retroviruses Flashcards
List an oncovirus, Lentivirus, and endogenous retrovirus associated with human disease
Oncovirus: Human T cell lymphotropic virus (aka HTLV delta retrovirus). Lentivirus: HIV. Endogenous retrovirus: HERV-K
HERV structures and infectivity
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.
Retroviruses structure- proteins, enzymes, genome
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
What does the Gag gene code for
matrix, capsid, nucleocapsid and protease
What does Gag-pol gene code for
RT and integrase
What are LTRs
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
Retrovirus life cycle and major requirement
- 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
HTLV-I transmission
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)
Human diseases caused by HTLV-I
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
Types of adult T cell leukemia/ lymphoma
- 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
HTLV-1 disease progression
HTLV-I infection > clonal proliferation by HTLV-I Tax > malignant expansion (alteration of host genome)
Adult T cell leukemia/lymphoma treatments
- 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
Describe HTLV-I associated myelopathy
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.
What factors influence whether HTLV-I infection will induce ATL or HAM?
ATL: immune evasion. HAM: strong immune response.
Which HIV type is a carcinogen
HIV-1
What kinds of cancers do HIV/AIDs pts get?
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
Why are HIV malignancies important
Major cause of death in HIV patients. Rates of AIDs defining cancers is decreasing/ staying constant but non-AIDS defining cancers is increasing.
Compare cancer devlopment in HIV positive vs negative patients
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
What factors contribute to cancer in HIV patients
- 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
Treatment of HIV malignancies
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
describe retroviral gene therapy
Moloney murine leukemia virus is used but the viral genes (gag, pol and env) are replaced with therapeutic gene.
Advantages of retroviral gene therapy
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
Disadvantages of retroviral gene therapy
capacity for therapeutic gene is small, infectivity limited to dividing cells, low titers, randomly integrates into genome (insertion mutagenesis)
