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IIH > Week 3 > Flashcards

Week 3 Flashcards

1
Q

Human immunodeficiency virus at risk groups

A

WHO defined key populations:
-men who have sex with men 21%
-IV drug users 13%
- sex workers and their clients
-mother to child 0.7%
- heterosexual contact is main transmission route for HIV; 49% of new infections

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2
Q

HIV infection and AIDS

A

Incubation period: 2-4 weeks
Acute infection: most people unaware they have been infected, fever, headache, rash, sore throat
Chronic infection: asymptomatic/latent, HIV replicating at low levels, can last for a decade or longer (some progress faster), transmission, eventually virus load greatly increases and CD4 T cell count drops
Acquired immunodeficiency syndrome: CD4 T cell count drops below 200 cells/mm, increased susceptibility to opportunistic infections, maximum survival approx. 3 years

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3
Q

HIV transmission

A

Bodily fluids; blood, breast milk, semen, vaginal secretions
Mother to child during pregnancy and delivery

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4
Q

HIV risk factors

A

Unprotected anal or vaginal sex
Another sexually transmitted infection STI such as syphilis, herpes, chlamydia, gonorrhoea, bacterial vaginosis. Inflammation and destruction of cells in region
Sharing contaminated needles, syringes, and other injecting equipment and drug solutions
Receiving unsafe injections, blood transfusions, and tissue transplantation and medical procedures that involve unsterile cutting or piercing
Accidental needle stick injuries

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5
Q

HIV lab testing and diagnosis

A

HIV antibody test: blood or oral fluids, routine
Nucleic acid test: blood, virus load, only used for high risk exposures
Antigen/antibody test: p24 antigen is made by infected cells, detected before antibodies

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6
Q

HIV types and strains

A

HIV-1 and HIV-2 are 2 distinct viruses
HIV-1 accounts for 95% of all infections worldwide
HIV-1 derived from gorillas and chimpanzees
HIV-2 more than 55% genetically distinct from HIV-1, concentrated in west Africa, less infectious than HIV-1 progresses more slowly than HIV-1 resulting in fewer deaths. NNRTI drugs ineffective against HIV-2. 8 known HIV-2 groups only A&B pandemic, derived from SIV from sooty mangabeys

HIV-1 group m most prevalent
Most ART drugs are tested in subtype B effective against wide range of subtypes

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7
Q

Human immunodeficiency virus

A

Theres no cure, no vaccine
Infected individuals have to take antiviral drugs for life
Drug resistant virus, drugs are expensive
Enveloped positive sense ssRNA virus
Contains two +ssRNA virus per virus particle
HIV is lentivirus (subgroup of retrovirus)
Two subtypes HIV-1 HIV-2

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8
Q

HIV lifecycle

A

Attachment and fusion
Viral RNA used to synthesise dsDNA by reverse transcriptase (RNA dependent DNA polymerase)
DsDNA circularises

  1. Attachment to host cell
    2 binding to CD4 membrane fusion
  2. Release of virion contents into the cell
  3. Reverse transcriptase transforms RNA into DNA
  4. Viral DNA integration in cell genome. Integrate enables viral DNA to integrate into human genome
  5. Production or viral RNA and proteins. Protease
  6. Production of integral membrane proteins gp41 gp120
  7. Budding of virus particles
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9
Q

HIV receptor and co receptors

A

Trimer: gp41, gp120, V3
CD4 binds and changes shape of gp120
Gp120 binds to coreceptor CCR4
Membrane fusion. 6 helix bundle formation

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10
Q

HIV lifecycle replication

A

1) dsDNA circularised and enters nucleus
2) dsDNA integrated into host genome, catalysed by enzyme integrase
3) HIV infection now permanent
4) HIV can either enter latency or enter into productive cycle
5) productive cycle
6) Pro-virus DNA transcribed into mRNA by host RNA polymerase and exported from nucleus
7) mRNA translated into proteins
8) viral proteins are assembled into virions
9) new progeny virus released by budding
10) virus particle matures and becomes infectious

