 5. D-type viral group 6. Lentiviruses 7. Spumaviruses Based on the similarities in amino acid sequences in the reverse transcriptase proteins of retroviruses (Coombs, Medscape, the retroviruses can be classified into: alpharetroviruses, betaretroviruses, gammaretroviruses, deltaretroviruses, epsilonretroviruses, lentiviruses and spuma-viruses (Table-1). The alpharetroviruses, betaretroviruses, and gammaretroviruses are considered simple retroviruses; the deltaretroviruses, epsilonretroviruses, lentiviruses, and spuma-viruses are considered complex (Coombs, Medscape). Group VI: RNA Reverse Transcribing Viruses Family Genus Type Species Hosts Retroviridae Alpharetrovirus Avian leukosis virus Vertebrates Betaretrovirus Mouse mammary tumor virus Vertebrates Gammaretrovirus Murine leukernia virus Vertebrates Deltaretrovirus Bovine leukemia virus Vertebrates Epsilonretrovirus Walley dermal sarcoma virus Vertebrates Lentivirus Human immunodeficiency virus 1 Vertebrates Spumavirus Chimpanzee foamy virus Vertebrates Metaviridae Metavirus Saccharomyces cerevisiae Ty3 virus Fungi Errantivirus Drosophila melanogaster gypsy virus Invertebrates Pseudoviridae Pseudovirus Saccharomyces cerevisiae Ty1 virus Invertebrates Hemivirus Drosophila melanogaster copia virus Invertebrates Table-1: Retroviruses classification (Retroviruses, MicrobiologyBytes) Avian sarcoma and leukosis viral group, mammalian B-type viral group, murine leukemia-related viral group, human T-cell leukemia–bovine leukemia viral and D-type viral group were formerly known as oncogenic retroviruses (Coffin, NCBI). Retroviruses are further classified into simple and complex categories based on the organization of their genomes. There are 3 major coding domains which are common to all the retroviruses. These domains have information for virion proteins. The domains are known as gag, pol and env. Gag directs the synthesis of internal virion proteins that form the matrix, the capsid, and the nucleoprotein structures. Pol contains the information for the reverse transcriptase and integrase enzymes and env contains information for the synthesis of the surface and transmembrane components of the viral envelope protein. In addition to all these major coding domains, there is one smaller coding domain common to all retroviruses. It is called pro and it codes for the virion protease. Simple retroviruses are those which carry only this elementary information. All oncogenic members except the human T-cell leukemia virus–bovine leukemia virus (HTLV-BLV) genus are simple retroviruses. Complex retroviruses code for additional regulatory non-virion proteins derived from multiple spliced messages. The additional coding domains include tat, rev, etc. HTLV-BLV and the lentiviruses and spumaviruses are complex retroviuses (Coffin, NCBI). Virion structure The virions are 80–100 nm in diameter. Their outer lipid envelope is made up of the viral glycoproteins. It is a bilayer. The protein core consists of viral replication enzymes and the viral RNA genome. The virion RNA is 7–12 kb in size. It is linear, single-stranded, non-segmented and of positive polarity. The RNA genome is diploid. It consists of two copies of linear single-stranded RNA linked by 7–11 bp regions near the 5 termini (Retrovirus resource site, Clontech). The internal protein core is the characteristic of various genera. Its shape and location differs with each genera (Coffin, NCBI) (Figures-1 & 2). The particle shapes can be divided into the following categories based on the retroviral class (Retroviruses, Nolan lab). 1. A-type particles: These are intracellular forms derived from endogenous retrovirus-like elements and the immature form of MMTV. They are immature. 2. B-type particles: These are extracellular forms of MMTV. They are characterized by a dense acentric nucleocapsid. They also have surface protein spikes. 3. C-type particles: These particles are formed at the surface of the cell at the site of budding. These are derived from lentiviruses. 4. D-type particles: These are similar to B-particles except that they lack surface protein spikes. They are formed from MMPV related viruses of sub-human primates. Figure-1: Structure of retrovirus (Retroviruses, Nolan lab). Figure-2: 3-D visualization of retrovirus structure (Retroviruses. Nolan lab). Genomic organization of retrovirus The genome of the retrovirus contains all signals necessary for gene expression. The signals necessary for gene expression are enhancer, promoter, transcription initiation, transcription terminator and polyadenylation signal. The genome is flanked by a LTR, the size of which is different for different viruses. Also, the function of LTR is restricted to some cells. Any integrated provirus which has stabilized has two LTRs: the 5 LTR and the 3 LTR. The 5 LTR normally acts as an RNA polymerase II promoter and the 3 LTR functions as the terminator sequence. An LTR consists of 3 main regions: U3, R and U5 regions. U3 is the first part of the genome to be reverse transcribed. The function of U3 is promoter/enhancer sequence and consists