HIV mutation and consequences Flashcards
How many people live with HIV
approx 39 mil
in 2022
2/3 of people of all people with HIV live in Africa
Who is at risk of HIV
- Men who have sex with men (21%)
- IV drug users (13%)
- Sex workers and their clients
- Mother to child (0.7%)
What is the main transmission route for HIV
Heterosexual contact
-Greatest transmission rate
-49% of new infections
How long is HIV incubation period
2 – 4 weeks
What happens during the acute stage of HIV
sympotoms
-most people don’t know they have been affected
symptoms
-fever
headache
-rash
-sore throat
looks like a flu or cold
What happens to T cells and antibodies during acute infection
- C- D4+ T cells decline temporarily;
- CD8+ T cells increase temporarily > trying to increase viral replication
- anti-HIV-1 antibodies appear
What happens during the chronic infection
- HIV is asymptomatic/latent
- It is replicating at low levels
- Can last for a decade or longer (some progress faster)
What happens to CD4, 8 cells during chronic infection
CD4+ cells gradually decline; CD8+ cells largely unaffected;(numbers remain the same)
Antibodies evolve.
What happens when HIV begins advance to AIDS
the virus load greatly increases and CD4 T cell count drops
-people get weight loss
-Malignancies (EBV can start to replicate when immune cells drop, can get many EBV lymphomas)
-Can get neurological symptoms
What is AIDS
what happens to t cells, b cells
- CD4 T cell count drops below 200 cells/mm
- CD4+ T cell depletion, loss of helper function
- B cells decrease/dysregulation
- impaired NK cell function
- Causes an increased susceptibility to opportunistic infections
surivial is around 3 years after you get AIDS
What infections are opportunistic when someone has AIDS
- Cryptococcal meningitis
- Toxoplasmosis
- Pneumocystis pneumonia (PCP); Pneumocystis jirovecii
- Oesophageal candidiasis
- Certain cancers, including Kaposi’s sarcoma
How can HIV be transmitted and what factors can put people at risk
How can the virus be transmitted?
- Bodily fluids: blood, breast milk, semen, vaginal secretions
- Mother to child DURING pregnancy and delivery
What factors can put people at risk
- Unprotected anal or vaginal sex.
- Sexually transmitted infection (STI) such as syphilis, herpes, chlamydia, gonorrhoea and bacterial vaginosis. → lots of immune cells, greater risk of virus getting through
- Sharing contaminated needles, syringes and needles and drug solutions.
- Getting unsafe injections, blood transfusions and tissue transplantation, and medical procedures that involve are unsterile piercing, cuts
- Accidental needle stick injuries
How do we test for HIV in a lab
HIV antibody test
-can test antibodies in blood or oral fluids
Nucleic acid test
-using blood
-tests virus load
-only used for high risk exposures
Antigen/antibody test
-p24 antigen is made by infected cells, detected before antibodies
What are the different strains and types of HIV
HIV-1 and HIV-2
Tell me about HIV-1
where it comes from, and how much infectiosn it accounst for worldwide
95% of all infections worldwide
come from gorillas and chimpanzees
Tell me about HIV 2
where we find it, what its like, the groups, where it comes from,
how infectious it is
- concentrated in West Africa
- less infectious than HIV-1
- progresses more slowly than HIV-1, resulting in fewer deaths
- Derived from Sooty Mangabeys (a type monkey that carry SIV)
- 8 known HIV-2 groups,-> A&B pandemic
NNRTI drugs ineffective against HIV-2
HIV-2: more than 55% genetically distinct from HIV-1
Why do the subtypes of HIV matter
what are the subtypes
HIV 1 is more complicated
-its an RNA virus so it mutates every time it replicates
-has 4 groups M, N,O,P
-M most common
-M has subtypes A,B,C
Why does HIV 1 having so many subtypes problamatic
If you wanted to vaccine yourself against HIV, you would need a vaccine that would target all 4 subtypes
What is the structure of HIV
- has two molecules of reverse transcriptase, in virus capsid that it takes into the cell with
- Enveloped positive sense ssRNA virus
- Embedded in envelope are 2 key Glycoproteins called GP41 and GP120 (help with entry to cell)
- at the end of RNA they have integrase proteins
- Contains two + ssRNA per virus particle
- HIV is a Lentivirus (subgroup of retrovirus)
Describe the lifecycle of HIV
It attaches to the CD4 and fuses
-releases it virus partciles
- Viral RNA used to synthesize dsDNA by reverse transcriptase (RNA-dependent DNA polymerase)
- the fact that it has two copies of reverse transciptase, when it enters in the cytoplasm it is immedulaty converted into DNA by the viral reverse transcriptase
- this is then shuttled into the nucleus
- this then viral DNA, have intergase enables the virus DNA to integrate into the human genome
- that its why you cant get rid of it
What recpetor binds to teh CD4 receptor
GP120 binds to CD4 receptor on target cell
How does HIV bind and fuse into the cell
1.HIV binds to the surface of a CD4 T cell
2. the GP120 receptor will specifically interact with the CD4 receptor.
