Not all CD4+ T-cells are created equal

One of the coolest things I learned last week in Banff is the ‘why’ behind an odd AIDS phenomena:

So you all might know that the cut-off, the mark for being diagnosed with AIDS (and not just ‘HIV-1+’) is a CD4+ T-cell count of <200 cells/mm3.

Okay, so, you lose all your CD4+ T-cells, your immune system loses its ability to work properly, and you start getting all these secondary infections– infections that ‘healthy’ people get, but they arent a big deal. But secondary infections are a big deal to AIDS patients, I mean, thats what they die of, not the HIV-1 specifically.

What is weird, is that HIV-1+ patients get Tuberculosis before they hit that ’200 cells/mm3′ mark. In fact, its one of the first signs of HIV-1 infection, a random ‘healthy’ person getting TB. Conversely, Cytomegalovirus doesnt reactivate until you are waaaaay below 200. You dont lose your ability to defend yourself against CMV until you are basically running on empty.

It appears as if the CD4+ T-cells that ‘remember’ TB are more susceptible to HIV-1 infection, while CD4+ T-cells that ‘remember’ CMV are protected from HIV-1 infection.

But how the heck would that work??

Early depletion of Mycobacterium tuberculosis-specific T helper 1 cell responses after HIV-1 infection

CD4+ T-cells that ‘remember’ TB secrete chemical messages that keep them in more of an ‘active’ state… precisely the kind of cell HIV-1 LOVES to infect.

On the other hand:

Autocrine Production of β-Chemokines Protects CMV-Specific CD4+ T Cells from HIV Infection

CD4+ T-cells that ‘remember’ CMV secrete chemical messages that are protective, mainly, one called MIP-1β. MIP-1β is the ligand to CCR5, one of the co-receptors HIV-1 needs to infect cells. So if MIP-1β is taking up all the available CCR5 slots, or the bounty of MIP-1β around causes the cell to downregulate CCR5, those cells would be protected from HIV-1 infection!

Similar research from another lab backs this up:

‘Self-Protection’ of Individual CD4+ T Cells against R5 HIV-1 Infection by the Synthesis of Anti-Viral CCR5 Ligands

This has a huge impact on how we design HIV-1 vaccines! What would be the point in making a vaccine against HIV-1, if all your CD4+ T-cells that ‘remember’ HIV-1 are killed off in the first round of HIV-1 infection?

So now all we have to do is figure out how to make a vaccine that generates CMV-like CD4+ T-cells, not TB-like cells! Easy-peasy… right?

Comments

  1. #1 MikeMa
    April 1, 2010

    Very cool but the differences in the CD4+ variants must be small, no? Are there markers for differentiating them?

    Do you build CD4+ molecules or do you culture them from blood samples?

  2. #2 jaranath
    April 1, 2010

    If you have taught me one thing, Abbie, it’s that with HIV, the answer to “…right?” is probably “WRONG!”

    Oh but to be wrong about that just this once…

  3. #3 Dave
    April 1, 2010

    Cool. . . . But what if the chemical messages that the CD4+ T cells excrete are part of or because of how the cells ‘remember’ their diseases? Then suddly this would become a far more complex problem.

  4. #4 Optimus Primate
    April 1, 2010

    Can I just say how much I ♥ PLoS? It’s so nice being able to actually, you know, read the papers linked to in science blags for a change. :)

  5. #5 dartigen
    April 1, 2010

    @MikeMa We would probably have to start by culturing them from blood samples, but eventually it might be possible to synthesize them.

    I guess we can hope, though jaranth is right – HIV is one of those irritating sorts of viruses that you think you’ve cured, and then it throws you another curveball.

    But this is worth looking into. Even if it all turns out to be wrong, at least we know what *not* to do.

  6. #6 jonathan
    April 1, 2010

    i love this blog. as an undergraduate biochemistry major, i find it fascinating. thanks!

  7. #7 the backpacker
    April 1, 2010

    Ugh! Do the layers ever stop with HIV? I guess I get to learn alot about virology and Immunology though, thanks!

  8. #8 cynical1
    April 3, 2010

    I guess I just don’t see how all of this doesn’t ultimately push the viral tropism to X4, which tends to be more virulent and deadly. The other thing I can’t reconcile is the rather unremarkable antiviral effects of (small molecule) R5 inhibitors in patients. Of course, the ‘small molecule’ part may actually be answer to that question because a ~400 MW inhibitor doth not make MIP1(alpha or beta) nor Rantes. Nevertheless, the drugs seem to work just dandy in vitro. I also think selective protection of a CD4+ subtype might protect the host against some opportunistic infections but there’s still the cytolysis that HIV delivers all by itself in infected cells, no?

  9. #9 ERV
    April 3, 2010

    cynical– The CCR5/CXCR4-tropic virus thing is ridiculous, even without this new info. CXCR4 are ridiculously more fit than CCR5 viruses. But CCR5 viruses are outcompeting the CXCR4 viruses in nature. And, CCR5 appear to be more transmissible. But it sucks. ???

    I think the protection provided to cells that are generating MIP-1β is just a location thing– all of the molecules are right there, available to the cell. Not a systemic therapy that might not be where it needs to be, at the concentration it needs to be.

    Im not sure I understand your last point– CD4+ T-cells that remember CMV are protected because either MIP-1β is occupying the CCR5 HIV-1 needs, or because the cells have downregulated CCR5 cause there is so much MIP-1β around. So they arent infected– Its not that theyre infected, but arent dying.

  10. #10 Micro
    April 3, 2010

    So many steps forward and jumps back… Who here is, frankly, sick and tired of every constant jubilation and disappointment in HIV/AIDS research ever since the declaration “that a vaccine will be available within two years” in 1984 by the U.S. Health and Human Services?
    Therefore, I propose a one-stop progress “compendium” on this dreadful disease. Medicine needs an “AIDS Clock” (modeled after the Doomsday Clock).

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