HIV virion One of the long-standing puzzles in the pathogenesis of AIDS is exactly why, in fact, untreated HIV leads to the inexorable loss of helper (CD4+) T cells that eventually manifests itself as immunosuppresssion.

It’s not that there are no explanations for the loss — rather there are too many possible explanations, and identifying the most important cause hasn’t been easy. Is it because the virus directly destroys the cells it infects? Do HIV-specific cytotoxic T cells recognize and destroy infected cells? Are particular subsets especially vulnerable, so that the obvious loss of circulating cells is just an indicator of the true underlying problem? All these are probably true, and may be contributers — even important contributers — to the CD4 cell loss. 1 But over the past few years, a bunch of experiments have shown that these more traditional causes are probably not enough to account for the observed loss. (For example, far more CD4 cells die than are ever infected with HIV.)

Instead, the chronic activation of T cells in HIV-infected humans seems to be particularly important. In a normal immune response, T cells recognize their target, become activated, divide and expand a thousand-fold, and then contract again. Obviously, if T cells just expanded every time we mount an immune response, we would quite soon consist of nothing but T cells, so the contraction phase — a phase of the normal immune response in which T cells die off — is critical to reset T cell numbers to something appropriate once again. Therefore, a normal consequence of T cell activation is T cell death. This can happen many times, and our overall T cell numbers remain remarkably constant; there is some kind of feedback mechanism that counts T cells and ensures that there aren’t too many or too few.

What happens if, rather than regular but limited periods of activation each time we encounter a new virus or whatever, we experience a constant activation of a large number of T cells at once? There would be a constant death of T cells as well. Experiments show that when this happens, the feedback mechanism is not perfect; more cells can be lost than are replaced.

T cell activation

Immune activation is a hallmark of HIV infection, and the rate and extent of CD4 T cell loss correlates very well with this activation. The first time I was exposed to this concept was in 2002,2 though I don’t know if this was the first time it was suggested. A very recent paper in Journal of Infectious diseases shows that even with very low levels of HIV viremia, T cell activation is correlated with CD4 T cell loss.3

Is this because there is a widespread immune response targeting HIV? Are the activated CD4 T cells all specific for HIV? That’s the simplest explanation, but it’s not the right one; few of the activated cells are specific for HIV.

Blogging on Peer-Reviewed ResearchA plausible alternative explanation was “bystander activation” — a spillover of the activation event, which is normally very closely targeted to a small number of specific T cells, into the large pool of neighboring T cells that are not specific for the original activating event.4 So is the chronic exposure to HIV causing bystander activation of neighboring cells, which then die? Probably not. “Bystander activation” was a popular concept in the early 1990s or so, but I think it was never universally accepted, and when tools to measure specificity of the activated cells became available (in the mid-1990s) it was quickly shown that almost all activation was in fact specific. Bystander activation probably does exist, but it’s a minor effect.

There are other possibilities. Perhaps HIV is killing or otherwise screwing up regulatory T cells (TRegs) — which are CD4 T cells — and these are no longer able to perform their usual function of tempering immune activation. Perhaps the rapid early loss of gut T cells results in chronic infection in the gut. Or perhaps there’s an autoimmune component to the activation.5

One reason this may be particularly relevant right now is the recent HIV vaccine fiasco , which has been widely discussed. (A particularly excellent discussion is at the Michael Palm Treatment Action Group blog, starting here and with many followup posts, especially including this one and this one .) Briefly, it seems possible that activation of the immune system by the vaccine — the generic adenovirus part, rather than the HIV-specific part — may have actually enhanced disease. It certainly sounds familiar, but it may be unrelated to the activation-induced cell death associated with AIDS progression.

  1. An important point is that cell death directly because of HIV infection may well be important in some subsets — in particular, gut T cells are probably rapidly killed by HIV infection. But the cells in circulation, that correlate with the progression to AIDS, are not.[]
  2. Sousa, A. E., Carneiro, J., Meier-Schellersheim, M., Grossman, Z., & Victorino, R. M. (2002). CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J Immunol, 169(6), 3400-3406.[]
  3. Relationship between T Cell Activation and CD4+ T Cell Count in HIV‐Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy. Peter W. Hunt, Jason Brenchley, Elizabeth Sinclair, Joseph M. McCune, Michelle Roland, Kimberly Page‐Shafer, Priscilla Hsue, Brinda Emu, Melissa Krone, Harry Lampiris, Daniel Douek, Jeffrey N. Martin, Steven G. Deeks. The Journal of Infectious Diseases 2008;197 []
  4. Bangs, S. C., McMichael, A. J., & Xu, X. N. (2006). Bystander T cell activation–implications for HIV infection and other diseases. Trends Immunol, 27(11), 518-524. []
  5. Rawson, P. M., Molette, C., Videtta, M., Altieri, L., Franceschini, D., Donato, T. et al. (2007). Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection. Nat Med. []