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Human Microbial Diseases Block 2 > HIV and AIDS > Flashcards

HIV and AIDS Flashcards

1
Q

When was AIDS first defined?

A

First defined in 1981

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2
Q

How many people have been infected since the start of the HIV epidemic?

A

74.9 million

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3
Q

How many people have died since the start of the HIV epidemic?

A

32 million

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4
Q

Why has the number of deaths decreased?

A

Related to the introduction of generic antiviral drugs driving down the price of antiviral therapy

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5
Q

Where are most HIV cases?

A

Africa

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6
Q

What are the HIV basic properties?

A
  • Lentivirus = slow growing retrovirus
  • Spherical enveloped virus
  • Approximately 100nm diameter
  • Prominent peplomers on the virus surface - spikes
  • Contain dense core 70-80 nm - shape variable
  • Positive stranded, diploid RNA genome - 2 RNA molecules are held together at the 5’ end by non-covalent interactions
  • RNA genome is protected by the nucleocapsid protein
  • Nucleocapsid layer is encapsulated by the capsid
  • Capsid is surrounded by a coat of matrix protein
  • All the proteins involved in the structure are encoded by the GAG gene
  • The outside layer is a lipid layer taken from the infected host cell
  • 2 glycoproteins are expressed on the surface encoded by the ENV gene - surface glycoprotein = gp120 and transmembrane protein = gp41
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7
Q

Describe HIV infection and cell entry

A
  • HIV recognises and attaches the CD4 antigen on the T cell lymphocyte
  • Requires cellular co-receptor - beta cytokine receptor CCR-5 or alpha cytokine receptor CXCR4
  • Both co-receptors are found on many cell types - including CD4/CD8 and macrophage
  • HIV in peripheral blood uses mainly CCR-5 - main tropism
  • gp120 binds to CCR5 (macrophage) or CXCR4 (T cell) co-receptor - allows tighter binding
  • gp41 inserts fusion peptide into the host membrane
  • Fusion peptide brings the viral envelope and host cell membrane together - allows fusion which releases the viral capsid into the host cytoplasm
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8
Q

What alleles does CCR-5 exist as?

A
  • Normal allele

- Defective truncated allele

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9
Q

How does being homozygous for delta32ccr5 affect HIV?

A

Highly resistant to HIV

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10
Q

What does Gag produce?

A

p55

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11
Q

What does the cleavage of p55 produce?

A
  • p24 (CA)
  • p17 (M)
  • p7 (NC)
  • p9 (pro)
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12
Q

What does Pol produce?

A

p100

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13
Q

What does p100 cleavage produce?

A
  • p14 (PR)
  • p32 (IN)
  • p66 (RT)
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14
Q

What does Env produce?

A

gp160

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15
Q

What does gp160 cleavage form?

A
  • gp120 (SU)

- gp41 (TM)

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16
Q

How does the Tat protein work?

A
  • Tat is an RNA binding protein that binds an RNA regulatory element called TAR
  • Tat responsive element (TAR) is within the 5’ untranslated region of the viral mRNA
  • In the early stages of infection the transcription of viral mRNA doesn’t occur efficiently as the RNA polymerase is not highly processive so only produces a set of abortive RNA
  • Abortive mRNA contains the TAR element that Tat binds to
  • Tat complex then recruits Cyclin T1 and Cyclin dependent kinase 9 (CDK9)
  • CDK9 has the ability to hyperphosphorylate the RNA polymerase II which increases processive transcription
  • This increases transcription of viral RNA
  • Increased processive transcription means the RNA polymerase II can now produce full length viral mRNAs
  • The complex assembled by TAR and Tat also induces phosphorylation of the negative effectors bound to RNA polymerase which causes them to be released - adds to the boost in efficacy of the polymerase
17
Q

How does the Rev protein work?

