Retroviruses Flashcards
What is the basic structure of a retrovirus?
+ ssRNA, enveloped
What conferes specificity of infection>
Transmembrane glycoproteins that mediate attachment to host receptors
What is carried in a retrovirion?
2 copies of + ssRNA, 50 copies of reverse transcriptase and integrase
Where does integration occur?
in the long-terminal repeats of several hundred base pairs found at both 5’ and 3’ ends of the RNA
What are the three major coding regions and what do they code for?
Gag: core proteins
Pol: reverse transcriptase, integrase and protease (RNase H)
Env: surface glycoproteins - determine viral tropism
How is the genome transcribed?
Single polycistronic mRNA transcript –> differential splicing for expression
-can be cleaved by proteolytic ensymes to form several proteins
What are the two main forms of retroviruses?
Exogenous: descrete viral particles that are transmitted from host to host
Endogenous: intrinsic part of host genome
What 3 circumstances allow a retrovirus to become an oncogenic virus?
1) Incorporate an oncogene into its genome
2) Insertion of viral genome adjacent to a cellular oncogene
3) Transforming cell by expression of transactivating proteins
What non-retrovirus uses reverse transcriptase?
HepB virus (partially ds circular DNA) uses RT and RNA intermediates as part of lifecycle
Name the 4 known retroviruses that cause disease in humans
Human T-cell leukemia viruses (HTLV I and II): delta retroviruses
HIV-1 and 2: lentiviruses
What is the significance of human endogenous retroviruses (HERVS)?
Compse 8% of human genome
Not capable of replication
Indicated in autoimmune diseases
How does HTLV-1 transmission occur?
Via infected lymphocytes, not through free virus
Blood transfusion, sexual contact, and vertical via placenta or lymphocytes in breast milk
What is the primary infected cell of HTLV-1?
CD-4 T lymphocytes
doesn’t kill the T cells like HIV does; merely causes imbalance between Th1 (way too many) and Th2 cells
How does HTLV1 cause cancer?
Poorly understood: does NOT encode an ocogene and doesn’t have constent integration site
What two HTLV-1 genes regulate Tcell proliferation?
Tax and Rex: activate expression of IL-2 and IL-2r
What two syndromes are caused by HTLV-1
Adult T-cell leukemia
- only develops in 1% infected individuals
- Incubation period >30years
- poor response and prognosis
HTLV-1 associated myelopathy: HAM or tropical spastic paraparesis
-slowly progressive debilitating disease of bran and spinal cord: gait stiffness, spasticity, lower leg weakness and bowel/bladder dysfunction
What disease may be associated with HTLV-2
Hairy cell leukemia
How many groups of HIV-1 are there? how did they arise?
4 groups, each from a separate introduction of SIV into humans
M: major (most common, almost all infections in US)
O: outlier (west-central africa)
N & P: extremely rare
What is predominant calde of HIV in US?
HIV-1 M Clade B
Where does HIV-2 occur?
West Africa and Caribbean
Slower and more benign clinical progression
Name the steps of the retroviral life cycle
1) Adsorption
2) Entry
3) Reverse transcription
4) Nuclear Import (doesn’t have to wait for cell to divide)
5) Integration
6) Transcription/RNA export
7) Translation
8) Assembly
9) Budding
What are the 2 major viral proteins of HIV involved in attachment and adsorption?
gp41: transmembrane
gp120: surface; antigenically variable
What is the icosahedral matrix (MA) antigen of HIV?
p17
What is the capsid antigen of HIV?
p24 (CA protein)
How many transactivating gene regulators are encoded by HIV?
7 vpu, vpr, nef, tat, rev, vif and nef
What 2 HIV surface proteins interact with host cell receptors?
gp120, gp41
What is the primary host cell receptor for HIV and where is it present.
CD4
T and B cells, macrophages, microglial cells (macrophage derived)
What are the two major coreceptors for HIV?
CCR5 and CXCR4 (chemokine receptors)
CCR5: binds gp120
-normally receptor for RANTES< MIP1a and b from macrophages
CXCR4 normally binds SDF-1 from stromal cells in lymph nodes and epithelial cells
What is the dominant coreceptor?
CCR5, M-tropic (macrophage)
955 of new infections
**As course progresses, viruses evolve to become T-tropic, CXCR4 viruses
Describe molecular mechanism of entry for HIV
1) Virus attaches to CD4 via gp120
2) Conformation change in V3 loop of gp120
3) Coformation change exposes co-receptor binding site
4) Binding of gp120 to CCR5 or CXCR4
5) Exposure of fusion domain of gp41
6) ph-independent conformation change in gp41: fusion of cellular and viral membranes with injection of the viral core into the cyoplasm
What family of retroviruses is used in labs?
Gammaretroviruses
What step in HIV life cycle do drugs targets always precede?
Integration: want to target early stages
What anti-viral drug targets entry phase?
Fusion inhibitor T20
Mutation in what gene makes people virtually immune to HIV infection?
CCR5 delta 32
What drugs target reverse transcription?
Block DNA Chain: AZT, tenofovir
Stop reverse transcriptase: nevirapine, efavirenz
Current targets for antiretroviral therapy?
Fusion Reverse Transcription Protease Integration (integrase) CCR5 Co-receptors