of transcriptional control elements. R region provides the sequence homology for strand transfer during reverse transcription of the RNA genome. U5 forms the 5- end of the provirus after reverse transcription (Retrovirus Resource Site, Clontech). Retroviral proteins The viral RNA encodes 3 genes called gag, pol and env. Gag codes for the capsid core proteins. It gives rise to four different polypeptides, of which 3 are common to all retroviruses. These are CA (capsid), MA (matrix) and NC (nucleocapsid). Pol codes for reverse transcriptase, integrase and protease and env codes for the envelope antigens namely, the transmembrane spike protein and the knob-like surface protein gp120. Together these form the surface antigen gp160 characteristic to retroviruses (Retrovirus Resource Site, Clontech) (Table-2). Name: Protein: Function: MA Matrix matrix protein (gag gene); lines envelope CA Capsid capsid protein (gag gene); protects the core; most abundant protein in virus particle NC Nucleocapsid capsid protein (gag gene); protects the genome; forms the core PR Protease Essential for gag protein cleavage during maturation RT Reverse transcriptase Reverse transcribes the RNA genome; also has RNAseH activity IN Integrase Encoded by the pol gene; needed for integration of the provirus SU Surface glycoprotein The outer envelope glycoprotein; major virus antigen TM Transmembrane protein The inner component of the mature envelope glycoprotein Table-2: Retroviruses proteins (Retroviruses, MicrobiologyBytes) The life cycle of the retrovirus The life cycle of a retrovirus begins in the nucleus of an infected cell. The retrovirus enters the host cell through the attachment of its surface glycoproteins to specific plasma membrane receptors of the host cell membrane leading to fusion of virus and cell membranes (Coffin, NCBI). This interaction of the virus and the host cell surface is highly specific. Infact, this specificity is the main determinant of the viral host range including the animal species and target cells within the host. After penetration into the cell, the RNA genome which is present in the core complex is transcribed into a double-stranded DNA with the help of reverse transcriptase. This occurs in the cytoplasm. Transcription of RNA to DNA involves 2 jumps of the reverse transcriptase from the 5′terminus to the 3′terminus of the template molecule resulting in duplication of sequences located at the 5′and 3′ends of the virion RNA. These sequences then occur fused in tandem on both ends of the viral DNA, forming the long terminal repeats (LTR) which ultimately regulate viral gene expression. The viral DNA is translocated into the nucleus where the linear copy of the retroviral genome is inserted into chromosomal DNA. This process is done with the help of integrase and is known as integration. The LTR regulate further replication and have a role in the pathogenesis of the disease (Coffin, NCBI). Integration is an important step in the viral replication because it leads to the formation of stable provirus. Provirus serves as the template for viral replication. Integration along with reverse transcription makes retroviral infection permanent (Coffin, NCBI). Also, the provirus achieves the status of a cellular gene. There upon, the cellular RNA polymerase II takes care of its expression and the cellular enzymes with the help of chromosomal RNA help in the replication of the provirus. A persistent infection may result from this process of integration, or the infected cell may be transformed and a malignancy induced. Transcription of the provirus which is controlled by the viral LTR generates spliced and unspliced mRNAs and full-length progeny RNA genomes (Coffin, NCBI). While control of proviral transcription in infections with simple viruses involves only LTR, in complex virus infections, trans-activating factors also are involved. Ultimately, the viral messages are translated on the cellular ribosomes. The products of translation along with the progeny RNA form viral particles and are released from the cell by budding of the plasma membrane. This is followed by proteolytic cleavage of virion polyproteins. This is done by viral protease and by cellular proteases. The steps thus involved in the replication of the virus are: attachment, penetration, uncoating, replication, assembly, egress and maturation (Figures-3 & 4). Although many retroviruses can cause cytopathology in the host cell, most replicate without killing the infected cell. Induction of tumor occurs by a process called insertional mutagenesis. This occurs due to integration of viral DNA into the host genome which then either makes the cellular genes activated or inactivated (Coffin, NCBI). Figure-3: Life cycle of retrovirus (Retroviruses, Nolan lab). Figure-4: Retrovirus replication cycle (Retroviruses, Book Rags). The host range of retrovirus As discussed before, the interaction between the retrovirus and the cell surface is highly specific and determines the host range, tissue specificity and the pathogenicity of the virus. The host range of a particular virus is known as tropism. Based on the tropism, the viruses can be classified into Retrovirus (Resource Site, Clontech): 1. Ecotropic viruses: These viruses replicate only in cells from the natural host or closely related species. 