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11
Q

HIV lifecycle; key stages where interruption is possible

A
  1. Binding
  2. Fusion
  3. Reverse transcriptase
  4. Integration
  5. Maturation
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12
Q

HIV - Highly active anti-retro-viral therapy HAART

A

The total failure of single drug therapy led to the adoption of multi drug combinations where 3 or more drugs with distinct resistance profiles and differing target genes are Co administered . Target different part of virus lifecycle
Typically:
- 2 different NRTIs and 1NNTRI
-2 different NRTIs and 1 protease inhibitor

NRTIs: nucleoside reverse transcriptase inhibitors
NNRTIs: non-nucleoside reverse transcriptase inhibitors
PIs: Protease inhibitors
FIs: fusion inhibitors also known as entry inhibitors
CCR5 antagonists also known as entry inhibitors
IIs: integrase inhibitors

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13
Q

Advantages and disadvantages of HAART

A

Advantages:
- highly specific- safe
- defined specificity
- relatively rapid to develop

Disadvantages:
-highly specific - limited utility for diverse viruses
-defined specificity - resistance mutation occurs rapidly
- relatively costly to manufacture

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14
Q

Nucleoside reverse transcriptase inhibitors NRTIs

A

Eg. Zidovudine, stavudine, lamivudine, abacavir, zalcitabine, emtricitabine, didanosine

Mechanism of action:
- incorporate into the DNA of the virus. Nucleoside phosphorylation. DNA polymerase
- compete with natural nucleosides
-obligate chain terminators
-inhibit transcription from RNA to DNA
-ultimately inhibits HIV replication

No effect on already infected cells

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15
Q

Zidovudine

A

Zidovudine AZT is a thymidine nucleoside analogue
OH group replaced with azido N3
Terminates incorporation of new nucleotides

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16
Q

Non-nucleoside reverse transcriptase inhibitors NNRTIs

A

Eg efavirenz, nevirapine, delaviridine
Mechanism of action:
- bind directly to reverse transcriptase near, but not at the polymerase active site
-distorts the RT enzyme and blocks conversion of RNA into DNA
-does not require activation by phosphorylation

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17
Q

Protease inhibitors PIs

A

Eg saquniavir, Indinavir, nelfinavir, amprenavir, fosamprenavir, ritonavir, lopinavir, atzanavir
Mechanism of action:
- HIV protease cleaves HIV polyproteins into structural proteins and enzymes required for assembly of new infectious virions
-protease inhibitors bind the protease and inhibit correct cleavage of viral proteins
-prevent HIV from being assembled and released from infected cells

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18
Q

Primary HIV infection

A

Virus infects immune cells at site of infection (CD4 and T cells, dendritic cells etc)
Virus is delivered to lymph nodes- congregation of immune cells infects loads
Active virus replication
High levels of viraemia and dissemination
Down regulation of virus replication by immune response
Virus set point reached after about 6 months

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19
Q

HIV infection and AIDS

A

Incubation period: 2-4weeks
Acute infection: most people unaware they’ve been infected swollen lymph nodes, fever, headache, rash and sore throat
CD4+ T cells decline temporarily CD8+ T cells increase temporarily, anti HIV 1 antibodies appear
Chronic infection: asymptomatic/latent, HIV replicating at low levels -transmission, can last for a decade or longer some progress faster, CD4+ cells gradually decline, CD8+ cells largely unaffected, CTL responses evolve, antibodies evolve. Acquisition of macrophage tropism

20
Q

AIDS

A

Acquired immunodeficiency syndrome
CD4 T cell count drops below 200 cells/ml
Increased susceptibility to opportunistic infections
Weight loss
Malignancies
Neurological symptoms
Maximum survival approx. 3 years
CD4 +T cell depletion, loss of helper function
HIV-specific CD4+/CD8+ T cell exhaustion
B cells decrease/ dysregulation
NK cell impairment of function

