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MCB55 > 23-24: HIV > Flashcards

23-24: HIV Flashcards

1
Q

overall timeline

A

1981: first clinical observation of AIDS

1983: isolation of HIV

1985: blood test for HIV

1987: AZT (first drug) approved

1996: combination therapy

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2
Q

1981: surprising illnesses among young homosexual men

A

june 5 - first reports in CDC MMWR
- case of 5 young men dying from pneumonia (unusual since it shouldn’t be affecting/killing young men)

at the same time in NY and CA, doctors finding patients dying from KS

search for a new virus

total of 159 cases recorded at the end of the year

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3
Q

1981: acquired immunodeficiency syndrome (AIDS)

A

CDC showing that it doesn’t only affect homosexuals, but also women, haemophiliacs, etc.

people with enlarged lymph nodes with their immune systems wiped out

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4
Q

1983: HIV discovery

A

2 years after the first case of HIV

barré-sinoussi and montagne taking biopsies from swollen lymph nodes of AIDS patients
- didn’t know what the virus was so called it lymphadenopathy-associated virus or LAV

new retrovirus isolated from a patient with AIDS

realisation that it wasn’t just the US and Europe, but affecting a large fraction of the population in africa (men, women, infants, etc.)

also the realisation that it wasn’t just sexual encounters but blood transactions (haemophiliacs)
- one infected blood donation contaminated everything since it was all pooled

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5
Q

1985: new blood test

A

federal government licensed an HIV antibody test and screening begins of blood supply

test did not prevent contamination to haemophiliacs
- can tell you you’re infected but no therapy

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6
Q

1987: first antiviral against HIV approved

A

approved in record time

zidovudine (AZT) as the first anti-HIV drug approved by the FDA
- miracle drug

AIDS patients rapidly showing signs of resistance to AZT

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7
Q

1996: combination therapy made available

A

need multiple drugs given at the same time targeting different viral proteins to control infection

up until 1995, getting HIV as a death sentence

developing drugs targeting at least 2-3 viral proteins given at once led to very efficient drops in the number of deaths but not infections

now at the point where HIV patients can have the same life expectancy as normal people as long as drugs are taken
- can keep the virus at bay completely

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8
Q

HIV/AIDS numbers

A

80 million infections from 1978 to the present

40 million deaths from AIDS

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9
Q

major region impacted globally by HIV/AIDS

A

25M infections in sub-saharan african

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10
Q

global HIV/AIDS epidemic today

A

number of people with HIV: 38M globally

number of new infections: estimation of 1.7M worldwide acquiring HIV in 2019

AIDS-related deaths: 690,000 deaths globally
- not dying from HIV but the inability to respond to infections

HIV testing: approximately 81% of people know their status
- needs to be higher but still a big win

HIV treatment access: 25.4M people accessing anti-retroviral therapy (ART) globally

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11
Q

HIV classification

A

first came from monkeys in a spillover event
- early on in the 1900s so maybe hundreds of years ago

hunters entering equatorial forests, hunting for bushmeat and killing primates
- contact with primate blood and spillover event

multiple spillover events through the 1900s
- gave rise to M, N and O clades of HIV

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12
Q

HIV1 and HIV2

A

HIV1 and HIV2 causing similar immunodeficiency disease in humans
- HIV2 mostly in africa

cause the same pathologies and same disease
- genetically different if we look at the sequence

HIV1 found in 80% of cases in the world (most dominant)

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13
Q

origination of HIV1

A

mixture of what is found in mona monkeys and red-capped mangabeys

recombination of the virus into a chimpanzee which then transmitted to humans

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14
Q

origination of HIV2

A

numerous cross-species transmission events yielding HIV2 groups A to H
- multiple spillovers

from primates (sooty mangabeys) to humans

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15
Q

how did SIV jump into humans?

A

likely to be blood-blood transfer during butchering of bushmeat

HIV chimp to human transition as a zoonosis
- however, not repeatedly spread from animal reservoir to human (unlike rabies)

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16
Q

HIV transmission

A

fully established in the population, human-human spread so no longer zoonotic

contact with body fluids from infected people
- blood from blood banks,
- semen/vaginal fluid
- breast milk

other routes of infection
- sharing needles (drug use/infections)
- unprotected sex

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17
Q

HIV vs. AIDS

A

HIV: human immunodeficiency virus

AIDS: acquired immunodeficiency syndrome

people who are infected with HIV do not necessarily have AIDS
- AIDS as one phase of HIV infection (late phase)

for a long period of time, people infected with HIV can have a competent immune system
- after, infected HIV individuals if untreated will develop AIDS and the immune system falls apart

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18
Q

what does AIDS result from?

