Fayth K. Yoshimura, Ph.D. September 7, of 7 RETROVIRUSES. 2. HTLV-II causes hairy T-cell leukemia

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1 1 of 7 I. Diseases Caused by Retroviruses RETROVIRUSES A. Human retroviruses that cause cancers 1. HTLV-I causes adult T-cell leukemia and tropical spastic paraparesis 2. HTLV-II causes hairy T-cell leukemia 3. HTLV is endemic to certain areas of the world; southern Japan, Melanesia, Caribbean, southern USA, and areas in South America and Africa infected. 4. HTLV-caused diseases are rare with <1% of world-wide population B. Human retroviruses that cause immunodeficiency 1. HIV-I and HIV-II cause acquired immunodeficiency syndromes C. Other animal retroviruses 1. Cancers a. Sarcomas - connective tissue b. Lymphomas and leukemias - hematopoietic c. Erythroleukemias - hematopoietic d. Reticuloendothelial tumors e. Mammary carcinoma 2. Immunodeficiency II. Nomenclature and Classification A. Why the name retrovirus 1. Genome of retroviruses consists of two identical strands of singlestranded, positive-sense RNA molecules 2. Flow of genetic information is RNA DNA RNA 3. Reverse transcription of RNA to DNA is catalyzed by an RNAdependent DNA polymerase (reverse transcriptase, RT). RT is an error-prone enzyme.

2 of 7 B. Genera 1. Avian leukosis virus-related (Rous sarcoma virus) 2. Mammalian C-type (feline leukemia virus) 3. B-type (mouse mammary tumor virus) 4. D-type (Mason-Pfizer monkey virus) 5.

2 2 of 7 B. Genera 1. Avian leukosis virus-related (Rous sarcoma virus) 2. Mammalian C-type (feline leukemia virus) 3. B-type (mouse mammary tumor virus) 4. D-type (Mason-Pfizer monkey virus) 5. HTLV-BLV group (HTLV-I and II, bovine leukemia virus) 6. Lentivirus (HIV) impairment a. Slowly progressive chronic infections involving neurologic 7. Spumavirus (human foamy virus) a. Foamy degeneration of infected cells b. No known disease C. Simple and Complex genomes Simple Genome:

3 3 of 7 Complex Genome: III. Virion Morphology

4 4 of 7 A. Spherical, nm in diameter B. Envelope membrane contains viral glycoprotein and cell lipids C. Icosahedral capsid D. Important viral proteins 1. SU 2. TM 3. PR 4. MA 5. CA 6. NC 7. RT 8. IN

5 5 of 7 IV. Retrovirus Replication

6 6 of 7 A. Transcription of Viral RNA 1. Unspliced RNA - structurally similar to cellular mrnas (5 -cap and 3 - polyadenylation). a. Viral genome b. mrna for structural proteins (Gag and Gag-Pol polyproteins) 2. Single-spliced mrna (simple genomes) a. Env polyprotein 3. Multiple-spliced mrna (complex genomes) a. Regulatory proteins (e.g., HIV Tat and Rev) b. Accessory proteins (e.g., HIV Vif, Vpr, Nef) B. Synthesis of Viral Proteins 1. Gag and Pol proteins a. Synthesized as polyproteins b. Gag and Gag-Pol polyproteins are cleaved into mature proteins by the viral protease (PR). 2. Envelope proteins (SU and TM) a. Produced by cleavage of a polyprotein b. Cellular protease responsible for cleavage

7 of 7 V. Mechanisms of Retroviral Transformation A. Cellular transformation is defined as a stable, heritable change in the growth control of cells. B.

7 7 of 7 V. Mechanisms of Retroviral Transformation A. Cellular transformation is defined as a stable, heritable change in the growth control of cells. B. Acutely-transforming retroviruses carry an oncogene of cellular origin 1. Oncogene is defined as a gene that causes cancer. 2. Cellular proto-oncogene is a normal cellular gene that can become an oncogene by some form of genetic damage or abnormal expression. 3. Acquisition of an oncogene by transduction. D. Types of Oncogenes

8 8 of 7 Study Questions: 1. A foamy retrovirus was isolated from a patient with AIDS. Based on what we know about this virus, a physician would conclude that: a). it is a virus that does not cause AIDS because foamy viruses are not pathogenic. b). it is a virus that does not cause AIDS because this virus causes adult T cell leukemia instead. c). it is a virus that is involved in the development of AIDS because of its association with HIV. d). it is a virus that is involved in the development of AIDS because it causes cytopathic effects in CD4+ T lymphocytes. Answer: a) is correct because foamy viruses do not cause any type of disease. 2. A virus was isolated from a patient with adult T cell leukemia. What is the property of this virus that best characterizes it? a). is a negative-stranded RNA virus that synthesizes plus-strand RNA. b). is a positive-stranded RNA virus that synthesizes negative-strand RNA. c). is a positive-stranded RNA virus that synthesizes plus-strand DNA. d). is a negative-stranded RNA virus that synthesizes plus-strand DNA. e). contains both RNA and DNA. Answer: c) is correct. The virus known to cause this disease is HTLV-I, which belongs to the retrovirus family.