A
  • Rev is a positive regulator of mRNA export
  • Binds the Reve Responsive Element (RRE)
  • RRE is a small RNA stem-loop
  • Binding of Rev recruits the exporting complex - Ran protein provides energy in the form of GTP - exportin
  • Results in the export of viral mRNA into the cytoplasm
  • Once in the cytoplasm Rev is released and shuttled back into the nucleus by an importin protein
  • CRS inhibits mRNA export
  • RRE counteracts their effect to trigger mRNA export by binding Rev
  • Single spliced mRNA contain the RRE and so require Rev for export
  • Double spliced mRNA don’t contain CRS or RRE so don’t require Rev for export
  • In the early phase all the mRNAs are produced but only the Rev independent mRNA can be exported into the cytoplasm where they are used to make Tat and Rev
  • In the late phase of transcription, Tat is able to promote the transcription of full mRNAs which are able to be exported by Rev
18
Q

How does vpu work?

A
  • While protein synthesis occurs in the ER, CD4 can bind gp160, a precursor of gp120 and gp41
  • If this premature binding occurs, the viral particle that is subsequently formed would be tethered to the receptor of the host cell
  • May also lead to viral particles without gp120 and gp41 on the surface due to being sequestered by CD4 - would mean these viral particles would be unable to infect cells
  • vpu binds to the transmembrane domain of CD4 at the ER surface
  • This induce ubiquitination and proteasome targeting of CD4
  • Means gp160 is free to assemble in the virus
19
Q

How is it decided if an mRNA will be translated or used in virion assembly?

A
  • Regulated by the Gag protein and NC protein processed from Gag
  • First the mRNA acts as mRNA to produce proteins - produces Gag protein and NC protein as well as other proteins
  • NC protein will bind mRNA - prevents efficient recognition by ribosomes
  • NC promotes the dimerisation and encapsidation of the viral RNA
  • Thing that drives the switch from mRNA action to encapsidation is the production of the NC protein - the more NC protein around, the more encapsidation will occur
20
Q

How is HIV transmitted?

A
  • Blood
  • Blood products - transfusion with contaminated blood or exchange of needles for IV drug users
  • Sex
21
Q

Describe HIV transmission during sex

A
  • Infected cells in semen/vaginal fluids are more important than free virus
  • Infected lymphocytes/macrophages attach to epithelia
  • Macrophages introduced from vagina traffic to lymphoid organs
  • Localised retention of lymphocytes aids virus transmission from one to another
  • Attachment stimulates virus release
  • Genital and anal ulcers increase the likelihood of transmission - increased inflammation means increased infected immune cells which means increased transmission
22
Q

What is the probability of HIV transmission during sex?

A

Probability of transmission per coital act ranges from 0.1-2%

23
Q

Describe the acute stage of HIV

A
  • First and second weeks
  • Burst of viraemia
  • Flu-like symptoms, headache, rash, lymphadenopathy
  • Majority of people don’t develop symptoms when first infected
  • Symptoms disappear within a week so are often mistaken for another viral infection
  • People are highly infectious during acute infection
24
Q

What happens in seroconversion?

A
  • First to 6th month
  • Production of antibody against HIV antigens
  • T cell activation to eradicate HIV particles
25
Q

Describe by asymptomatic stage of HIV

A
  • Up to 20 years
  • Clinical latency - no symptoms
  • No virological latency - virus keeps replicating in the lymph nodes which acts as a reservoir
  • Constant T cell activation decreases defence against other infections
  • With treatment can make this phase last for 3-4 decades
26
Q

Describe clinical immunodeficiency

A
  • AIDS develops
  • Infections with conditions rare in immunocompetent people - can’t fight opportunistic infections
  • Neurological illness
  • Ultimately leads to death
27
Q

Describe the destruction of cells by HIV

A
  • Destruction of T cells is central to pathogenesis in AIDS
  • Infects CD4 positive T cells
  • HIV is cytolytic, budding viruses decreases membrane strength leading to cell death
  • Exposure of viral gp120 on the surface of infected cells induces immune response
  • Release of soluble gp120 can bind CD4 and target immune response to uninfected cells
  • Immune response will cause destruction of CD4+ T cells
28
Q

