03/09c Retroviruses I

Question 1

How do you determine if a retrovirus is involved in a chronic condition or disease? Name nine criteria

Answer 1

1) Strength of association
2) Consistency of association
3) Specificity of association - is the disease unique to exposure
4) Temporality - does disease follow exposure?
5) Biological gradient - does increased dose lead to more rapid onset or severe symptoms
6) Plausibility
7) Coherence
8) Experiment
9) Analogy - comparable association with a related virus or disease

Question 2

What is a retrovirus?

Answer 2

A virus that has an RNA genome and uses a viral reverse transcriptase (RT) enzyme to produce a complimentary DNA (cDNA) copy

Question 3

What were the first pathogenic human retroviruses that was discovered?

Answer 3

Human T Cell Leukemia Virus (HTLV) 1 & 2

Human Immunodeficiency Virus (HIV)

Question 4

How do retroviruses differ from other single-stranded RNA viruses?

Answer 4

Retroviruses have an enzyme in the viral particle - reverse transcriptase
Their ssRNA genome is a template for cDNA

Question 5

What types of diseases are associated with retroviruses?

Answer 5

Rapid and long-latency malignancies (leukemia)
Wasting diseases
Neurological diseases
Immunodeficiency syndromes (AIDS)

Question 6

What organisms do retroviruses infect?

Answer 6

Humans
Cats
Mice
Chickens
Horses, goats, cows

Question 7

What is similar between ALL retroviruses?

Answer 7

Virion structure - physical properties
Genome organization
Replication mode

Question 8

How are retroviruses classified?

Answer 8

Based on sequence homology

Question 9

What is the basic genomic structure of a retrovirus?

Answer 9

Genome is a dimer of linear, (+) sense, single-stranded RNA
Each virus has Gag (structural proteins), Pol (replication enzymes), and Env (envelope) genes
Different retroviruses have other unique genes, some of which may be regulatory

Question 10

What is encoded by the Gag gene?

Answer 10

Matrix protein (membrane-associated)
Capsid and nucleocapsid proteins

Question 11

What is encoded by the Pol gene?

Answer 11

Protease - cleaves proteins during maturation
Reverse transcriptase
Integrase - for integration into host genome

Question 12

What is encoded by the Env gene?

Answer 12

Viral attachment factors - surface glycoprotein and transmembrane protein

Question 13

What are endogenous retroviruses?

Answer 13

Ancient retroviruses that integrated into our genomes a long time ago
Have been found to be associated with certain diseases (cancer, neurological diseases, autoimmune disorders) but none have been found to be causitive

Question 14

What disease is caused by HTLV-1 infection?

Answer 14

Adult T cell leukemia and tropical spastic paraparesis - only in about 5% of cases
Some reports of coinfection with HIV (10-15% of cases)
Most cases of infection with HTLV-1 are asymptomatic

Question 15

What human retroviruses do not cause disease?

Answer 15

HTLV-2 and HTLV-5

Have been shown to be ASSOCIATED with certain leukemias, but not causative

Question 16

What are HTLV-3 and HTLV-4?

Answer 16

Emerging human retroviruses
Not yet shown to cause human diseases
No known human-to-human transmission of either virus

Question 17

What are two genes that are unique to HTLV?

Answer 17

rex - regulates unspliced Gag mRNA inside the cell

tax - regulatory gene involved in transcription of the genome

Question 18

How does the accessory gene tax lead to the particular pathology of HTLV?

Answer 18

Tax stimulates production of IL-2 receptor expression

IL-2 receptor cascade leads to abnormal T cell proliferation, which predisposes the host to T cell leukemia

Question 19

How does HTLV gain access to the host cell?

Answer 19

Hijacks GLUT-1 (ubiquitous glucose transporter) and uses it for attachment

Question 20

Where is the highest prevalence of HTLV?

Answer 20

Southwest Japan

Caribbean

Question 21

How is HTLV transmitted? List three ways

Answer 21

Transfusion of blood from an infected donor (before 1989)
Sexual contact with a seropositive partner for several years
Breast milk from a seropositive mother

Question 22

How is HTLV diagnosed?

Answer 22

ELISA

PCR

Question 23

What are the clinical manifestations of HTLV infection?

Answer 23

Adult T cell leukemia

Tropical spastic paraparesis - inflammation of the eye, joints, lung, muscle, and skin

Question 24

How is HTLV infection prevented?

Answer 24

Screening of blood products

Education to prevent unprotected sexual contact or sharing of needles

Question 25

How is HTLV infection treated?

Answer 25

Glucocorticoids for tropic spastic paraparesis
Chemotherapy for adult T cell leukemia
Antiretroviral drugs?

Question 26

With what conditions might XMRV be associated?

Answer 26

Chronic fatigue syndrome? Prostate cancer? maybe

It does NOT meet causation requirements!

Question 27

How does HIV-2 infection differ from HIV-1?

Answer 27

HIV-2 is less common than HIV-1

HIV-2 infections progress much slower than HIV-1 (most infected individuals die of unrelated causes)

Question 28

How do retroviruses maximize the number of proteins than can produce with a small genome?

Answer 28

Overlapping reading frames

Question 29

What is the significance of the 5` LTRs in the HIV genome?

Answer 29

Long terminal repeats - contains promoter and enhancer elements that are targets for host and viral regulatory proteins to activate transcription

Question 30

What is TAR?

Answer 30

Viral regulatory element that is downstream of the 5` LTR

Binds to Tat

Question 31

What are the two regulatory auxiliary proteins of HIV? What are their functions?

Answer 31

Tat - binds to TAR and stimulates transcription by facilitating initiation and elongation
Rev - regulates viral mRNA production, facilitates export of unspliced or singly spliced RNAs

Question 32

What are the four accessory auxiliary proteins of HIV? What are their functions?

Answer 32

Nef - can increase or decrease virus replication, help the virus hide from the immune system, and enhances virion infectivity
Vif - increases virion infectivity and is involved in assembly
Vpr - facilitates nuclear entry so the virus can integrate into the host genome
Vpu - involved in virus release