retroviruses

Question 1

List an oncovirus, Lentivirus, and endogenous retrovirus associated with human disease

Answer 1

Oncovirus: Human T cell lymphotropic virus (aka HTLV delta retrovirus). Lentivirus: HIV. Endogenous retrovirus: HERV-K

Question 2

HERV structures and infectivity

Answer 2

Makes up 8-10% of human genome. Most HERVs are defective and cant produce virus. HERV-K and HERV-W are active and may be associated with dz.

Question 3

Retroviruses structure- proteins, enzymes, genome

Answer 3

Structural proteins: Envelope (gp120 and gp41), Matrix (p17) plus capsid (p24) which come from Gag. Viral enzymes: RT, integrase, protease. Viral genome: two RNA molecules

Question 4

What does the Gag gene code for

Answer 4

matrix, capsid, nucleocapsid and protease

Question 5

What does Gag-pol gene code for

Answer 5

RT and integrase

Question 6

What are LTRs

Answer 6

Long termina repeats found at the beginning and end of retrovirus genome. Formed by reverse transcription of retroviral DNA. Cis elements required for reverse trxn, viral gene trxn, splicing, virus integration and packaging

Question 7

Retrovirus life cycle and major requirement

Answer 7

1. binding/entry: Env (gp120) binds to CD4 and chemokine receptors CCR5 and CXCR4. 2. RT: viral reverse transcriptase (inefficient and error prone). 3. Retroviral genome integration: viral integrase. Required for virus replication and trxn. 4. Viral gene trxn: Tat transactivator. 5. Virus assembly and release: Vpu required for release. 6. Virus maturation: requires protease

Question 8

HTLV-I transmission

Answer 8

Mother to child via breast feeding, sex, infected blood products, sharing needles. Transmission relies on direct cell to cell contact (there are no Cell free HTLV-I virions in serum of infection people)

Question 9

Human diseases caused by HTLV-I

Answer 9

Adult T cell leukemia/lymphoma, HTLV-I associated myelopathy (tropical spastic paraparesis), Uveitis. Other possible dz include arthritis, pneumonitis, urinary tract disorders, increased susceptibility to infectious dz

Question 10

Types of adult T cell leukemia/ lymphoma

Answer 10

1. Acute ATL: 60% of ATL pts. Median survival is 6 months. Pts susceptible to opportunistic infection. 2. Lymphomatous ATL: Similar to acute but few circulating abnormal cells. 3. Chronic ATL: median survival is 2 years. Less of a leukemic phase. Can progess to acute form. 4. Smoldering ATL: median survival >5 yrs. Minimal abnormalities of peripheral blood cells

Question 11

HTLV-1 disease progression

Answer 11

HTLV-I infection > clonal proliferation by HTLV-I Tax > malignant expansion (alteration of host genome)

Question 12

Adult T cell leukemia/lymphoma treatments

Answer 12

1. Multi agent regimen: vincristine, cyclophosphamide, doxorubicin, prednisone, ranimustine, vindesine, etoposide, and carboplatin plus G-CSF. 2. Antiviral: zidovudine (AZT) plus interferon alpha. 3. Allogeneic hematopoietic cell transplant: complete remission in some

Question 13

Describe HTLV-I associated myelopathy

Answer 13

aka tropical spastic paraparesis. Resembles MS- weakness or stiffness of legs. 1/3 are bedridden in 10 yrs. Possibly autoimmune destruction of neural cells: T cells are infected, produce cytokines which activate CTLs (IL-2), NK cells (TNF) and macrophages (IFN-gamma) which release chemokines and adhesion molecules. Also Macrophages activate B cells which release antibodes and activate complement.

Question 14

What factors influence whether HTLV-I infection will induce ATL or HAM?

Answer 14

ATL: immune evasion. HAM: strong immune response.

Question 15

Which HIV type is a carcinogen

Answer 15

HIV-1

Question 16

What kinds of cancers do HIV/AIDs pts get?

Answer 16

AIDS defining (increase as T cells drop): Kaposi sarcoma, Non-hodgkins lymphoma, cervical cancer. Non AIDS-defining (not dependent on T cell number): anal cancer, Hodgkins lymphoma, liver cancer, skin cancer, head and neck, lung, kidney

Question 17

Why are HIV malignancies important

Answer 17

Major cause of death in HIV patients. Rates of AIDs defining cancers is decreasing/ staying constant but non-AIDS defining cancers is increasing.

Question 18

Compare cancer devlopment in HIV positive vs negative patients

Answer 18

In HIV positive pts cancer: develops at younger age, progresses more rapidly to invasive cancer, has higher tumor grade, more aggressive disease course, poorer outcomes, higher rate of relapse

Question 19

What factors contribute to cancer in HIV patients

Answer 19

1. viral co-infections: HPV, HBV, HCV, EBV, HHV8. 2. Behaviors: tobacco use (MSM). 3. Direct: transactivation of proto-oncogenes by HIV Tat, inhibition of p53 by HIV, pro-angiogenesis

Question 20

Treatment of HIV malignancies

Answer 20

Antiretroviral agents can inhibit or induce CYP450 which degrades chemo agents. Also there are overlapping toxicities with HIV meds and chemo such as myelosuppression, nausea/vomiting, hepatotoxicity, neuropathy, nephropathy

Question 21

describe retroviral gene therapy

Answer 21

Moloney murine leukemia virus is used but the viral genes (gag, pol and env) are replaced with therapeutic gene.

Question 22

Advantages of retroviral gene therapy

Answer 22

Wide host range, stably integrate into host cell genome (long term expression of transgene), can easily modify genome for use as vector, non-pathogenic in humans

Question 23

Disadvantages of retroviral gene therapy

Answer 23

capacity for therapeutic gene is small, infectivity limited to dividing cells, low titers, randomly integrates into genome (insertion mutagenesis)