HIV Flashcards
What are key components of HIV virus structure?
Enveloped ssRNA.
2 single strands of RNA within lipid-bilayer derived viral envelope, from host PM.
Gp120 and Gp41 are expresssed on surface of viral particle.
Reverse transcriptase and Integrase within nuclei capsid.
How does HIV infect cells generally?
HIV primarily infects CD4+ T cells (Th cells).
Gp120 attachment to CD4+ CD4 receptors.
Fusion of viral and host cell membranes, followed by viral particle uncoating and release of viral material.
Reverse transcriptase converts viral ssRNA into DNA.
Viral DNA is imported into the nucleus and is integrated into host DNA using Integrase.
How does HIV replicated within host cell after infection?
After integrase has integrated viral DNA into host DNA.
= Transcription of viral DNA forms viral mRNA, which is expoeted and undergoes translation.
Viral RNA and protein assemble at cell surface and there is budding of new viral particles at cell surface.
Viral particles are released and extracellularly undergo maturation from a single protein into individual.
Gag-pol gene encodes a single long polypeptide chain for many viral proteins.
- During maturation, individual viral proteins are formed from gag-pol polypeptide with viral proteases.
GP120 and co-receptors?
HIV Gp120 binds mainly to CD4 receptors, but infection also involves co-receptors.
Main ones are CCR-5 and CXCR4 = chemokine receptors…
HIV strains usually selective use of either CCR-5 or CXCR4, but rare cases can utilise both, individually…
Gp120 + CCR5/CXCR4.
How does HIV use co-receptors?
gp120 attaches to CD4 receptor on T cell.
gp12- undergoes conformational change upon binding, bringing gp120 into close contact with co-receptor (CCR5/CXCR4).
Binding to co-receptor exposes HIV gp41 on viral surface.
gp41 attaches to T cell surface and penetrates membrane, forming a pore.
Disrupted membrane allows fusion and viral entry.
= Viral membrane contains trimeric glycoprotein spikes containing a gp41 and gp120 subunit.
What are characteristics of cell populations in HIV infection?
Chronic immune ACTIVATION!!! and CD4 T cell depletion.
= immune dysfunction.
Major contributor to pathogenesis is immune activation.
Manifested in many ways: T cell proliferation, increased CD38 expression on CD4 and CD8 T cells.
B cells, NK cells, T cells and macrophages all increased activation!!!
Elevated T cell proliferation and expression of CD38, both CD4 and CD8 cells.
BUT
Global CD4 cell depletion, depsite proliferation.
= more T cell receptors, more cells to infect, and these infected T cells won’t be able to mount an effective immune response despite proliferating!
What causes death most after HIV infection?
Tuberculosis.
Opportunistic infections.
HIV-TB and co-infection most common cause of death.
Infected with HIV increases chance that new infection with M. tuberculosis will lead to TB disease…
= most potent factor for progression of infection to disease…
Lifetime risk of active TB= 50% vs 5-10% in non-HIV infected.
Presence of other infections allows HIV to multiple more quickly!!!
What are the ways to treat HIV?
AZT was the first developed - targeting reverse transcriptase.
most drugs target RT and protease.
BUT
Resistance - as virus mutates, using a single treatment can provide short-term benefit, but long term seves to select resistant mutants.
Current treatment involvdes a combination = HAART!!!
What are the classes of HIV anti-virals?
NRTIs = AZT (Nucleoside RT inhibitors)
NNRTI’s = non-nucleoside RT inhibitors.
Protease inhibitors.
Fusion inhibitors = Fuzeon/
Integrase inhibitors.
CCR5 entry antagonists…
How do NRTI’s work?
AZT.
AZT is a pro-drug that needs to be converted to AZT-triphosphate first to be active chain terminator.
NRTIs = Nucleoside RT inhibitors act as chain terminators at substrate binding site of RT.
NRTI, like AZT-triphosphate, resembles nucleoside substrates.
AZT-3pi acts as a chain terminator, with a azide group instead of hydroxyl grou, such that its nucleoside group cannot be cleaved from triphosphate to monophosphate into order to form phosphodiester bond..
How do NNRTIs work?
Efavirenz.
NNRTIs are non-nucleoside analgoue RT inhibitors.
= prevent viral DNA replication through allosteric inhibition, causing conf. change to active site, to block DNA polymerisation.
How do protease inhibitors work?
During reproduction cycle of HIV, a specific protease is needed to process GAG_POL polyproteins into mature HIV components.
All approved Protease Inhibitors for HIV contain a hydroxyethylene bond instead of normal peptide bond.
= Hydroxyethylene bond makes protease inhibitors non-scissile substrate analogues of HIV protease.
= cannot be cleaved.
Darunavir.
What is Fuzeon?
Fusion inhibitor by blocking entry of HIV into CD4 T cells.
Designed to mimic gp41, displace gp41 components and prevent normal fusion.
During gp41 exposure, its hydrophobic terminus embds into PM.
HR2 begins to coil into grooves of trimeric HR1 domain in a process = zipping.
Zipping destabilises PM and Viral membrane, punching a fusion pore into both membranes…
= Allowing HIV capsid to pass through PM.
Fuzeon is large peptide mimic of HR2 of gp41… Fuzeon binds to HR1 and prevents zipping from taking place - blocking infection.
What is the role of Gp120, chemokine receptors and gp41 in HIV infection?
Gp120 and chemokine receptor binding (CCR5/CXCR4), exposes gp41.
gp41 contains two repeat heptad domains called HR1 and HR2.
During gp41 exposure, its hydrophobic terminus embds into PM.
HR2 begins to coil into grooves of trimeric HR1 domain in a process = zipping.
Zipping destabilises PM and Viral membrane, punching a fusion pore into both membranes…
= Allowing HIV capsid to pass through PM.
What are entry inhibitors - Maraviroc?
Maraviroc blocks attachment of gp120 to CCR5 chemokine co-repceptor.
= halts replication by preventing entry.
Maraviroc is a CCR5 inhibitor - so is only effective against CCR5 strains of HIV.
CXCR4 strains will be unaffected!!!
