HIV Flashcards
What kind of virus is HIV?
What is it replicated by?
-ssRNA retrovirus
- replicated by reverse transcriptase
Where is HIV most common?
How many people were newly infected in 2022?
- low and middle income countries
- 1.3 million infected in 2022
- almost half from Eastern and Southern Africa
What are the different types of HIV virus?
- HIV-1 M is pandemic
What are the origins of HIV?
- zoonotic disease
- independent zoonotic infections believed to have generated several HIV lineages
- transmission cross-species likely due to hunting or keeping primates as pets
What are the common structural properties of retroviruses?
- 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
What do the gag, pol and env genes encode for in the HVI genome?
- env = surface and transmembrane proteins
- pol = protease, integrase and reverse transcriptase
- gag = matrix and inner capsid core
- each encoded as polyprotein precursors and cleaved
What are accessory genes?
- not required for replication
- allow immune surveillance, aid in the release of virus from cells, or allow nuclear import
Aprt from the 3 structural genes found in all retroviruses, what other genes does the HIV genome encode?
- tat activates viral genes
- rev aids in transportation of late mRNAs into the cytoplasm
- 4 accessory genes
What kind of cells do HIV infect and how do they enter them?
- 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
How does HIV replication occur in the cell?
- 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
How does HIV integrate its genome into the host genome after producing dsDNA?
- 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
What cells other than CD4 T cells can HIV infect?
- monocytes
- immune cells and cells from the CNS
Which tissue does initial HIV infection occur in? How does it spread?
- 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
How do CD4 T cells respond to infection?
- APCs such as DCs show antigens through T cell receptors via MHC class II
- causes T cell differentiation and migration to site of infection
How does HIV exploit antigen presentation in lymph nodes to infect CD4 T cells?
- 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
Describe primary and acute phases of HIV infection?
- 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
Describe clinical latency of HIV infection
- 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
What are HIV permissive and non-permissive CD4 T cells?
- 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)
If so few CD4 T cells are permissive to HIV infection, why do so many die?
- 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
Why is infection of macrophages by HIV different to CD4 T cells?
- slower DNA synthesis
- bystander effects not really seen
Define AIDS
- acquired immune deficiency syndrome
- terminal stage of HIV infection
- defined based on presence of HIV infection and low CD4 T cell count
Name 3 viral and 3 host factors that affect spread of progression to AIDS in untreated HIV
- multifactorial - all untreated HIV will lead to AIDS apart from in a few small few
What are long-term non-progressors of HIV infection?
- 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
What are elite controllers of HIV?
- 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
What are 4 immune activation factors that reduce/slow progression to AIDS?
- minimal bystander pathology
- low levels of CD4 apoptosis
- lack of microbial translocation
- preserved CD4 T cell homeostasis and lymphoid tissue architecture
Antiretroviral drugs can target and block every important step in HIV replication. What are they? (8)
- entry
- transport and nuclear import
- reverse transcription
- integration
- transcription by host
- translation by host
- assembly
- budding and maturation (polyprotein cleavage)
How has HIV treatment developed over time?
- 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
What makes injectable HIV drug formulations good?
- fewer drugs and administrations
- can persist in the plasma for weeks or months
- usually inhibit integration or reverse transcription
- similar efficacy to oral
Describe the effectiveness of monotherapy, two drug therapy and combination therapy for HIV
- 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
How do antiretrovirual drugs affect the immune system of individuals with HIV?
- induce CD4 T cells recovery
- often by the time people are diganosed their counts are very low and only partial recovery may occur
If ART is used correctly what happens in 1-6 months + another 6 months and beyond?
- 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
What percentage of those living with HIV are under viral load suppression?
- 53%
- poor coverage WHO suggests 90%
Why does the large majority of transmission of HIV occur? (human reasons)
- ignorance
- lack of medical care
- people unaware of their infection
- those not taking or receiving proper treatment
What is pre-exposure prophylaxis (PrEP)?
- 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
What happens to HIV viral load of ART is stopped?
- rebounds
- able to continue damaging CDT cells and transmit between people
Why is a cure for HIV needed over ART? (5)
- 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
What kind of side effects can ART have?
- neuropathy, hepatitis, rash, nausea, CNS disurbances, fever
- the longer the drugs are taken for the higher the chance of side effects
Why is lifelong compliance hard to obtain with ART HIV tharepy? Why is this a pporblem
- 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
What is the difference between a sterlizing cure and a functional cure?
- 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
How can HIV persist in immune cells? persistence states (3)
- 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)
By what 3 mechanisms can latently HIV infected cells persist?
- 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
5 individuals have been cure of HIV so far. How?
- 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
What are some pros of using autologous HSC therapy agaisnst HIV (3)?
- available for most patients
- no need for matched donors
- no graft vs host disease
What are some cons of using autologous HSC therapy against HIV (3)?
- SCs may need 100% gene modification
- virus reservoirs are reduced but not eliminated
- likely still require combination therapies
What are some pros of using allogenic HSC therapy against HIV? (3)
- complete replacement of host cells with donor cells
- potential elimination of viral reservoirs
- may not require genetic modification
What are some cons of using allogenic HSC therapy against HIV (2)?
- 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
What are some common limitaitons of both autologus and allogenic HSC therapy? (4)
- 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
What approaches are there to potentially cure HIV? (6)
- engineered autologous HSCs
- ART during the acute phase
- shock and kill
- block and lock
- broadly neutralising antibodies
- metabolic approach
- likely need combinations
How could autologous HSCs be modified for HIV treatment?
- 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
What can happen if ART is given in acute HIV (in theory)
- 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
What is the shock and kill HIV cure approach?
- 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
What is the broadly neutralising antibodies approach to curing HIV?
- 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
What is the block and lock approach to curing HIV?
- use ART along with tat inhibitors to push cells into deep latency
- virus cant replicate or spread
- hard to achieve experimentally
What s the metabolicc approach to curing HIV?
- 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