3.This triggers a conformation change in gp120 enabling it to bind to its coreceptor -> CXCR4
4.further changes in shape happen so that GP120 is moved our of the way,
5. GP41 can penetrate into plasma cell membrane of target cell
5.this helps brings the envelope of HIV closer to plasma membrane
6. Viral envelope is made up of plasma membrane of target cell (like a wolf in sheeps clothing)
7.this creates a pore through which viral capsid is delievered into the t cell
How does the virus replicate when in teh cell
- dsDNA is circularized and enters the nucleus
- dsDNA integrated into the host genome, catalysed by enzyme integrase
- so the host cell does the heavy lifting for you, every time the cell replicates
- HIV infection is now permanent
- HIV can either enter latency or enter into the productive cycle.
What happens in the productive cycle
- Pro-virus DNA transcribed into mRNA by host RNA polymerase and exported from nucleus.
- mRNA translated into proteins.
- Viral proteins are assembled into virions
- New progeny virus released by budding
- Virus particle matures and becomes infectious
- get a polyprotein,
- virus encodes protease, cleaves polyprotein into single proteins
- so that you an form the capsid
- matures the virus
What are the 5 stages of the lifecycle
- Binding
- Fusion
- Reverse transcription
- Integration
- Maturation
guess what this means, we can target these stages using drugs
What is a problem with anti-retroviral therapy
and what do we do to solve this
a single drug can fail, because the HIV may become resistant
-therefore we use multidrug combos, with distinct resiatnce progoles that can target different genes when adminstered together
-we use can use
– 2 different NRTIs + 1 NNTRI
- 2 different NRTIs + 1 protease inhibitor
What are the advantages of anti-retroviral therapy
-Highly specific - for virus proteins, (safe for humans)
-Defined specificity
-easy to develop them
What are the disadvantages of anti-retroviral therapies
-Highly specific - limited utility for diverse viruses (remember we have bare subtypes)
-Defined specificity means that - resistance mutation can happen
- costly to manufacture (problamatic becasue thjis can cause accessibley issies around the world)
What does NRTIs stand for
Nucleoside reverse transcriptase inhibitors
How do Nucleoside reverse transcriptase inhibitors work
- Incorporate into the DNA of the virus
- Compete with natural nucleosides, because they look like normal nucleosides
- so they compete with your own cell
- They are obligate chain terminators
- insert into the growing DNA chain and stop it from growing anymore
- Inhibit transcription from RNA to DNA
How? - Your nucleoside analogue, undergoes 3 phospylralatiosn mediated by cellular enzymes
- then the tri pshoprylated base reacts with hydroxyl group and catalyses the addition of you’re nucelotide addition to growing DNA chain
- essientail you have the OH
- ** inhibits HIV replication.**
Do NRTIs work on infected hiv cells
No effect on already infected cells
- because they are specific to HIV proteins,
- they stop HIV replicating but don’t have an effect on cells already infected by it
Give some examples of NRTIs
Zidovudine, Stavudine, Lamivudine, Abacavir, Zalcitabine, Emtricitabine,
How does zidovudine work
- the OH group is replaced with azido group
- so its gets inserted into the growing DNA
- which terminates the chain
How do NNRTIs work
Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
- Bind directly to reverse transcriptase near, but not at the polymerase active site
- changes the shape of polymerase active site to blocks conversion of RNA into DNA
- Does not require activation by phosphorylation.
Name some NNRTIs
Examples: Efavirenz, Nevirapine, Delaviridine
How do protease inhibitors work
- HIV protease cleaves HIV polyproteins into structural proteins and enzymes required for assembly of new infectious virions. (REMEMBER FROM EARLIER)
- Protease inhibitors bind the protease -and inhibit correct cleavage of viral proteins.
- Prevent HIV from being assembled and released from infected cells.
Give an example PIs
Examples: Saquniavir, Indinavir, Nelfinavir, Amprenavir, Fosamprenavir, Ritonavir, Lopinavir, Atazanavir
What is cross resistance
- Mutations in resistance to HIV protease inhibitors at or around the active site at codon 82
- this changes the shape of the molecule
- mutations that are resistant to one drug leads to resistance to many members of the same drug family → so easy to get drug resistance
How do drugs become resistance to NNRTIs
- 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
How does HIV become resistance to NRTI
- Steric hindrance
- cause a change in the shape of reverse transcriptase, so the drug can’t interact with reverse transcriptase anymore,
- Altered interactions with the 3’OH of the incoming dNTP
- Enhanced ATP binding
- Excision of NRTIs.
I be real just learn to, and pray
Why is it hard to make a HIV vaccine?
- HIV has genetic variability
- Glycan shielding of the envelope glycoprotein means that this can restrict neutralsing antibodies
-GP 41 and 120 are embedded in the viral envelop
-HIV Env is one of the most highly glycosylated proteins known.
-so restrict penetration of antibodies to envelope - It develops resistamce to antibodies, so it escapes the immune system
-Antibodies usually bind to and neutralises the orignal virus.
- But then these antibdoies fails to neutralize rapidly emerging variant → because the virus looks so different
Remember teh antibody one
Constant evolution of new antibodies makes it harder to make a vaccine,
because the virus keeps evading the immune system
So what do we need to make a successful vaccine for HIV
- Broadly neutralising antibodies
- inhibit all HIV strains
- overcome glycan shield
- inhibit initial infection