2. Xenotropic viruses: These cells replicate only in cells of foreign origin and not in the host. 3. Amphotropic viruses: These viruses replicate both in the natural host and foreign cells. Diseases caused by retroviral infections Retroviruses can cause a range of diseases in various hosts (Table-4). The most common diseases caused by these viruses are lymphomas and leukemias. Retroviruses that induce malignancies are avian sarcoma/leukosis viruses, mammalian C-type viruses; B-type viruses, D-type viruses; and the human T-cell leukemia virus group. However, most oncogenic retroviruses are simple C-type viruses. The infections cause significant morbidity and mortality. Some of these disorders have significant agricultural impact, crippling farm animals during their most productive years. Genus Virus Host Common tumor(s)a Comments leukosis Avian sarcoma/ ALV/RAV chicken bursal lymphoma, erythroblastosis multiple strains; some isolates can induce wasting or osteopetrosis Mammalian C-type REV chicken/other birds lymphoma multiple strains of varying pathogenicity; some isolates induce a wasting syndrome FV mouse acute erythroleukemia contains replication-defective component and helper virus; RV mouse acute erythroleukemia similar to FV Fr-MLV mouse erythroleukemia helper virus found in FV stocks; induces long latency erythroid disease Gross MLV mouse thymic lymphoma originally a viral mixture isolated from spontaneous AKR thymomas Graffi MLV mouse myeloid leukemia one of several viruses that can induce leukemias involving myeloid cells AKR-SL3-3 mouse thymic lymphoma ecotropic virus closely related to endogenous viruses isolated from AKR thymomas MCF-247 mouse thymic lymphoma representative of many MCF viruses isolated from AKR thymomas; endogenous viral recombinant Mo-MLV mouse thymic lymphoma exogenous MLV RadLV mouse thymic lymphoma viral mixture isolated from radiation-induced tumors in C57BL/6 mice; MAIDS virus isolated from one substrain SRS 19-6 mouse erythroid and myeloid leukemias, T- and B-cell lymphomas component of a viral mixture isolated from inbred Chinese mice; broad spectrum of disease is unusual Cas-Br-E MLV mouse nonthymic lymphoma infection usually causes CNS disease; from wild mice 4070A mouse nonthymic lymphoma amphotrophic virus; representative of several strains from wild mice FeLV cat thymic lymphoma multiple strains arising from natural infections; variants induce anemias and immunodeficiency GALV primate myeloproliferative disease, lymphoma multiple strains; infection probably not always associated with disease B-type MMTV mouse mammary carcinoma, thymic lymphoma multiple strains; proviruses in lymphomas contain deletions in the LTR D-type JSRV sheep pulmonary carcinoma mechanism of tumor induction remains unknown HTLV/BLV BLV cow B-cell lymphoma only a small percentage of infected animals develop tumors HTLV-1 human adult T-cell leukemia only a small percentage of infected individuals develop tumors; also associated with CNS disease Unclassified WDSV fish sarcoma representative of several piscine retroviruses Table-3: Oncogenic retroviruses (Coffin, NCBI). Retrovirus infections in humans: There are 6 distinct retroviruses which infect humans. They are human T-cell lymphotrophic virus type 1 (HTLV-1), HTLV-2, HTLV-3, HTLV-4, HIV-1 and HIV-2. HTLV-1, HTLV-2, HIV-1, and HIV-2—are actively spreading in epidemics. Reports have shown that approximately 20 million people worldwide are infected with either HTLV-1 or HTLV-2. While HTLV infections cause lymphoproliferative disorders, HIV induces only lymphocytosis. HTLV infections: The unusual pathogenesis of HTLVs is due to their unique genome among retroviruses. Though it has a genome similar to other retroviruses, the genome also includes a fourth sequence (xP). This leads to pathogenic products like Tax, Rex, p12, p13, and p30 (Wainscoat, eMedicine). HTLVs predominantly infect and integrate in lymphocytes, especially T-cells, but they can also infect other cell lines. HTLV-1 primarily infects CD4+ cells, whereas HTLV-2 primarily affects CD8+ cells. There are not many epidemiological studies pertaining to these viruses because of their low replicating nature. In non-endemic countries such as the United States, HTLV-1 has a seroprevalence of 0.01-0.03% (Wainscoat, eMedicine). HTLV-1 is endemic in a tribe of hunter-gatherers in the Philippines and Mashadi Jewish people of northern Iran. HTLV-2 is endemic in southwestern Japan, South America, northern Oceania, tropical Africa, and the Caribbean basin, in certain American Indian tribes and in injection drug users and their sexual partners (Wainscoat, eMedicine). The primary mode of HTLV-1 transmission is breastfeeding. Other modes of infection are blood-product transfusions, sexual contact, child birth and injections. The risk of vertical transmission of HTLV-1 from an