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
What is the disadvantage of antiretroviral drugs?
Many have side effects that can be debilitating
Outline and give examples of how virus specific processes can be used as drug targets in terms of entry
Entry inhibitors
- Interact with the host cell receptors & prevent the virus from interacting
- e.g Maraviroc= CCR5 inhibitor but for some people over time the virus evolves and uses a different receptor
- e.g fusion inhibitor Enfurvitide (T20) which prevents the conformational rearrangements needed to bring the two membranes together
Outline and give examples of how virus specific processes can be used as drug targets in terms of reverse transcriptase
-prevent viral RNA changing to DNA
2 classes:
1.) Nucleoside- analogue reverse transcriptase inhibitors (NRTI)= incorporated into elongating DNA chain; no 3 ‘OH leads to chain termination eg Abacavir
2.) Non-nucleotide reverse transcriptase inhibitors (NNRTI) = Allosteric RT inhibitors- do not bind active site; block initiation of RT eg Nevirapine
Outline and give examples of how virus specific processes can be used as drug targets in terms of integrase inhibitors
Raltegravir binds the active site of integrase & blocks the strand transfer reaction
Outline and give examples of how virus specific processes can be used as drug targets in terms of protease inhibitors
Inhibit the HIV protease specifically to prevent cleavage of Gag and Gag-pol to mature proteins rendering new virus particle non-infectious
What is HAART?
- Highly active anti-retroviral therapy
- Combination therapy
- Difficult for HIV to simulataneously mutate to avoid combos of drugs
- Most common combo= NRTI& NNRTI or protease inhibitor
- It is not a cure; it control HIV replication to below detectable levels in the blood but the virus is never eradicated
- Cessation of treatment leads to a rebound of HIV replication
Explain the term ‘latent viral reservoirs’
The barrier to an HIV cure is the integrated provirus
Describe how we can prevent HIV infection
- condoms
- male circumcision
- Pre- exposure prophylaxis
- Topical microbicides-gels containing antiretroviral drugs or compounds that inactivate the virus. Problems with mucosal microlesions
