Human Retroviruses Flashcards
1
Q
Human diseases possibly associated with retroviruses
A
- Human T-cell lymphotrophic virus 1 (HTLV-1)
- Leukemia/lymphoma
- Human foamy virus (HFV)
- Lymphoblastoid cells
- Cancer etiology unknown
- Human endogenous retrovirus K (HERV-K)
- CML
- Breast cancer
- Prostate cancer
- Melanoma
- Autoimmune diseases (MS, RA, psoriasis, T1D)
- HIV
- Kaposi’s sarcoma
- Non-Hodgkins lymphoma
2
Q
Retrovirus structure
A
- HIV as “prototypical retrovirus”
- 2 copies of RNA genome packaged inside capsid
- Surrounding capsid - matrix
- Outside matrix - envelope, derived from host cytoplasmic membrane
- 2 membrane proteins: gp120, gp41
3
Q
3 essential genes in viral genome
A
- Gag
- Encodes matrix, capsid, nucleic acid-binding proteins
- Pol
- Encodes protease (PR), reverse transcriptase (RT), integrase (IN)
- Env
- Proteins determine host range
- Derived from host cytoplasmic membrane
4
Q
Proteins encoded by pol gene
A
- Protease (PR)
- Cleaves viral polyproteins
- Reverse transcriptase (TR)
- Copies viral RNA genome –> dsDNA that contains long terminal repeats (LTRs)
- Very inefficient
- Drug target
- Copies viral RNA genome –> dsDNA that contains long terminal repeats (LTRs)
- Integrase (IN)
- Integrates dsDNA made by RT into host genome = viral persistence
- Integrated DNA also known as proviral DNA
- Integrates dsDNA made by RT into host genome = viral persistence
5
Q
Unique features of retroviruses: reverse transcription
A
- Initiation of infectious cycle begins 1 of 2 ways
- Integration into host chromosome
- Envelope proteins bind to receptors on host cell and dump contents into cytoplasm OR
- Endosomes take virus into host cells then dump contents into cell
- Viral uncoating
- In cytoplasm: RT makes dsDNA containing necessary LTRs
- Productive infectious cycle begins when viral DNA enters nucleus, integrates into host DNA
- Viral mRNAs made by host polymerase
- Viral mRNAs processed by host splicing and polyadenylating enzymes
- Retroviruses mature by budding from plasma membrane (just like other enveloped viruses)
6
Q
3 mechanisms by which retroviruses contribute to development of cancer
A
- Acute transforming
- Nonacute transforming
- Trans-activation
7
Q
Acute transforming mechanism
A
- Some onco-retroviruses have a viral oncogene, derived from cellular proto-oncogenes
8
Q
Non-acute transforming mechanism
A
- Addition of virus genome into host’s genome
- 2 types of non-acute transformations:
- Insertion activation: virus sticking strong promoter/enhancer directly in front of proto-oncogene not normally expressed in host’s genome
- Enhancer activation: genome insertion many thousands of base pairs away
- Can include growth factors, growth factor receptors, signal transduction proteins, and transcription factors
9
Q
Trans-activation
A
- Very comple - Not covered well in lecture
- Rare
- Involves accessory genes
- Takes a long time
10
Q
Human T-cell lymphotrophic viruses (HTLV): epidemiology and associated diseases
A
- HTLV-1: δ-retrovirus that infects human T lymphocytes
- Epidemiology:
- Isolated in Japan, Caribbean countries, South America, Africa, parts of Iran
- Transmission: sexual contact, blood products, needles, mother –> child during breastfeeding
- Effective transmission relies on cell to cell contact
- Associated diseases:
- Adult T-cell leukemia/lymphoma (ATL)
- HTLV-1 associated myelopathy (HAM) a.k.a. tropical spastic parapesis
- Overall increased susceptibility to other diseases
11
Q
Adult T-cell leukemia/lymphoma (ATL): types, treatment
A
- Lymphoproliferative disorder - poor prognosis, difficult to treat
- Tumor derived from single transformed cell infected by virus
- 4 types:
- Acute (50-60%): most patients die within 6 months of dx
- Chronic type + lymphoma type (together 20%) - 2 year survival
- Smoldering is slow and least aggressive (5%)
- Treatment: all current chemotherapeutic regimens fail to treat ATL - some therapies are promising:
- Stem cell transplanation
- Monoclonal Abs against T-cell leukemia cells
- Anti-virus drugs
12
Q
ATL: clinical characteristics, histologic features
A
- Enlargement of peripheral lymph nodes
- Skin lesions due to leukemic cell infiltration
- Lytic bone lesions and as a result, hypercalcemia
- If acute, patients also have:
- Increased ATL cells
- Systemic lymphadenopathy
- Pulmonary lesions
- Hepatosplenomegaly
- Immunodeficiency –> opportunistic infections often present, increase with course of disease
- Histology: flower-like nucleus, easy to distinguish
13
Q
HTLV-1 associated myelopathy (HAM) a.k.a. tropical spastic parapesis
A
- Autoimmune disease
- Seems to be due to strong immune response to HTLV-1 antigens, including increased chemokine levels
- Resembles MS:
- Progressively paralytic disease of CNS
- Demyelination of spinal cord nerves –> weakness, stiffness, paralysis of legs, resulting in many patients bedridden within 10 years
- 2:1 ratio F:M
- Tx: corticosteroids for some symptomatic relief
- Uveitis: swelling/irritation of uvea (middle layer of eye), provides most of the blood supply to the retina
14
Q
AIDS-defining cancers
A
- Increased incidence with decreased CD4 counts
- Kaposi Sarcoma: HHV-8
- Non-Hodgkins lymphoma: EBV, HHV-8
- Cervical cancer: HPV
15
Q
Non-AIDS defining cancers
A
- Not affected by CD4 counts
- HAART increasing survival of people with HIV – shift in natural spectrum of HIV related disease –> more non-AIDS defining cancers
- Large range of common cancers