A

CD4+ T-cell depletion which causes severe immunosuppression and an increase in opportunistic infections

type of white blood cells which are important to control how the immune system responds to pathogens
- without CD4 T-cells, the entire immune system cannot function

virus infects CD4 T-cells so the virus kills these cells
- you can replenish CD4 T-cell population but it takes energy and the virus continually kills them
- at some point, the immune system cannot replenish the population anymore so massive loss

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19
Q

importance of CD4 T-cells as the master conductor of the immune system

A

help B cells make antibodies
- without CD4 T-cells, no antibodies

helps CD8 T-cells (CTLS)
- entire adaptive immune system eliminated

allows recruitment and activation of innate immune cells
- macs, DCs and neutrophils called to come to the infection site to hunt for pathogens only do so when CD4 T-cells tell them to do so

without CD4 T-cells, nothing from the immune system

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20
Q

opportunistic infections

A

normally benign infections in healthy people
- bacterial, fungals, protozoal or viral

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21
Q

HIV-TB co-infection

A

major killer
- TB in healthy individuals is controlled by CD4 T-cells so when they are lost, if people are infected with TB, they cannot control it and will die from it
- deadly combination

mycobacterium TB responsible for almost 1/3 of estimated 1.2M HIV-related deaths globally in 2014
- almost entirely in africa

lethal synercy
- resistance to mycobacterium TB requires CD4 T-cells

22
Q

events occurring after HIV1 infection

A

initial peak of viremia (number of virus found in the body) and symptoms
- 50-90% symptomatic (fever or any kind of viral infection)
- generally 5-30 days after exposure and lasts for 2 weeks (fever, fatigue, headache, nausea, vomiting, diarrhoea, lymphadenopathy, weight loss)

viremia controlled and reaches a low level
- virus can hide and replicate but to a low level

for years, virus replicates at a low level
- number of CD4 T-cells slowly declining as virus kills them
- virus replicating in CD4 T-cells dying (CD4 dying as well because targeted by the immune system)

CD4 T-cells reach low enough levels (~400) to no longer sustain immune responses
- virus replicates out of control, succumbing to opportunistic infections
- virus is no longer controlled, no immune system, and virus spikes

AIDS as the most severe form of immunosuppression known

23
Q

why does the number of CD4 T-cells gradually decline?

A

CD4 T-cell infection leads to CD4 T-cell death which leads to CD4 T-cell replacement and the cycle continues

immune system continually tries to make new CD4 T-cells but at some point, you exhaust the capacity of the body to make CD4 T-cells

24
Q

types of HIV tests

A

typically performed on blood since you are infected for life and can look for antibody presence against HIV

antibody test: most rapid tests and only self-test approved by US FDA
- requires antibodies so it cannot be done soon after exposure (needs 5-10 weeks for antibodies to be made)

antigen/antibody test: done in labs
- looks for the virus itself, or proteins released by the virus (antigen called p24)
- p24 produced before antibodies develop

nucleic acid test (NAT): HIV viral load test which tells you if someone has HIV or how much virus is present in the blood
- detects HIV sooner than other types of test
- considered for people who have had recent/possible exposure

25
Q

how do we ensure that the blood donor pool is HIV-free?

A

HIV incidence in first-time donors estimated at 2-3 cases/100,000 people annually

use NAT where it can be detected sooner and is more sensitive
- can always detect some viruses in the blood which are not latent

sensitivity of tests matter
- cannot detect HIV within the grace period so when there is infection, HIV can be replicating in just the tissue but not the blood
- enough to cause infection but not enough to detect in the test

26
Q

grace period of HIV lab tests

A

window period where very recent HIV infections cannot be detected

for the most sensitive RNA assays, this can be between 10-16 days
- infected people have contaminated blood but it won’t be picked up by the test

blood banks tend to screen people with high-risk habits (homosexual men
- until 2015, homosexuals with at least one sexual encounter since 1997 forbidden from giving blood

now, since 2020, homosexual men with at least one sexual encounter in the last 3 months cannot give blood