Describe the HIV pathogenesis in acute infection

A
  • High viral load
  • Initial replication leads to transient decrease in T cells and burst of viraemia
  • CD4+ T cells are killed by the viral budding which leads to a decrease in T cell numbers
  • Infected cells targeted by immune system, cytotoxic T cell and antibodies - start clearing CD4+ cells
  • Amount of available cells for infection will start to decrease - the virus will then go into latency
  • Viral load decrease, viruses clears from blood, remains in lymph nodes - establishes clinical latency in the lymph node
29
Q

How does HIV establish clinical latency?

A
  • HIV drives the differentiation of more cells that are susceptible to HIV
  • Viral promoter within LTR are under the control of cellular activator of transcription (ATF) like NFkappaB
  • Virus binding to TCR CD4 activates NFkappaB to induce T cell proliferation
  • Also stimulate LTR and viral transcription - the virus kills T cells that are attacking them
  • Virus replicates in lymph nodes
  • Activated T cells are infected and then a subfraction of these differentiate into latently infected memory T cells
  • Memory T cells last for a long time in the body and keep the HIV infection through the integrated viral genome
30
Q

Describe the molecular mechanisms driving HIV latency

A
  • Upstream of the TAR element in the LTR there are lots of different promoter binding sites - a lot of TFs are required to stimulate transcription of the HIV genome
  • 2 proteins produced by infected cells are able to act as restriction factors for the transcription of HIV - TRIM22 and IFI16
  • These proteins are interferon inducible proteins which have the ability to inhibit the Sp1 transcription factor - a key transcription factor in controlling HIV transcription
  • This means they are able to block the reactivation of HIV from latency
  • Other restriction factors - TRIM25 - ZAP
  • These proteins have the ability to suppress HIV gene expression at a later stage - prevent either mRNA packaging or the translation of HIV
  • Expression of genes is also controlled by chromatin packaging - epigenetic level
  • In the latent stage a number of proteins called histone deacetylase complexes can bind to chromatin and deacetylate histone proteins - inhibits the binding and recognition of promoters by the RNA polymerase II, blocking transcription
  • When HIV reactivates the HDACs is reverted by histone acetyltransferase proteins - acetylate histones to activate binding of promoters
  • When HATs is active the HIV genes can be transcribed
  • When HIV is latent multiple molecular mechanisms work together to suppress expression of HIV genes and production of HIV particles
31
Q

What is the error rate of reverse transcriptase?

A

1-10 errors per RNA synthesised

32
Q

What are the benefits to the virus for coming out of latency?

A
  • Transmission - in latency can’t transmit to new cells or infect another person
  • Gives a chance for the virus to mutate - can produce new strains
33
Q

How is HIV detected?

A
  • ELISA and western blot
  • Nucleic acid detection
  • CD4+ T cell count
34
Q

Describe using ELISA to detect HIV

A
  • Serological diagnosis
  • Detects immune response
  • Very sensitive
  • Detects all persons except the first few weeks of infection
  • Very rapid
35
Q

Describe using western blot to detect HIV

A
  • Detects HIV proteins

- Can give false positives

36
Q

Describe using nucleic acid detection for detecting HIV

A
  • Viral load testing = measurement of HIV levels in the blood
  • High levels are 10,000 viruses per ml of blood
37
Q

Describe the onset of AIDS-Kaposi Sarcoma

A
  • Common in elderly and usually mild - usually takes a long time to develop
  • AIDS patients develop KS young and in an aggressive form
  • Affects internal organs
  • Tumour of spindle cells of vessel walls - leads to visible lesions
  • Vessel leakage gives visible lesions
  • Oral Kaposi’s pathogenic for HIV
  • Associated with human herpes virus-8 co-infection
38
Q

How is HIV infection controlled?

A
  • Behaviour modification - wear condoms - get tested

- Chemotherapy - largely after event and expensive

Human Microbial Diseases Block 2 (10 decks)

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