Immunology exam 3: HIV pathogenesis

all done (mostly with speech to text so if issues beware)

What type of virus is HIV?

Lentivirus

components of HIV

integrase, protease, reverse transcriptase & RNA genome surrounded by nucleocapsid, all surrounded by envelope with gp120 spikes connected to gp41

What does this image show?

natural course of HIV infection

What is the hallmark of HIV infection?

Gradual depletion of CD4 T cells

when does HIV become AIDS?

CD4 < 200 cells/ul

what are some characteristics of AIDS (3)

Opportunistic infections (candida, cytomegalovirus, etc), cancers (lymphoma, etc), AIDS dementia

 phases of HIV infection

HIV infection, primary infection (flu like symptoms, detectable Ab against it), asymptomatic phase (viral load comes down, CD4 T cell slowly depleating), symptomatic phase (AIDS)

three different clinical courses of HIV infection

Rapid (AIDS 2 yrs post infection), typical (8-9 years for AIDS to develop), slow (10+ yrs for AIDS to develop)

factors that influence the clinical course of HIV infection (3)

The specific virus you have, immune response (adaptive T cell response), genetic background (protective genotypes)

 There can theoretically be 10^10 variants produced per day within any single infected person. Explain why there are only millions of viral variants within a person usually

Many mutations caused defects and make the virion be less feasible

What does this image show?

Just how diverse HIV is: HIV in one person is comparable to the global influenza pandemic in 1996 (influenza already needs a new vaccine every year) and the HIV present in Congo is so variable

Explain this image

Due to a selection pressure, you can go from only one variant having a specific mutation to all viruses sharing the escape mutation

 what are selection pressures for HIV (3)

Escape of CTL, neutralizing antibodies, antiviral drugs, etc

adaptive immune response against HIV (2)

CD8 T cells, antibodies

what do CD8 T cells do with HIV infected cells?

They kill them

what do CD8 T cells need to kill?

detection on HLA-I

What is special about each HLA

Each HLA-allele presents distinct peptides (9 to 11 amino acids long)

 CTL long

Cytotoxic T lymphocyte

What is special about positions two and the last position in an amino acid sequence to be presented on MHC

They are the ones that attach to MHC (anchor residues), if altered, the peptide will not bind to that MHC

what happens if there's a mutation in the second position of an amino acid sequence

There will be no presentation on MHC

what happens if there's a mutation outside of the second or last position in an amino acid sequence

It will be presented on MHC, but there will be no recognition by the TCR

what happens as a result of viral escape mutations

Loss of immune control

what was the international controller study?

Genome wide association study for control of HIV infection, analysis of genetic variation in a multinational consortium

what is TL9

Amino acid sequence with nine amino acids: it starts with a T and ends with an L

what does TL9 bind to?

HLA-B7

SNP long

Single nucleotide polymorphism- what most genetic variation in humans is, called that when variation is present in >1% of the population

How much of the variation in the human genome is due to SNPs

90%

Where can SNPs occur?

in both coding and noncoding regions of the human genome

Which SNP was found relevant with HIV infection

Chromosome 6: genetic variation found in HLA-B peptide binding pocket (determining peptide binding) (specifically HLA- B57/B27 associated with slow disease course and B35 associated with rapid disease course)

What is special about HLA-B57? (4)

It was able to control HIV infection for over 10 years, it presents viral epitopes from conserved regions of the virus (gag, nef), viral escape from these regions associated with attenuation of fitness, it has a very high affinity for TCR (strong CD8 T cell response)

What is the HIV spike made of?

gp41 (connect viral envelope) and gp120 (actual spike)

 was the antibody response associated with disease progression

no, need to HIV is relatively immunogenic, and majority of people were found capable of eliciting neutralizing antibodies against assumed conserved and vulnerable epitopes

What was HIV sensitivity to autologous antibodies?

HIV escapes from autologous neutralizing antibody responses- they happen too slowly to be able to fight off the virus

What is this image show?

Sensitivity of viral isolate to autologous antibodies

What does the image show?

How HIV escapes the autologous antibody response

Summary of cellular immune response to HIV

Efficient T cell response, viral escape: evasion of CTLs and drives viral evolution, which sometimes leads to viral attenuation

Summary of humoral immune response to HIV

Broadly neutralizing antibodies found in 30% of the patients, viral escape: neutralizing antibodies are ineffective but drive viral evolution

 most common ART regimen

Reverse transcript inhibitor and integrase inhibitor

drawbacks of ART (2)

HIV persists and viral reservoir during ART, no immune control after interruption ART

time to eradication with ART

Over 73 years

 three current research focuses with HIV

Reduction/ elimination of viral reservoir, boosting of immune response, vaccine development