(V) 26: HIV Pathogenesis Flashcards
First document cases of AIDS
in big metropolitan areas: LA + NY
Young men were having serious lung infections
- pneumocystis pneumonia caused by a fungus (should have a strong enough immune system to fight it)
- found out they had HIV + AIDS = no immune sustem
Some men had Kaposi Sarcoma (rare in younger pop.)
- lesions around neck, back + mouth
- “new” form of cancer
AIDS
Acquired Immune Deficiency Syndrome
Lots of misinformation about the virus
BUT transmission can also occur at BIRTH or HETEROSEXUALLY or with NEEDLES
AIDS Numbers
Ppl die from AIDS every couple of seconds
ppl living with AIDS is larger than Canadian population
AIDS has ravaged populations more effectively than war
Global HIV/AIDS
most infections are in SUB-SAHARAN AFRICA
COVID vaccine is less effective in certain parts of the world partly b/c of HIV rates around the world (ex. less effective in South Africa - immune system is not strong)
cART
combined Antiretroviral therapy
cocktail - many drugs attack virus @ various stages of replication = regulates replication
- suppresses virus from replicating
- need to take DAILY to be effective
When did HIV/AIDS therapy increase?
When the annual meeting of the International AIDS Society was held in South Africa in 2000
- after this, more ppl in subsaharan Africa got antiretroviral therapy
Income and HIV
Lower income = higher rate of infection
Retroviridae
Family of virus
Subfamily: Lentiviruses
(+)ssRNA virus
2 viruses from subfamily infect humans: HIV-1 + HIV-2
- have an ENVELOPE
- Rev. Transcriptase makes DNA from RNA
- ssDNA CANNOT be transcribed
- cellular DNA Poly makes dsDNA (can be integrated into genome forever)
- dsDNA is transcribed to mRNA
Retrovirus Life Cycle
Early
1. Binding
2. Fusion and entry (envelope fuses w/ host cell memb. + loses shell)
3. Uncoating; Reverse transcription
4. Nuclear entry (dsDNA enters into nucleus of cell)
5. integration (enzymes snip parts of viral DNA + integrates itself into host chromosomal DNA)
Late
6. Transcription
7. Translation
8. Assembly
9. Budding
10. Maturation
HIV proteins and envelope
Surface protein (SU) = gp 120
Transmembrane protein (TM) = gp41
Capsid protein (CA) = p24
viral envelope glycoproteins embed themselves within envelope
- glycoproteins interact WITH HOST
SU
Surface protein = gp120 (glycoprotein and 120 is molecular weight)
VIRAL RECEPTOR
TM
Transmembrane protein = gp41
FUSION PROTEIN
CA
Capsid protein = p24
CAPSID PROTEIN
capsid box that protects genome
How do retroviruses integrate in host genome?
Due to production of dsDNA in retroviruses
Reverse Transcriptase
Polymerase lacks 3’-5’ exonuclease activity (proofreading)
- results in 1-10 NUCLEOTIDE ERRORS per synthesis
these errors cause heterogeneity in retroviruses = a collection of variants or QUASISPECIES (every case is unique = why HIV is so hard to treat)
Retrovirus genome parts
Gag: protective structural proteins
Pol: Polymerase; make protease (pr) proteins; enzyme
Env: envelope; genome region makes proteins embedded in envelope
Gag
Protective structural proteins
Made up of:
- MA: matrix
- NC: nucleocapsid
- CA: capsid
Pol
Polymerase
- makes protease proteins
Made up of:
- PR: protease (molecular scissors)
- RT: Reverse Transcriptase
- IN: integrase (snips genome to allow integration)
Env
Envelope
Made up of:
- SU/gp21: surface protein
- TM/gp41: transmembrane protein
Retrovirus genome
(+) ssRNA
7-10 kb long w/ nucleocapsid (NC)
Integration of Retroviruses
PROVIRAL DNA (dsDNA) is integrated into cellular genome
- proviral DNA is transported from cytoplasm to nucleus
done by viral enzyme, INTEGRASE (in chromosomal AND viral DNA)
- integrase snips BOTH proviral + chromosomal DNA
- can get integration of viral DNA into human sequences forever
Integrase
enzyme that snips both proviral and chromosomal DNA (and is expressed in both)
- can cause permanent integration of viral DNA into human sequences
- removes two 3’-terminal nucleotides on each strand
- viral DNA is inserted
- free 3’ OH ends are ligated into a cleaved segment of host genome
Origins of HIV/AIDS
- cases in Central Africa
- likely started in Zaire (now DRC)
- almost all sex workers in Zaire and Rwanda were HIV+
HIV Diversity
HIV-1 is the most prominent HIV virus (lots of variability)
- based on sequence alignments
- HIV-1 is split into 4 groups: M, N, O, P
- HIV-1 Group M is major (90%) and is split into 9 subtypes A, B, C, D, F, G, H, J, K and CRFs
MOST of HIV-1 viruses are group M
Each group of HIV-1 (M,N,O,P) represents a transfer from an animal to a human
Main group of HIV in North America
HIV-1, Group M, subtype B
Subtypes of HIV-1
Subtypes A, B, C, D, F, G, H, J, K , CRFs
C: most prevalent in Africa
B: high in North America
D: quicker death
CRFs: usually in sex workers that have been infected many times
New subtype L in November 2019
Main group of HIV worldwide
Group C is most prevalent in the world
Highest subtype of HIV-1 in Africa
Group C
CRFs
Circulating Recombinant Forms
- mixture of various subtypes
- very pathogenic
- common in sex workers who acquire different variants from multiple partners
What subtype is most common in white MSM in South Africa?
Group B
MSM: men who have sex with men
HIV-2
less common
- not as transmissible
- not as deadly
- does not progress to AIDS as quickly
HIV-1 source
HIV-1 is likely fro SIV cpz (simean immunodeficiency virus - chimps)
sequencing showed it was similar to the lentivirus (SIV)
SIV and HIV-1
- virus measured in fecal samples of chimp populations
- chimps don’t swim = can isolate SIV populations by water
- two types of chimbs both express SIV: Pan troglodytes schweinfurthii, Pan troglodytes troglodytes
SIV from PAN TROGLODYTES TROGLODYTES matches HIV-1 (origin)
Old Word Monkeys
Old Word Monkeys have virus but are not sick (non-pathogenic)
chimps are vegetarians but must have eaten infected Old Word Monkeys to get SIV which was then transmitted to humans
Not pathogenic to Old Word Monkeys but pathogenic to chimps
HIV-1 Tranmission
4 chimp cross-over events to humans
- epicentre was Kinshasa (Zaire)
BUSHMEAT HUNTING - for fur and meat
- exchange of blood btwn humans + chimps – biting, machetes, etc.
- there was likely an ACCELERATOR
First transmission to human is thought to be group M
Accelerator for HIV-1 Transmission
Could be:
European colonization: urban centres, sex workers
- men transported themselves to Africa and created sex worker industry = contributed to spread of HIV
Intro to health cate to African population
Ways HIV-1 is transmitted
Sexually-transmitted; IV drug use; blood transfusions; at birth
1/1000 chance to transmit HIV during coital act
HIV-1 is pretty whimpy - 10% bleach, heat, air drying or pH variance will inactivate it
