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HIV Flashcards

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USMLE® Step 1 flashcards
1
Q

What kind of virus is HIV?
What is it replicated by?

A

-ssRNA retrovirus
- replicated by reverse transcriptase

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2
Q

Where is HIV most common?
How many people were newly infected in 2022?

A
  • low and middle income countries
  • 1.3 million infected in 2022
  • almost half from Eastern and Southern Africa
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3
Q

What are the different types of HIV virus?

A
  • HIV-1 M is pandemic
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4
Q

What are the origins of HIV?

A
  • zoonotic disease
  • independent zoonotic infections believed to have generated several HIV lineages
  • transmission cross-species likely due to hunting or keeping primates as pets
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5
Q

What are the common structural properties of retroviruses?

A
  • envelope - attachment and entry
  • matrix and inner capsid core encoded by gag gene
  • reverse transcription RNA-DNA
  • integrate retrotranscribed DNA into the host genome to allow integration and chronic infection
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6
Q

What do the gag, pol and env genes encode for in the HVI genome?

A
  • env = surface and transmembrane proteins
  • pol = protease, integrase and reverse transcriptase
  • gag = matrix and inner capsid core
  • each encoded as polyprotein precursors and cleaved
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7
Q

What are accessory genes?

A
  • not required for replication
  • allow immune surveillance, aid in the release of virus from cells, or allow nuclear import
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8
Q

Aprt from the 3 structural genes found in all retroviruses, what other genes does the HIV genome encode?

A
  • tat activates viral genes
  • rev aids in transportation of late mRNAs into the cytoplasm
  • 4 accessory genes
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9
Q

What kind of cells do HIV infect and how do they enter them?

A
  • CD4 T cells
  • attach to CD4 receptors and trigger a conformational change leading to binding of the core receptor to the host cell
  • viral envelope can then fuse with the cell membrane and enter
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10
Q

How does HIV replication occur in the cell?

A
  • reverse transcriptase has polymerase and RNAse activity
  • RNA binds to cellular primers and synthesis of DNA occurs and forms a heteroduplex
  • RNAse activity degrades the RNA leaving ssDNA
  • RT then creates a second strand of DNA and dsDNA is formed
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11
Q

How does HIV integrate its genome into the host genome after producing dsDNA?

A
  • dsDNA binds integrase to form a reintegration complex
  • moves to the nucleus
  • integrase removes 2 nucleotides on the 3’ end leaving a highly reactive hydroxyl group that covalently binds host DNA
  • ends without removed nucleotides protrude and are seen as an error and get fixed into the DNA by host machinery
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12
Q

What cells other than CD4 T cells can HIV infect?

A
  • monocytes
  • immune cells and cells from the CNS
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13
Q

Which tissue does initial HIV infection occur in? How does it spread?

A
  • at the mucosa
  • spreads to the lymph nodes where there are lots of immune cells
  • infects immune cells that enter the bloodstream and spread to organs around the bosy
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14
Q

How do CD4 T cells respond to infection?

A
  • APCs such as DCs show antigens through T cell receptors via MHC class II
  • causes T cell differentiation and migration to site of infection
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15
Q

How does HIV exploit antigen presentation in lymph nodes to infect CD4 T cells?

A
  • encounters DCs at the mucosa that bind HIV and transport it to the lymph nodes to present antigens to CD4 T cells
  • T cells recognise the HIV antigens by their receptors and co-receptors
  • the viral envelope protein exploits this and causes a conformational change that allows interaction with co-receptors leading to fusion and entry
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16
Q

Describe primary and acute phases of HIV infection?

A
  • lag of a few weeks before primary becomes acute
  • acute phase is characterised by a peak in viral RNA
  • this peak is overcome despite initial CD4 T cell loss
  • becomes clinical latency
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17
Q

Describe clinical latency of HIV infection

A
  • often no symptoms
  • can still transmit infection
  • progressive loss of CD4 T cells until the immune system stops functioning
  • this can then be exploited by opportunistic pathogens
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18
Q

What are HIV permissive and non-permissive CD4 T cells?

