HIV/AIDS Flashcards
What is the origin of HIV-1?
SIV (siminan immunodeficiency virus)
What 3 polyproteins do retroviruses synthesise?
- ) Gag: group specific antigen
- )Pol: polymerase
- )Env: envelope glycoprotein
What do each of the polyproteins made by retroviruses make up?
- ) Gag: makes up the viral core proteins:
- MA(matrix)
- CA (capsid)
- NC (nucleocapsid) - ) Pol: makes up enzymes:
- PR (protease)
- RT (reverse transcriptase)
- IN (integrase) - ) Env: makes up glycoproteins:
- SU( surface)
- TM( transmembrane)
Define Reverse transcription
Copying of an RNA template (the viral genome) into a double-stranded DNA copy
-Reverse transcriptase enzyme used
Define integration
Covalent insertion of viral cDNA into the genome of the infected cell to form the provirus
-Integrase enzyme used
What is a consequence of integration
- Following integration, an infected cell cannot be cured of a retroviral infection, other than by killing that cell.
- Makes it impossible to eradicate naturally an infected animal or a retroviral infection (persistence for life)
Outline the structure of the mature HIV-1 particle
- Outer envelope consists of a lipid bilayer with protruding env spikes
- Shells of gag proteins lie inside the envelope
- Gag forms a shell itself in the immature particle
- In the mature particle, MA associated with the membrane
- CA forms the conical capsid
- NC coats the viral RNA genome
- The core contains two genomic RNA strands (plus stand) and about 50 copies of each viral enzyme( PR, RT & IN)
- cellular factors can also be packaged
Outline the basic steps of viral replication
- ) Attachment &receptor binding
- )Membrane fusion (entry)
- ) Uncoating &reverse transcription
- ) Nuclear import
- ) Integration
- ) Transcription
- ) RNA processing
- ) Nuclear export
- ) Translation
- ) Assembly
- ) Budding
- ) Maturation
How long does the retrovirus life cycle take under permissible conditions?
24 hours
Which membrane proteins are responsible for entry of HIV-1?
What tropism does this result in? What is the consequence of this?
- HIV-1 entry requires CD4 and a chemokine receptor (CCR5/CXCR4)
- This results in HIV-1 beig tropic for CD4 expressing cells such as helper T cells and macrophages
- The loss of these results in immunodeficiency ( &AIDS)
What is the significance of Reverse transcriptase being unable to proofread?
Introduces mutation & allows the virus to rapidly escape from immune responses
State the different modes of HIV-1 sequence diversification
- copying errors(drift)
- recombination(shift)
- drift plus shift
What are clades?
Different subtypes ( groups of related viruses)
Explain the 3 distinct enzymatic activities of reverse transcriptase
- ) RNA-dependent DNA polymerase
- can catalyse the RNA template becoming DNA - ) RNAasH ( cleaves RNA from RNA/DNA hybrid)
- Can degrade the viral RNA once the transcription has occured - ) DNA-dependent DNA polymerase
- Can help making the double stranded DNA needed for integration into the cell
Outline the HIV-1 regulatory /accessory proteins
- Tat- potent activator of viral transcription
- Rev- mediates unspliced RNA nuclear export
- Vif-critical regulator of virus infectivity
- Nef- immune modulator, T cell activation, virus infectivity
- Vpu-immune modulator, virus release
- Vpr- cell cycle, virus nuclear import, resistance modulator
- They may be therapeutic targets for the future
- They have diverse functions; all essential in vivo
How can HIV be acquired?
- Sexual transmission
- IV-drug use
- Blood transfusion
- Mother-to-child
Outline the different levels of HIV progression
- ‘Normal progressor: majority of individuals will progress to AIDS in 8-10years
- Rapid progressors: don’t control primary infection well and succumb to AIDS within 1-3 years
- Long term non-progressors: maintain low-level detectable viral RNA in the blood but can remain AIDS-free indefinitely
- ELITE CONTROLLER: <50 copies of viral RNA/ml of blood. Remain AIDS free indefinitely. (Genetic associations with MHC haplotype)
How is acute HIV infection controlled?
-By a strong CD8+ T cell response; neutralizing abs arise much later
Outline the significance of GALT in acute HIV-1 infection
- major target tissue
- HIV spreads rapidly to the CD4+ T cells in the lymphoid tissue of the gut
- During acute infection the GALT is virtually denuded of T cells
- The immune-integrity of GALT never recovers, even during therapy
- Does permeability of the gut to microbial components(i.e bacterial LPS) cause the chronic immune activation associated with HIV-1 infection
Describe the mechanisms of central memory CD4 T cell depletion in chronic infection
- Cytopathicity= direct cell killing by the virus( Syncytia,increased cell permebility, apoptosis)
- Cytotoxic T cell (CTL)- mediated killing of infected cells
- Immune hyperactivation, partly driven by microbial translocation, and indirect cell death ( HIV infection induces a state of high cell turnover, yet <1% CD4 T cells are infected
- Turnover & renewal= homeostatic strain, which ultimately drains the memory T cell pool
- Diminished regeneration of T cell populations
1. )Thymic dysfunction= reduced thymocyte proliferation
2. )Loss of lymphoid & lymph node architecture
3. ) Bone marrow dysfunction
Define seroconversion
The period of time during which the HIV abs develop and become detectable
-Generally takes place weeks before the initial infection
How is HIV diagnosed?
- ELISA (enzyme linked immunosorbent assay) test for the presence of anti-p24(capsid) abs in the serum. Only detects individuals who have seroconverted ( approx 3 months after infection)
- A positive sample is re-tested using a different ELISA and/or western Blot
- A negative p24-test does not mean that an individual is uninfected-just may not have seroconverted
- Confirmation by quantitative reverse transcription-linked polymerase chain reaction (RT-PCR) to detect HIV genomic RNA in the blood- estimate of the number of virus particles (copy number) per milliliter of blood
- Only RT-PCR is capable of diagnosing HIV infection before seroconversion
Define Epitope
The part of an antigen molecule to which an antibody attaches itself
Explain host genetics and HIV-1 pathogenesis /transmission in terms of the beneficial genetic attributes in humans
-MHC heterozygosity= lots of variation in your MHC molecules; can be helpful in overcoming the viral escape in your T cell epitopes
-HLA-B57, -B27, etc= associated with long term lung progressors/ELITE controllers if you have this type of haplotype you’re likely to be able to control your disease
-HLA-C(-35-SNP)= stops the viral protein from pulling of the T cell receptors from the cell surface, so those cells can be readily killed by CD8 T cells
CoR(e.g Delta32/CCR5)= these mutations make you insusceptible to HIV