21
Q

AIDS-defining opportunistic infections

A

Cryptococcal meningitis
Toxoplasmosis
Pneumocystis pneumonia PCP; pneumocystis jirovecii
Oesophageal candidiasis (yeast)
Certain cancers, including Kaposi’s sarcoma

22
Q

HIV replication is error prone

A

Error rate approx. 1 per genome per replication cycle
In vivo an HIV infected person may produce 10^9 virus particles/day
The rapid replication of the virus together with the error rate and high viral load causes the virus to evolve rapidly
The rapid evolution of the virus makes problems with:
-drug resistance
-vaccine design

23
Q

Cross resistance

A

Mutations in resistance to HIV protease inhibitors often occur in and around the active site at codon 82 changing the shape of the molecule
Mutations to resistance to one drug often leads to resistance to many members of the same drug family

24
Q

Drug resistance

A

Drugs do not cure HIV, they suppress replication
Drug need to be taken for the life of the patient
For drugs to be effective replication must be blocked completely
At least 3 drugs in combination must be employed to block viral replication/evolution

HIV is sequenced and for each mutation:
-fold decreased susceptibility is compared to wild type virus
-mutations in drug resistance positions are mapped
-new mutations are compared to most common mutations at drug resistance positions
-thousands of sequences and multiple ARV drugs available

25
Q

NNRTI resistance mechanisms

A

Mutations reduce interactions between RT and the bound drug
Cause steric hindrance with the bound drug
Make it more difficult for NNRTI to enter binding pocket on RT
Indirect effects

26
Q

NRTI resistance mechanisms

A

Steric hindrance
Altered interactions with the 3’OH of the incoming dNTP
Enhanced ATP binding
Excision of NRTIs- displaces drug from chain and replaces with nucleotide

27
Q

Drug resistance- Zidovudine AZT

A

Excision involves pyrophosphorolysis (the reverse of polymerisation)
AZT resistant RTs preferentially excise AZT-MP
AZT resistance mutations enhance the ability of RT to bind to ATP the in vivo pyrophosphate donor
AZT is excised easily because the long azido (N3) group interferes with translocation; an AZT terminated promer preferentially resides at the N (active) site where it can be excised

28
Q

Why is it difficult to make an HIV vaccine

A

Enormous genetic variability of HIV
Glycan shielding of the envelope
Immune escape

29
Q

Glycan shielding of the envelope glycoprotein

A

Env is the only target for broadly neutralising antibodies
HIV Env is one of the most highly glycosylated proteins known
Half its mass consists of host derived N-linked glycans
Glycans restrict penetration of antibodies to envelope

30
Q

Immune escape

A

HIV mutates as it replicates and develop resistance to antibodies over time
Original B cell clone is expanded in response to primary infection
Ab binds to and neutralises founder virus
This Ab fails to neutralise rapidly emerging variants
Ongoing somatic hyper mutation of original B cell clone produces bnAbs that can neutralise emerging variants
We need antibodies to be broadly neutralising to inhibit initial infection
This appears to happen in 3 waves:
After initial strain specific Ab response;
-broadly neutralising Ab (bnAbs) emerge against V2
-escape from V2 bnAb by new variants elicits a new response against another CD4 binding site
-further escape is followed by a 3rd wave against unknown epitope
-each new wave generates new bnABs

31
Q

For a successful vaccine

A

Broadly neutralising antibodies
Inhibit all HIV strains
Overcome glycan shield
Inhibit initial infection

32
Q

Anti microbial resistance AMR

A

The acquired ability of a microbe to resist the effects of an anti microbial
Can occur in bacteria, viruses, fungi and Protozoa