A
  • only 5% of cells are permissive
  • permissive cells support HIV infection and replication via coreceptors such as CRR5 (memory T cells)
  • non-permissive cells inhibit infection or life cycle and lack coreceptors (naive T cells)
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19
Q

If so few CD4 T cells are permissive to HIV infection, why do so many die?

A
  • bystander effects
  • nonpermissive cells can be abortively infected and still get killed by the immune system (caspase 1)
  • permissive T cells release viral particles, cytokines, chemokines etc that can lead to pyroptosis, inflammation etc that can damage other cells
  • ENV binding co-receptors can lead to T cell apoptosis
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20
Q

Why is infection of macrophages by HIV different to CD4 T cells?

A
  • slower DNA synthesis
  • bystander effects not really seen
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21
Q

Define AIDS

A
  • acquired immune deficiency syndrome
  • terminal stage of HIV infection
  • defined based on presence of HIV infection and low CD4 T cell count
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22
Q

Name 3 viral and 3 host factors that affect spread of progression to AIDS in untreated HIV

A
  • multifactorial - all untreated HIV will lead to AIDS apart from in a few small few
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23
Q

What are long-term non-progressors of HIV infection?

A
  • remain asymptomatic or have very slow disease progression
  • less affected by AIDS and have higher CD4 T cell counts
  • strong CD8 T cell responses and genetic and immunological factors
24
Q

What are elite controllers of HIV?

A
  • long-term progressors with very low or even undetectable viral loads
  • may experience blips but will come back under control
  • very strong HIV specific CD8 T cell response and protective genetic factors in genes such as HLA
25
Q

What are 4 immune activation factors that reduce/slow progression to AIDS?

A
  • minimal bystander pathology
  • low levels of CD4 apoptosis
  • lack of microbial translocation
  • preserved CD4 T cell homeostasis and lymphoid tissue architecture
26
Q

Antiretroviral drugs can target and block every important step in HIV replication. What are they? (8)

A
  • entry
  • transport and nuclear import
  • reverse transcription
  • integration
  • transcription by host
  • translation by host
  • assembly
  • budding and maturation (polyprotein cleavage)
27
Q

How has HIV treatment developed over time?

A
  • use to have to take lots of pills at different times of day
  • now down to as little as one pill once per day delivering lots of drugs at once
28
Q

What makes injectable HIV drug formulations good?

A
  • fewer drugs and administrations
  • can persist in the plasma for weeks or months
  • usually inhibit integration or reverse transcription
  • similar efficacy to oral
29
Q

Describe the effectiveness of monotherapy, two drug therapy and combination therapy for HIV

A
  • virus overcomes monotherapy easily due to its high mutation rate
  • takes longer for two drug but still does
  • cobination therapy with 3 drugs known as ART stability inhibit HIV in mostH
30
Q

How do antiretrovirual drugs affect the immune system of individuals with HIV?

A
  • induce CD4 T cells recovery
  • often by the time people are diganosed their counts are very low and only partial recovery may occur
31
Q

If ART is used correctly what happens in 1-6 months + another 6 months and beyond?

A
  • takes 1-6 months to get to an undetectable viral load
  • 6 months of being at this level then allows one to become effectively no risk of transmitting HIV as long as this is maintained
32
Q

What percentage of those living with HIV are under viral load suppression?

A
  • 53%
  • poor coverage WHO suggests 90%
33
Q

Why does the large majority of transmission of HIV occur? (human reasons)

A
  • ignorance
  • lack of medical care
  • people unaware of their infection
  • those not taking or receiving proper treatment
34
Q

What is pre-exposure prophylaxis (PrEP)?

A
  • Drugs given before or after exposure to decrease the liklihood of infection
  • not a vaccine
  • can reduce the risk of sexually aquired by >90% and by blood 70%
  • use has reduced new infections in the US
  • reduces replication
35
Q

What happens to HIV viral load of ART is stopped?

A
  • rebounds
  • able to continue damaging CDT cells and transmit between people
36
Q

Why is a cure for HIV needed over ART? (5)

A
  • drug resistance rates growing across the world
  • cost of drug and regular screening is high
  • ART has many side effects that worsen over time
  • need life long compliance
  • stigma
37
Q

What kind of side effects can ART have?

