hiv/aids Flashcards
what is the origin of hiv-1
SIV chimpanzees (cpz), it is a hiv like virus haboured in oldworld primates
how is it believed that hiv became a pandemic
went from monkeys into humans via zoonotic transmission, plausible explanations are the west african bushmeat trade
what type of virus is hiv
retrovirus
what are the three polyproteins synthesised by a retrovirus e.g hiv
gag(group specific antigen)
pol(polymerase)
env(envelope glycoprotein)
what proteins make up the gag polyprotein
viral core proteins matrix,capsid and nucleocaspid
what proteins make up the pol polyprotein
enzymes: PR (protease), RT (reverse transcriptase), IN (integrase)
what proteins make up the env polyprotein
SU (surface), TM (transmembrane)
what is definition of retrovirus
viraL GENOME IS STORED as rna so reverse transcriptase needed to make dna. then integration occurs in which there is covalent insertion of viral cdna into genome of infected cell, using integrase
what is the consequence of integration in an infected cell
to cure retroviral infection you need to kill all cells containing viral genome, however cells go into latent phase, not producing any viral proteins so can’t be spotted by immune system
describe structure of mature hiv-1 particle
hiv is envelope virus, has a lipid bilayer with protruding env spikes, inside the envelope there are shells of gag proteins. MA associates with the membrane, ca forms conical caspid, and nc coats viral rna genonome, the core has two rna stands, about 50 copies of viral enzymes.
cellular factors can also be packaged. like cylclophillin
how does mature hiv1 particle differ to immature one
In the mature par7cle, MA associates with the membrane, CA forms the conical capsid, and NC coats the viral RNA genome. The core contains two genomic RNA strands (plus strand), tRNALys3, and about 50 copies of each viral enzyme (PR, RT and IN).
what does hiv require to enter the host cell and what cells is hiv trophic for
two receptors cd4 and chemokine receptor (CCR5/CXCR4), trophic for cd4 and macrophages
what are the three distinct enzymatic activities of reverse transcriptase
- RNA-dependent DNA polymerase
- RNAasH (cleaves RNA from RNA/DNA hybrid)
- DNA-dependent DNA polymerase
what is reverse transcriptase made of
RT is a heterodimer of p66 and p51 subunits.
describe some modes of hiv sequence diversification
copy errors, reverse transcriptase has no error checker, recombination(shift), drift plus shift, these factors all accelerate viral diversification
why is viral diversification important to appreciate
Contribu7ons to – immune escape, drug resistance,
phenotypic changes and natural history?
what clades of HIV dominate
HIV-1 Sequence Diversity (B & C clades predominate)
what is a clade
different subtypes of related viruses called clades, nucleotide sequence cant differ by more than 30 per cent, clades don’t have sig phenotype diff, but big implications for hiv vaccination
how does CDNA produced by reverse transcriptase integrate in cell genome
integrase cleaves 3’ end 2 nucleotides gone, triggers host repair mechansims which then integrates the foreign material into the host genome randomly (some areas are favoured)
why are scientist interersted in hiv1 regulatory/acessory proteins
diverse functions all essential, adapters that facilitate molecular interactions, contribute to evasion of host control mechanisms such as immune system, can they be targeted with therapeutics
what is tat
potent activator of viral transcription
what is rev protein
mediates unspliced rna export
what is vif protein
critical regulator of virus infectivity
what is nef protein
immune modulator, tcell activation, virus infectivity
what is vpu protein
immune modulator, virus release
what is vpr protein role
cell cycle, virus nuclear import, resistance modulator
describe the balance between a host cell and a virus in terms of the virus attempting to replicate
it is a delicate balance, host cells have measures to prevent virus from replicating but viruses have counter measures too
what does tetherin do and how is it opposed
tetherin stops virus from being relased from cell surface, opposed by vpu which marks tetherin for degradation
what does apobec3 do to protect host cell from hiv and how does virus oppose this
apobec3 changes c to u mutagenesis inhibiting reverse transcriptase, vif counteracts this
what does SAMHD1 do to stop hiv replication and how does the virus antagonise this process
it supress RT in myeloid cells hydrolysing dntps , countered by vpx
what does serinc do and how isit countered in hiv infection
serinc stops viral entry however it is countered by nef
draw out the typical course of hiv infection
viral load is high initially, cd4 drop from 100 to around 600, immune system takes some control and viral load drops to a set load, there is a latency period and then progression to aids where viral load rises and cd4 decrease. this is where you can get opportunistic infections
describe a crucial feature of hiv1 replication
obligate formation of the provirus , one of the biggest hurdles to devloping a cure, SO IF WE CAN “WAKE UP” ALL OF THE PROVIRUS IN
LATENTLY
INFECTED CELLS IN PRESENCE OF ONGOING DRUG
THERAPY
describe the risk of hiv transmission via sex
genrally lower significantly high in male male sex. risk is also significantly enhanced if there are other stds or epithelial lesions
what form of hiv transmission has the greatest estimated risk
blood transfusion, then iv drugs use needle sharing, then mother to child
explain how hiv is transmitted mucosally
hiv1 breaches mucosal barriers, transmitted virus are ccr5 trophic, other celles can be infected dendrites, 0.1% hiv1 exposure results in transmission.
