Lec 7 HIV (Final Start Pt 2) Flashcards
HIV
Complex retrovirus > 8 genes
gag (1 ORF), pol (Ribosomal frame shift), env genes
Infects and affects CD4+ cells (T-cells) + other (immune) cells
Acquired Immunodeficiency Syndrome (AIDS)
Two types HIV-1 and HIV-2
– differ in order and number of viral genes
HIV Life cycle
- Attachment to receptor
- Enters, loosens capsid structure to release reverse transcriptase, structural protins, integrase, protease, ssRNA genome, and 2 non-identical RNA molecules.
1 is chewed for acting as translocase, which jumps everywhere to cause recombinance and makes it problematic!
- Lys-tRNA used w/ reverse transcription
- Integrase adds vDNA into genome in loose spot, preferably near spots that r expressed a lot
- Auxillary proteins are made:
- Splicing
- Bring the viral genome out
EARLY: Make regulatory protein.
Rev protein switches to make full length transcripts later, and shuttles unspoiled vDNA to make new genomes out of it.
Assemble virion at the cell surface, bud out of the envelope. Gag, pol incorporated into membrane to make immature form, which is cleaved by viral protease to make mature form. Gains virulence.
HIV viral types
Infection vs. Affection
AIDS
HIV-AIDS is the one we normally talk about. It infects MANY cells, including GI tract, epithelial, CD4, brain cells, causing neurological problems.
HIV-H: Slimming: disrupts GI function, indigestion.
HIV-1 is seen around the world, epidemic form
HIV-2 is less pathogenic
Affects cells: more immune cells die than cells infected! Insane bystander effect. Infected cells release viral proteins that kill uninfected cells.
AIDS could be acquired by ANYTHING.
Origins of HIV subtypes
ORIGIN
HIV-1 comes from CHIMPs, SIV, CPZ is common ancestor. NOT as serious infection as seen in humans! Still hurts them though.
HIV-2 might come from HIV pseudomaganes. They are infected by HIV cut do not get HIV symptoms! Have a LOT of HIV! Chimps are somewhat in-between this and humans (cope better than humans). The chimps initially infected by HIV were all wiped out.
When hunters killed chimps for meat, they cut themselves, got HIV-1 !
HIV when it gained attention
Patient 0
The first serious cases of HIV-AIDS came in 1981.
We think we are exposed so the virus adapted to humans in early 1900s in Belgian Congo. Found common viral ancestors in 1950’s.
As people entered the congo and nearby places, the disease spread worldwide and now anyone can get it!
The jump from primates to humans is still occurring b/c new HIV variants are coming to humans eg. SIV in a French lady who did not hunt!
HIVs recombine to make different mosaics from CRS, common recombinant forms, which are fusions of common versions! Tough to treat
Patient 0 was thought to be the person who spread the disease across the world. NOT TRUE! He was one of many people who brought it in! He does not exist!
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Epidemic proportions: MORE than 1% of pople in an age group: everyone past the age of 20-20, common in 40-49
Washington: White House and Capitol Hill: 2.3% and around 3% everywhere else. Observed due to socio-economic status, similar to Africa!!
HIV Pathogenesis
Mechanism CD4+ T-cell depletion
Pathogenesis
More cells die than they are actually infected, by secretions of dead cells and secretions by immune systems, and more virus is replicated than bone marrow cells can supply CD4s
Mechanism CD4+ T-cell depletion (simplified):
Virus kills cells after infection
Secreted viral or host cell factors induce:
• Cell death of bystander cells (i.e. uninfected cells)
• Inflammation
• Release of other “toxic” host molecules like Reactive oxygen species
Tat, Nef, Vpr genes
Induce host transcription to make Tat, which can be taken up by other cells.
Nef is released from cells and induces apoptosis in neighbouring cells!
Vpr triggers host apoptosis.
All 3 and envelope trigger apoptosis, inflammation and indirect toxicity.
Some people do not develop HIV-AIDS symptoms but are infected, b/c Nef is deleted! BUT the virus can mutate to cause pathogenesis anyway somehow!
Antiviral therapy
Antiviral therapy targets parts of life cycle
Integration, maturation, entry, protein secretion targeting drugs.
LATENT stage: no symptoms seen yet, after integrating into host. Yet the virus continues to replicate.
As CD4 lymphocytes decrease, virus replicase a lot more!
Viremia: normal time
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We have immune responses
Seroconversion
HIV is recognized by IS very well, and make Ab, but they do not target the parts of the virus that make infections.
People who make these antibodies all the time are able to better fight off the virus, any of us should be able to make them but not everyone does. This is the main focus of research.
Virus replicates a lot, tough to see, in the GI tract.
Molecular distance from the progenitor virus continues to increase all the time
Antiretroviral Therapy
- Viral entry Inhibitors
If only 1 nucleoside inhibitor is given the virus will easily adapt to it. You have to give multiple
- Reverse Transcriptase inhibitors
nucleoside or non-nucleoside inhibitors - Viral entry Inhibitors
a) Chemokine analog to CD4 co-receptor! Block this step and prevent infection BUT chemokine CCR5, if knocked out, can cause side effects.
b) Fusion Inhibitors: small peptide that must be injected to work as a rescue therapy. Blocks conformation change in envelope, so virus cannot fuse w/ cell membrane.
3. Integrase inhibitors are the best but are extremely toxic! No new cells will be infected b/c once the virus integrates and silences, it will never be cured.
4. PROTEASE INHIBITORS: BLOCK virus MATURATION (gag processing)
All the drugs are toxic b/c they have unintended rxns
Drug resistance development even under HAART
- Viral entry Inhibitors
a) Chemokine analog
- CHEMOKINE analogue prevents step 3 (PREVENT FUSION PEPTIDE INSERTION into the target membrane
T20 fusion prevents step 4 but b/c its a peptide you must inject it. T20 PREVENTS HAIRPIN FORMATION and MEMBRANE FUSION
- Protease prevents virion maturation
INHIBITED PROTEASE PREVENTS RELEASE of VIRAL CORE PROTEINS, so PREVENTS INFECTIVITY
- Reverse Transcriptase inhibitors
nucleoside or non-nucleoside inhibitors
Their mechanisms, weakness
Nucleosides DO NOT HAVE 3’OH so you terminate transcription
NON NUCLEOSIDE INHIBITORS BIND to REVERSE TRANSCRIPTASE, disrupt structure, PREVENT cDNA formation (copy DNA)
Mutations in the reverse transcriptase change its shape so the real, good nucleotides fit in and ignores drugs completely! OR changes amino acids to privet non-nucleoside
Protease inhibitors and integrase inhibitor also become ineffective d.t. resistance, due to a.a. modifications!
No HIV Vaccine
HIV Drug resistance
No HIV Vaccine
During infection the REVERSE TRANSCRIPTASE CANNOT PROOFREAD, MAKES ~ 1 MISTAKE in replicating genome.
It becomes resistant to vaccine as molecular distance increases from progenitor virus