infected mother is 20%. Seroconversion contaminated transfusion occurs in 40-60% cases (Wainscoat, eMedicine). HTLV-2 is also transmitted in a similar way. Initial infection with a HTLV-1 virus is innocuous. Acute infection is rarely seen or diagnosed. But the leukocytes eventually proliferate in the bloodstream or the CNS and many of them develop untreatable and rapidly fatal leukemia after a few decades of latent infection. HTLV infections also cause debilitating myelopathy, uveitis, infectious dermatitis and other inflammatory disorders. As far as HTLV-2 is concerned, only disease associations are proposed. Diseases caused by HTLV-3 and 4 are yet to be identified (Wainscoat, eMedicine). HTLV-1 causes mainly four diseases. They are adult T-cell leukemia, HTLV-associated uveitis, HTLV-1–associated infective dermatitis and HTLV-1–associated myelopathy. HTLV-2 is linked to atypical hairy cell leukemia and large granular lymphocytic leukemia. Some researchers have linked HTLV-2 to pneumonia, bronchitis, and tuberculosis (Wainscoat, eMedicine). There is no treatment for acute HTLV infection. All those detected with these infections must be counseled against the possibility of developing the above discussed diseases in future. HIV infections: HIV is a lentivirus. Like other lentiviruses, the HIV virus has a long latent period, causes persistent viremia, infection of the nervous system and weakens host immune responses. HIV primarily affects CD4 T lymphocytes and monocytes. It is primarily transmitted through sexual contact. Other modes of transmission are parenteral transmission and perinatal transmission. Currently, it is estimated that there are more than 38 million HIV infections worldwide with 95% of these in developing countries, generally in sub-Saharan Africa and Southeast Asia (Dubin, eMedicne). Infection due to HIV leads to various other infections due to immunosuppression and culminates in acquired immune deficiency syndrome (AIDS). The patient can present with various symptoms which include weight loss, recurrent episodes of fever, dysphagia, thrush, recurrent respiratory or gastrointestinal infections, skin lesions and rashes, neurological symptoms and mental symptoms. Specific diagnosis is based on HIV antibodies - Enzyme-linked immunosorbent assay and HIV antibodies - Western blot. Treatment involves mainly antiretroviral drugs which inhibit viral replication and to reduce morbidity and death. However, these drugs cannot cure the infection. Along with these antiviral drugs, associated problems must also be treated. Diseases caused by Avian leukosis viruses (ALVs) ALVs can affect chicken, Hungarian partridge, Japanese quail and pheasants. The most commonly occurring tumor caused by ALVs is lymphoid leukosis. Other tumors include nephroblastomas, hemangiomas, osteopetrosis and myeloblastosis-myrlocytomatosis. The lymphoid leukosis tumors are predominantly B-cell lymphomas. They have their origin in the bursa fabricus of the young chicken. The malignant lymphocytes can metastasize in the liver. These viruses can multiply in all tissues and organs of susceptible chickens. However, the richest concentrations are in the medullary macrophages in the bursa, the sheathed capillaries in the spleen and throughout the myocardium of the heart. The ALVs are released into the environment through the magnum of the oviduct and the Lieberkuhn glands in the intestine of the host. The viruses can enter the albumen of the egg and then into the allantois of the chicken embryo (Bagust, RIRDC). The viruses can affect the fertility, chick hatchability, rate of growth and liveability of the eggs. Infestation of commercial eggs with ALVs can affect the quality of eggs which include reduction in egg weight and shell thickness (Bagust, RIRDC). Infection with ALV-J is associated with myeloid leukosis. Other conditions caused by this virus are infectious bursal disease, chicken anemia and Mareks disease (Bagust, RIRDC). ALVs are transmitted by virus shedding to egg albumen and infection of the embryo. Infection also occurs through close contact with hatchmates or penmates. These viruses can be detected by ALV-antigen ELISA and PCR (Bagust, RIRDC). Other infections caused by retroviruses: Murine leucosis viruses cause murine leukemia. Mammary tumor viruses of mice cause breast cancer in mice. It can be infected by oral, subcutaneous and intra-peritoneal routes. A number of retroviruses have been incriminated in the cause of leucosis and sarcoma in various species like cat, hamster, rat, guinea pig and monkey. Conclusion Retroviruses are single stranded RNA viruses with reverse transcription properties. They cause many diseases in various hosts. The most significant infection is HIV infection which is causing alarming epidemic in the world. There is no cure for infection with retroviruses. References Bagust, T, Fenton, M & Reddy, M. “Avian leukosis virus sub group J.” Rural Industries Research and Development Corporation (RIRDC). 2004. 28 Nov 2007 Coffin, John, Hughes, Stephen & Harold, Varmus. "Retroviruses." NCBI. 28 Nov 2007 Read More