what • Implies that physical barriers, and
innate/intrinsic defenses are quite
effective
Most transmissions result in a single
founder virus infecting the recipient
how does acute infection differ from chronic infection in hiv1, acute being before the adpative immune system
primary target in acute phase are cd4 cells, majority are mucosal, up to 60% can be lost due to cytopathicity of hiv1, apoptosis + ctls
in acute hiv1 transmission what tissue is a major target
galt tissue, hiv spreads rapidly to the cd4 cells here, the immune integerity of the gut never recovers and you can get chronic immune activation there
explain the four classes of progressors in hiv infections
viral load predicts survival time, normal progressor will have aids 8-10 years, rapid progressors will have aids in 1-3 years, long term non progressors and elite controllers
what controls acute hiv infection
controlled by a strong CD8+ T cell
response, neutralizing antibodies arise much later
how does hiv affect the memory cells
cd4 t cells deplete due to cytoxi killing or apoptosis, immune hyperactivity results in more tcells being activated and this makes them more susceptable to destruction. results in loss of cd4 t cell memory pool and thymic bone marrow dysfunction
intially viremia of hiv is controlled by cytoxic cd8 cells but not cleared why does this control eventually fail
hiv1 escapes cd8 evntually by mutations eavding adaptive immunity
what is the problem with continued t cell activation and general inflammation state
activates more t cells which are substrates for continued infection depleting t cells
how do you diagnose hiv1
either elisa which detects individuals who have seroconverted after 3 months, or rtpcr which is ONLY test that can diagnose before 3 months, looks at virus particles per millitre of blood
describe in detail elisa
only detects hiv1 infections in those who have seroconverted after 3 months, so if done before 3 months a negative test may not be conclusive, a positive sample will be retested using elisa or western blot
what is the significance of opportunistic infections in hiv 1
once you start getting this almost inevitably leads to death
name some opportunistic infections associated with aids
herpes simplex virus 1/2 oral, genital or anal, fungal pneumonia,kaposi sarcoma, toxoplasmosis, tuberculosis
name Classic HIV-1-associated ODs fungal ones
Fungus infections: Pneumocystis carinii Histoplasma Cryptococcus Coccidioidomyces
name Classic HIV-1-associated ODs bacterial ones
mycobacteria, TB, MAI etc
pneumococcus
non-typhoid Salmonella
name some beneficial genetic attributes in humans to hiv1
mhc heterozygosity, hla c, hlab57,kir,cor,ccr5 ligands
what is maraviroc
CCR5 inhibitor (Chemokine receptor antagonist) Maraviroc, prevents entry into cell
what is enfurvitide
stops viral fusion to potential host cells (tcells)
discuss nrti which is one of the classes of rt inhibitiors
1.Nucleoside-analogue reverse transcriptase inhibitors (NRTI)
Incorporated into elongating DNA chain; no 3’OH leads to chain termination
Examples: Zidovudine/AZT; Lamivudine/3TC; Abacavir; Tenofovir
discuss what nnrti stands for and what this class of rt inhibitors does give examples
Non-nucleoEde Reverse transcriptase inhibitors (NNRTI). Allosteric RT inhibitors – do not bind active site
Block initiation of RT; examples: Efavirenz; Nevirapine
what is raltegravir
binds active site integrase blocking strand transfer reaction
describe the action of protease inhibitors
inhibit hiv protease to prevent cleavage of gag and gag pol to mature proteins so virus particle is non infection
describe Haart
Highly Active Anti-Retroviral Therapy (HAART)
(Combination therapy)
3 is the magic number – Difficult for HIV to
Simultaneously mutate to avoid combinations
of drugs
All resistance mutations in HIV enzymes comes with a fitness cost
(mutants replicate less efficiently that wildtype often requiring 2nry
Mutations to cope
what are the most common haart combinations
2 nrti one nnrti or protease inhibitor, rmeber haart is not a cure, it controls hiv replication below detectable, but stop treatment and hiv will rebound back
what are the challenges associated with hiv1 vaccine development
hiv envelope is sole target for antibodies, highly variable virus, highly glycosylated, needs to provide sterlising immunity
how can we try to prevent hiv
condom use, male circumcision, prep, microbicdes, vaccines
if bone marrow transplant appears to have cured one hiv suffeere why dont we dish it out to everyone
bone marrow transplant is dangerous surgery and impractical when ind can take haart and live indfinetly, rather focus on finding specifc drugs that activate latent infected cells while taking haart