33
Q

Antibiotic sites of action

A

Bacterial cell wall and membrane
Nucleic acid synthesis
Protein synthesis

34
Q

Development of AMR at the bacterial population level

A

Mechanism of AMR:
-production of enzymes that degrade antimicrobial (eg beta lactamases)
-change in binding site )eg MecA gene penicillin binding protein)
-membrane permeability (eg aminoglycosides)
-efflux pumps (eg pseudomonas)
Acquisition of AMR:
- de novo (occurs due to a mutation in chromosomal DNA)
-inducible resistance (enzyme switches on when antibiotic present)
-transmitted (eg plasmids)

35
Q

AMR is a natural biological survival strategy

A

Resistance in bacteria:
-methicillin-resistant staphylococcus aureus (MRSA)
-vancomycin resistance enterococci spp. VRE
-extended spectrum beta-lactamase producing enterbacteriaceae spp ESBL
Many of these organisms are associated with hospital acquired infections

36
Q

Resistance in tuberculosis TB

A

Multidrug- resistant tuberculosis (MDR-TB):
-resistant to rifampicin and isoniazid
-3-5% of new cases of TB
-can require much longer treatment
- higher mortality

Extensively drug resistant tuberculosis XDR-TB:
- resistant to rifampicin, isoniazid, fluoroquinolones and injectable agent- nearly 10% of MDR-TB are XDR-TB
-24m RX +/- surgical resection
-30-50% survival

37
Q

Resistance in malaria

A

2016 resistance reported to first line artemisinin- based combination therapies ACT in SE Asia
Along the Cambodia/Thailand border plasmodium falciparum has become resistant to almost all anti-malarial drugs

38
Q

Resistance in HIV:

A

7% and 10-20% of people starting ARVs in developing and developed healthcare settings had drug resistant HIV (2010 WHO data)
Drug resistance in up to 40% of patients restarting ARVs

39
Q

Existence in influenza

A

All influenza A in humans have shown resistance to M2 inhibitors (amantadine and rimantadine)
Resistance to neuraminidase inhibitors (oseltamivir) remains low (1-2%)

40
Q

AMR accelerated by

A

Drug prescribing
Drug access
Drug quality
Veterinary use
Global travel - 1 in 3 travelers acquired ESBL- producing bacteria in stool samples. 75% of these had travelled to SE Asia, median duration of colonisation was 30 days, 12% probability of transmission to household member
Environment- untreated human sewer samples from 60 countries, AMR gene variability by region, strong correlation with socioeconomic and environmental factors

41
Q

Measuring antibiotic resistance

A

Phenotypic testing:
-main method in clinical practice
- examines the growth of bacteria in presence of known concentrations of antibiotics
-key concept: minimum inhibitory concentration MIC: the minimum in vitro concentration of an antibiotic that inhibit a certain amount of growth (eg MIC50= concentration of antibiotic that will inhibit 50% of growth)

Genotypic testing:
- identify genes associated with anti microbial resistance using PCR or sequencing
-not widely used in clinical practice but used for surveillance and for research
- huge potential for rapid detection of AMR

42
Q

UK AMR strategy 2019-2024

A

Reducing exposure to antimicrobials
Optimising the use of antimicrobials- give specific ones for the microbe
Investing in innovation, supply and access

43
Q

Reducing exposure to antimicrobials

A

Lower burden of human infection
Greater global access to clean water and sanitation
Lower burden of animal infection
Minimise spread of AMR through the environment (community, hospital, human animal transmission)
Better food safety

44
Q

Optimising the use of antimicrobials

A

Optimal use of antimicrobials in humans:
-improved diagnostics
-antibiotics stewardship programmes
-monitoring data
Optimal use of antimicrobials in animals
surveillance of AMR in humans
Surveillance of AMR in animals

45
Q

Investing in innovation, supply and access

A

Basic research
Development of new therapeutics
Wider access to therapeutics
Development and access to diagnostics
Development and access to vaccines
Better quality assurance of AMR health products

46
Q

Management of AMR at the individual level

A

1 in 3 patients receive antibiotics in hospital
Antimicrobial prescribing guidelines— drug selection and duration
Screening for AMR and infection control procedures

IIH (10 decks)

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