9 9 of 7 ded RNA virus that synthesizes negative-strand RNA. c). is a positive-stranded RNA virus that synthesizes plus-strand DNA. d). is a negative-stranded RNA virus that synthesizes plus-strand DNA. e). contains both RNA and DNA. Answer: c) is correct. A virus known to cause this disease is HTLV-I, which belongs to the retrovirus family. 2. Retroviruses: Answer: c) is correct. 3. A foamy retrovirus was isolated from a patient with AIDS. Based on what we know about this virus, a physician would conclude that: a). it is a virus that does not cause AIDS because foamy viruses are not pathogenic. b). it is a virus that does not cause AIDS because this virus causes adult T cell leukemia instead. c). it is a virus that is involved in the development of AIDS because of its association with HIV. d). it is a virus that is involved in the development of AIDS because it causes cytopathic effects in CD4+ T lymphocytes. Fayth K. Yoshimura, Ph. D. November 11, 1996 Medical Microbiology, Ch. 43 (pp ) Study Questions 1. The HTLV-BLV group of retroviruses have the following characteristics, except: a). fall into the lentivirus genus. b). use reverse transcriptase to replicate. c). have a complex genome. d). cause leukemias. e). encode the tax protein. 2. Retroviruses: a). are negative-stranded RNA viruses that synthesize plus-strand RNA. b). are positive-stranded RNA viruses that synthesize negative-strand RNA. c). are positive-stranded RNA viruses that synthesize plus-strand DNA. d). are negative-stranded RNA viruses that synthesize plus-strand DNA. e). contain neither RNA nor DNA. 3. Spumaviruses cause: a). hairy cell leukemia. b). sarcoma.

10 10 of 7 c). acquired immunodeficiency syndrome. d). no known disease. e). mammary carcinoma. 4. The proviral DNA: a). is packaged into the retrovirus particle. b). is composed of a single-stranded molecule. c). is integrated into the chromosome of an infected cell. d). remains in the cytoplasm of the infected cell. 5. The following is true of retroviruses, except: a). have simple and complex genomes. b). have enveloped virions. c). have transduced oncogenes. d). encode a tumor suppressor protein. e). encode their own RNA-dependent DNA-polymerase.

11 11 of 7 Fayth K. Yoshimura, Ph. D. November 11, 1996 Medical Microbiology, Ch. 43 (pp ) Page 4 of 5

12 12 of 7 Fayth K. Yoshimura, Ph. D. November 11, 1996 Medical Microbiology, Ch. 43 (pp ) Answers: 1. a). fall into the lentivirus genus. 2. c). are positive-stranded RNA viruses that synthesize plus-strand DNA. 3. d). no known disease. 4. c). is integrated into the chromosome of an infected cell. 5. d). encode their own RNA-dependent DNA-polymerase.

13 13 of 7 Exam Questions: Retroviruses Fayth K. Yoshimura 11/8/96 I have written three sets of two questions each: Main exam: 1. The following characteristics are true for retroviruses EXCEPT: a. their genome consists of two identical negative-strand RNA molecules. b. their virions are spherical. c. they are enveloped viruses. d. they cause immunodeficiencies and cancers. e. they replicate through a DNA intermediate. 2. Insertional mutagenesis: a. is the mechanism by which an oncogene is transduced by a retrovirus. b. explains how retroviral DNA integrates into the chromosome. c. involves the regulation of transcription of a proto-oncogene by retroviral sequences. d. is how an adenovirus infects a cell. Retake exam: 1. These characteristics describe an oncogene EXCEPT: a. it is involved in cellular transformation. b. it is a cancer causing gene. a. it is derived from normal cellular DNA sequences. c. it is derived from a proto-oncogene. d. it is transduced by orthomyxoviruses. e. it is transduced by retroviruses. 2. The replication cycle of retroviruses involves: a. synthesis of negative-strand RNA. b. synthesis of double-strand DNA. c. reverse transcription of a negative strand RNA. d. a DNA-dependent RNA polymerase. e. a RNA-dependent RNA polymerase. Backup: MATCHING: Choose A-E (use each option only once) for 1-2. A. Cause many different kinds of cancers, including sarcomas and mammary tumors. B. Cause immunodeficiencies and cancers. C. Cause leukemias involving erythrocytes. D. Cause only immunodeficiencies. E. Cause leukemias involving mature T cells. 1. HTLV-I and HTLV-II: 2. Human retroviruses:

14 14 of 7 Answers to questions (F. Yoshimura). Main exam: 1. a. 2. c. Retake exam: 1. d. 2. b. Backup: 1. E. 2. B.

Retroviruses. ---The name retrovirus comes from the enzyme, reverse transcriptase.

Retroviruses. ---The name retrovirus comes from the enzyme, reverse transcriptase. Retroviruses ---The name retrovirus comes from the enzyme, reverse transcriptase. ---Reverse transcriptase (RT) converts the RNA genome present in the virus particle into DNA. ---RT discovered in 1970.