27
Q

simian immunodeficiency virus (SIV)

A

presents in primates which give rise to HIV in humans

28
Q

HIV is not unique

A

syndrome it causes is unique

29
Q

HIV as a retrovirus

A

retroviruses have small RNA genomes

use of an enzyme called reverse transcriptase to make a DNA copy of their RNA genome

DNA copy of the viral genome can be inserted into the host DNA genome
- can hide dormant or latent for years and be impossible to detect

eventually, it will transcribe new copies of the viral DNA from the integrated DNA copy and assemble new infectious viral particles which contain an RNA genome to infect new cells
- once in a while, reactivation and the cycle begins again

30
Q

HIV structure

A

virion with two S-shaped molecules in the middle
- RNA associated with viral proteins
- identical genomes with reverse transcriptase

envelope surrounding and protecting the virus
- viral proteins inserted into the envelope
- proteins responsible for reacting with receptors (similar to spike with COVID)

envelope proteins called gp120 and gp41
- gp120 associated with attachment to receptors
- gp41 associated in the fusion with a new cell

immune system only sees/detects these proteins

with an immune response and vaccination, you want to generate antibodies against gp120 since it is the only thing to detect the virus and prevent infection

31
Q

viral proteins of HIV

A

gp120, gp41, protease, integrase, reverse transcriptase

32
Q

HIV viral genome

A

carried in the viral particle in two copies
- single strand of RNA of 9749 nucleotides and a few genes

GAG, POL and ENV as key genes found in all retroviruses
- find these in the human genome as well

LTR encodes instructions for the expression and packaging of the genome

ACC as additional accessory genes

33
Q

multiple viral proteins are made from the three key precursor proteins (GAG, POL, ENV)

A

GAG:
- matrix protein
- capsid protein
- essentially forms the shell of the virus to protect the genome

POL:
- reverse transcriptase
- protease
- integrase
- cuts strands into different pieces which become different proteins with different functions
- forms enzymes and proteins

ENV:
- formation of gp120 and gp41
- long protein cut to form these proteins

34
Q

accessory factors

A

lentiviruses have additional accessory factors while retroviruses all have GAG, POL and ENV

proteins have specialised roles in the viral life cycle (immune evasion)
- distinguish HIV from other retroviruses

35
Q

viral life cycle: entrance of HIV

A

part 1

gp120 attaches to CD4 receptors on T-cells
- recognises CD4 molecule on the surface of T-cells
- presence of CD4 required

gp41 mediates membrane fusion, so viral capsid and RNA genome are delivered
- changes structure and allows fusion of the cellular envelope of the virus with the cellular membrane of the host, realising the virus into the cytosome

HIV can infect CD4 T-cells, macs and DCs (all important to immune response) since they all express CD4

36
Q

role of the co-receptor in the viral life cycle

A

CD4 is necessary but not sufficient to mediate viral entry

second receptor called co-receptor required to permit viral entry
- CCR5 or CXCR4

CCF5 and CXCR4 as chemokine receptors
- normal function to detect chemokines (chemical signals) which tell immune cells where to go in the body

gp120 binds to CD4, which brings it into contact with CCR5/CXCR4
- changes the structure of gp120 and then allows for exposure with gp41, then fusion

37
Q

intrinsic resistance to HIV

A

some individuals intrinsically resistant like prostitutes in africa who never got infected despite numerous exposure

one group of resistant individuals found to harbour a genetic mutation in their CCR5 gene (32bp deletion)
- rendered CCR5 non-functional and not expressed
- virus can see CD4 but cannot find CCR5 to continue infection

body can do without CCR5 and it is not essential

38
Q

Berlin patient

A

timothy ray brown developing leukaemia unrelated to HIV 10-15 years ago

typically wipe out immune system and give them bone marrow cells, which will reconstitute and become the source of immune cells so development of a quasi-normal immune system

with brown, infection with HIV so depletion of immune cells and replacement with bone marrow would mean that HIV still infects and kills all the new bone marrow cells

so, they screened for blood donors with CCR5 genetic mutations and gave him that
- bone marrow reconstituted immune system
- now HIV-free

