Maths and HIV Flashcards
Continuous same levels of viral load is observed for 10 years in HIV.
Is it continuous low virus production/ low loss – or high viral production but high loss?
Stop viral replication - check half life of preexisting virus : 2 days only.
So virus isn’t really latent, it keeps on replicating a lot, just T cells can control them for a long time, and HIV has enormous evolution capacity since it doesn’t go latent and keeps on replicating for years and doesn’t get eliminated by immune cells.
It mutates a lot too. (Quasispecies)
Mathematical calculations show that you need more than 1 drugs to prevent evolving/escaping from medicine.
Why CD4+ T cells are gradually lost in a long time period?
3 theory:
- HIV induced cytopathicity: HIV activity kills CD4 cells one way or another.
- Interference with thymic output = HIV cuts the thymic T cell production
- HIV causes chronic immune activation
Does only infected cells die?
No. There’s much more apoptotic cells than infected.
Most of them were CD8!
Apoptotic cells and infected cells had very little overlap = most of the infected cells weren’t dying, other cells were dying
Interference with thymic output - kids mice study
Maybe HIV interferes with production/replenishment of CD4 T cells? So even if they don’t die that much, you’d eventually run out of cells.
. Infect the thymus with HIV, humanized mice.
Obv normal infection doesn’t start in thymus with an intrathymic infection, but CD4 T cells there can also be infected – so the study has a point.
Kids dying from HIV = had way less thymocytes compared to normal kids!
Problem: In kids, thymus is useful to create new CD4 T cells, but in adults, does it even have a role? Thymus shrinks with age, and especially after 40, it doesn’t add much to T cell pool.
Interference with thymic output - adults - TREC measurements
Thymus shrinks with age, and especially after 40, it doesn’t add much to T cell pool.
Study this: Check markers that show CD4 production by thymus. Measure TRECs (T cell receptor excision circle) in VDJ.
Parts of the DNA is cut out during recombination, and they form stable DNA circles.
It’s good for our purpose since VDJ rearrangement only occurs in thymus.
In thymus, newly formed cell has TREC, but when it goes to periphery and starts dividing, TREC won’t be divided since it’s simply not on the genome anymore. It will be given randomly to 1 of the daughters, and TRECs keeps being diluted as the cells divide. So their formation occurs only in thymus, and not through cell division.
Normal thymus:CD4 T cells from 0 to age of 80, they decrease. Reflects what happens to thymus, in childhood it’s big, in adulthood it shrinks, starts producing fewer T cells.
Patients with no thymus is checked, dashed line is healthy individual line. So if you don’t have thymus, you have around 10-fold decrease in TREC. (so newly made T cells) HIV infected patients in early stage = similar shift in TREC content! So maybe there’s HIV induced thymic impairment. TREC content might be low since HIV is infecting the thymus, and thymus starts making fewer CD4 T cells.
Describe how the number of available naive T cells change over time in body:
dN/dt =C (t)+ pN-dN
rate of naive t cells = number of t cells produced in thymus + cell division - apoptosis.
dN/dt= (rate of the naive T cell numbers changing)
C = (number of T cells produced by thymus on daily basis) Dependent on time since production will be high for a child, low for elder.
Should cell division be dependent on the cells that are present at time 0? Yes. Since if there’s a person who already has low T cell counts to start with, they will divide less.
p constant= Every naïve T cell’s chance to undergo cell division
So the thymus output is constant in a short time frame and independent of the preexisting T cells, but T cells coming from cell division depend on the T cell count in prior.
How to describe cell death? Same with division, introduce another constant:
d constant= Every naïve T cell’s chance to die
Describe how the number of TRECs change over time in body:
dT/dt= dC(t)-dT
trec change = thymus production * dilution factor (replication outside thymus) - apoptosis
dT/dt=(rate of TREC number changing) constant d ( around 1/4)=number of cells that have TREC from thymus Again the thymus contribution should be added with C(t). But not all the cells that come out of thymus have the TREC, because there’s already some replication/dilution going on inside the thymus. So another factor d, need to be added. Its ¼. So ¼ cells that come out of the thymus have TREC. You don’t gain TRECs from division, so you don’t add it to TREC equation. You will lose TRECs when naïve T cells die, it’s also dependent on how many TRECs you had initially = d*T.
How’s the average TREC content should be if thymus output declines = It should decline?
Conclusion - does HIV effect thymus?
Interestingly, it stays the same with mathematical model. Because not only TRECs but also naïve T cells number decrease, when TRECs decrease.
However, we know that they decline IRL. The thing is, naïve T cells are replaced fast compared to TREC number. So as thymus production stops, naïve T cells start to multiply more to compensate it. Number of T cells isn’t very effected, and TRECs are diluted.
So no, HIV doesn’t stop the thymus or anything. Just T cell proliferation increase with infection. T cells proliferate way more in HIV infected individuals.
Cause of CD4 T cell loss = Chronic immune activation
Mangabey monkey = no immune activation, no disease.
So when there’s no chronic activation = no AIDS. If you would stop rather than continuously fighting with it, you’d probably do better.
Monkeys show that.
So you see a lot of CD4 T cells die that aren’t infected with HIV, so it’s like some type of exhaustion going on. Also CD8 T cells have the same trend, but they are much better in refilling the loss. So you lose CD4 T cell levels but not CD8 ones overall. There’s some intrinsic differences in replenishing between those two types.
Your cells just get tired.
