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Inflammation block > HIV/AIDS > Flashcards

HIV/AIDS Flashcards

1
Q

What is the origin of HIV-1?

A

SIV (siminan immunodeficiency virus)

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2
Q

What 3 polyproteins do retroviruses synthesise?

A
  1. ) Gag: group specific antigen
  2. )Pol: polymerase
  3. )Env: envelope glycoprotein
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3
Q

What do each of the polyproteins made by retroviruses make up?

A
  1. ) Gag: makes up the viral core proteins:
    - MA(matrix)
    - CA (capsid)
    - NC (nucleocapsid)
  2. ) Pol: makes up enzymes:
    - PR (protease)
    - RT (reverse transcriptase)
    - IN (integrase)
  3. ) Env: makes up glycoproteins:
    - SU( surface)
    - TM( transmembrane)
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4
Q

Define Reverse transcription

A

Copying of an RNA template (the viral genome) into a double-stranded DNA copy
-Reverse transcriptase enzyme used

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5
Q

Define integration

A

Covalent insertion of viral cDNA into the genome of the infected cell to form the provirus
-Integrase enzyme used

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6
Q

What is a consequence of integration

A
  • 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)
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7
Q

Outline the structure of the mature HIV-1 particle

A
  • 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
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8
Q

Outline the basic steps of viral replication

A
  1. ) Attachment &receptor binding
  2. )Membrane fusion (entry)
  3. ) Uncoating &reverse transcription
  4. ) Nuclear import
  5. ) Integration
  6. ) Transcription
  7. ) RNA processing
  8. ) Nuclear export
  9. ) Translation
  10. ) Assembly
  11. ) Budding
  12. ) Maturation
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9
Q

How long does the retrovirus life cycle take under permissible conditions?

A

24 hours

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10
Q

Which membrane proteins are responsible for entry of HIV-1?

What tropism does this result in? What is the consequence of this?

A
  • 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)
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11
Q

What is the significance of Reverse transcriptase being unable to proofread?

A

Introduces mutation & allows the virus to rapidly escape from immune responses

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12
Q

State the different modes of HIV-1 sequence diversification

A
  • copying errors(drift)
  • recombination(shift)
  • drift plus shift
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13
Q

What are clades?

A

Different subtypes ( groups of related viruses)

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14
Q

Explain the 3 distinct enzymatic activities of reverse transcriptase

A
  1. ) RNA-dependent DNA polymerase
    - can catalyse the RNA template becoming DNA
  2. ) RNAasH ( cleaves RNA from RNA/DNA hybrid)
    - Can degrade the viral RNA once the transcription has occured
  3. ) DNA-dependent DNA polymerase
    - Can help making the double stranded DNA needed for integration into the cell
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15
Q

Outline the HIV-1 regulatory /accessory proteins

A
  • 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
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16
Q

How can HIV be acquired?

A
  • Sexual transmission
  • IV-drug use
  • Blood transfusion
  • Mother-to-child
17
Q

Outline the different levels of HIV progression

A
  • ‘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)
18
Q

How is acute HIV infection controlled?

A

-By a strong CD8+ T cell response; neutralizing abs arise much later

19
Q

Outline the significance of GALT in acute HIV-1 infection

A
  • 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
20
Q

Describe the mechanisms of central memory CD4 T cell depletion in chronic infection

A
  • 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
21
Q

Define seroconversion

A

The period of time during which the HIV abs develop and become detectable
-Generally takes place weeks before the initial infection

22
Q

How is HIV diagnosed?

A
  • 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
23
Q

Define Epitope

A

The part of an antigen molecule to which an antibody attaches itself

24
Q

Explain host genetics and HIV-1 pathogenesis /transmission in terms of the beneficial genetic attributes in humans

A

-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

25
Q

What is the disadvantage of antiretroviral drugs?

A

Many have side effects that can be debilitating

26
Q

Outline and give examples of how virus specific processes can be used as drug targets in terms of entry

A

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
27
Q

Outline and give examples of how virus specific processes can be used as drug targets in terms of reverse transcriptase

A

-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

28
Q

Outline and give examples of how virus specific processes can be used as drug targets in terms of integrase inhibitors

A

Raltegravir binds the active site of integrase & blocks the strand transfer reaction

29
Q

Outline and give examples of how virus specific processes can be used as drug targets in terms of protease inhibitors

A

Inhibit the HIV protease specifically to prevent cleavage of Gag and Gag-pol to mature proteins rendering new virus particle non-infectious

30
Q

What is HAART?

A
  • 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
31
Q

Explain the term ‘latent viral reservoirs’

A

The barrier to an HIV cure is the integrated provirus

32
Q

Describe how we can prevent HIV infection

A
  • condoms
  • male circumcision
  • Pre- exposure prophylaxis
  • Topical microbicides-gels containing antiretroviral drugs or compounds that inactivate the virus. Problems with mucosal microlesions

Inflammation block (27 decks)

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