39
Q

CRISPR babies and embryo editing

A

world’s first genetically engineered babies where he took out CCR5 since people who are deficient can function normally but will be resistant to HIV

40
Q

viral life cycle: reverse transcription and integration

A

part 2

RNA genome reverse transcribed into a double-stranded DNA copy with reverse transcriptase

DNA copy brought to the nucleus where integrase cuts the human genome at random, attaching the RNA genome to our own genome

virus can be integrated and silent for a long time (latent)
- virus therefore silences itself
- never get rid of HIV

41
Q

mutation rate of replicating HIV

A

phenomenal mutation rates in reverse transcriptase as a polymerase

for polymerase, 3 mutations per cell division typically

in HIV reverse transcriptase, about 1 mutation every time it copies a genome
- 10,000bp

42
Q

immunological considerations of HIV mutation rates

A

low estimate of virion release into blood as 10B virions daily

every virus slightly different from each other, with one or two point mutations

on average, every possible mutation at every position in the HIV genome predicted to occur annually

43
Q

HIV viral quasispecies and bottlenecks

A

infected with one HIV virus, but the whole population of viruses varies from each other by one or two point mutations

44
Q

consequences of HIV mutations (quasispecies)

A

helps the virus evolve and evade antibodies

immune system always playing catch up to eliminate the virus that already has an advantage

hard to develop antivirals since the virus develops antiviral resistance
- if we target reverse transcriptase, the drug will fit into a pocket and lock it from being functional/effective
- mutations in the virus make the size of pockets different so the virus can escape and the drug doesn’t fit

only advantage is that viruses with mutations which may be resistant are typically not that good
- virus forced to acquire many mutations, each of which is associated with a disadvantage for the virus

45
Q

integrated DNA copy of the HIV RNA genome

A

provirus

46
Q

viral life cycle: assembly and release

A

part 3

integrated provirus directs the creation of new RNA viral genomes with transcription, and new viral proteins with translation

reactivation when viral RNA leaves the nucleus, using viral genomes, which are translated to make viral proteins

protease cuts larger proteins into smaller proteins (reverse transcriptase, integrase, etc.)
- powerful target for chemical drugs

assembly of new viral particles and release

47
Q

immune response to HIV

A

neutralising antibodies to prevent gp120 from binding to host cells
- only viral protein exposed so targeted
- gp120 however shielded by carbohydrates (sugars) so it is hard to detect
- also that gp120 mutates which prevents recognition of the site by antibodies
- virus can easily escape antibody responses

CD8 T cells kill viral-infected cells
- good CD8 T cell responses requires help from CD4 T cells which decline with AIDS
- becomes less efficient as infection continues
- CD8 T cells recognise peptides presented by MHC molecules but peptides also mutate while CD8 8 cells only recognise the exact copy of the peptide

responses partially control but cannot eliminate HIV
- replicates, mutates and outruns the immune system

48
Q

why is there no HIV vaccine?

A

not clear what kind of immunity to be elicited to provide protection
- B cells and CTLs are good responses but what do we try to make more of?

not clear on how to solve HIV mutability and variability
- can generate a good response to wipe out the virus but always some mutated viruses that can take over the host again so you lose efficacy

49
Q

treatment for HIV infection

A

highly active antiretroviral therapy (HAART)

combination of multiple drugs to prevent emergence of drug-resistant variants
- reverse transcriptase, protease, integrase and viral fusion inhibitors

doesn’t really help with emergence of variants since mutant viruses probably already exist but are relatively low and kept under control
- statistically the viruses already exist

drugs cannot cure HIV
- latent in the DNA for the life of cells

50
Q

HIV treatment: PrEP (pre-exposure prophylaxis)

A

reduces changes of getting HIV from sex by 99% and from injecting drug use (>74%)

requires high levels of adherence, protects only against HIV and not other STDs

pills taken daily that inhibit reverse transcriptase
- descovy and truvada

shots every two months as long-lasting integrate inhibitor
- apretude

51
Q

HIV treatment: PEP (post-exposure prophylaxis)

A

use of antiretroviral drugs (3 distinct drugs) after a single high-risk event to stop HIV seroconversion
- during sex
- sharing needles/syringes for drug infection
- sexual assault

has to be started as soon as possible to be effective
- within 72 hours of possible exposure

MCB55 (30 decks)

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