A
  • neuropathy, hepatitis, rash, nausea, CNS disurbances, fever
  • the longer the drugs are taken for the higher the chance of side effects
38
Q

Why is lifelong compliance hard to obtain with ART HIV tharepy? Why is this a pporblem

A
  • people may not take if they’re feeling fine, getting bade side effects or forget/don’t want to
  • this can increase drug resistance, increase transmission and allow their disease to progress
39
Q

What is the difference between a sterlizing cure and a functional cure?

A
  • sterilizing means complete elimination of all infected cells
  • functional means elimination of enough infected cells to stop post-therapy disease progression perhaps by inducing effective immunity
  • a functional cure is more likely
40
Q

How can HIV persist in immune cells? persistence states (3)

A
  • persistant (producing virions)
  • replication defective (produxing viral proteins)
  • latent (producing nothing but silently surviving in the cell, biggest contirbuter and cant be killed bcontributory ART)
41
Q

By what 3 mechanisms can latently HIV infected cells persist?

A
  • viral replication - infected cell infects a new one at a different site
  • latent cell longevity - latently infected cells persist for a long time
  • latent cell proliferation - memory cells persist but not forever, replicate at a slow rate bringing integrated HIV DNA with it
42
Q

5 individuals have been cure of HIV so far. How?

A
  • stem cell transplant
  • donor has a rare mutation in the CCR5 co-receptor that provides resistance to HIV
  • need everything to match
  • allogenic stem cell transplants have high morbidity
43
Q

What are some pros of using autologous HSC therapy agaisnst HIV (3)?

A
  • available for most patients
  • no need for matched donors
  • no graft vs host disease
44
Q

What are some cons of using autologous HSC therapy against HIV (3)?

A
  • SCs may need 100% gene modification
  • virus reservoirs are reduced but not eliminated
  • likely still require combination therapies
45
Q

What are some pros of using allogenic HSC therapy against HIV? (3)

A
  • complete replacement of host cells with donor cells
  • potential elimination of viral reservoirs
  • may not require genetic modification
46
Q

What are some cons of using allogenic HSC therapy against HIV (2)?

A
  • possibilty of finding matched donors with CCR5 deletion is very low
  • geater chance of mortality due to graft vs host disease an/or immunosuppresive therapies
47
Q

What are some common limitaitons of both autologus and allogenic HSC therapy? (4)

A
  • costs
  • not feasble in resource limited places
  • both have morbidity/mortality
  • only really applied in people with specific co-morbiditied such as cancer that may benefit from stem cell therpies
48
Q

What approaches are there to potentially cure HIV? (6)

A
  • engineered autologous HSCs
  • ART during the acute phase
  • shock and kill
  • block and lock
  • broadly neutralising antibodies
  • metabolic approach
  • likely need combinations
49
Q

How could autologous HSCs be modified for HIV treatment?

A
  • engineering them to not express CCR5
  • difficult to ensure that the mutate cells will take over as they have no clear selective advantage
  • might just die from bystander effects anyway
50
Q

What can happen if ART is given in acute HIV (in theory)

A
  • immune system will be able to control the virus itself after treatment
  • occurs in 15% of those in actute
  • however most people only find out about their infection after the acute hpase
51
Q

What is the shock and kill HIV cure approach?

A
  • use of latency reversing agents to force viral DNA to be replicated again
  • can then be recognise by the immune system
  • not yet successful in the lab
52
Q

What is the broadly neutralising antibodies approach to curing HIV?

A
  • virus is so variable it is hard for antibodies to neutralise it
  • some people people produce Abs that affect all or most HIV strains
  • could give these as therapy
  • still doesnt affect latent virus
53
Q

What is the block and lock approach to curing HIV?

A
  • use ART along with tat inhibitors to push cells into deep latency
  • virus cant replicate or spread
  • hard to achieve experimentally
54
Q

What s the metabolicc approach to curing HIV?

A
  • using cellulary metabolism to target latent cells for destruction
  • oxidative phosphorylation genertates ROS that acucumulate
  • cells with HIV upregulate the natrual defeenses against these
  • could try to inhibit these leading to a partially selective death
  • also used in cancer
55
Q
A

Medical virology (15 decks)

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