Immune Activation and AIDS Pathogenesis

Donald L Sodora; Guido Silvestri


AIDS. 2008;22(4):439-446. 

In This Article

To what extent (if any) does immune activation reflect homeostatic pressure on the T-cell compartment?

There is wide consensus that during pathogenic HIV/SIV infection the level of T-cell proliferation and turnover is significantly increased when compared to that of healthy individuals. Conceptually, an increased T-cell turnover could reflect homeostatic proliferation in response to the cell losses induced by the virus or, alternatively, immune responses to antigenic stimulation and/or pro-inflammatory signals. These mechanisms are not mutually exclusive and in fact may be interrelated,[41] but it should be kept in mind that while the above-mentioned 'tap-and-drain' model postulated an almost perfect quantitative balance between the rate of infected cell death on the one hand, and the rate of a compensatory/homeostatic CD4 T-cell proliferation on the other, several observations suggested a much more complex and indirect mechanistic and causal relations between CD4 T-cell killing by virus, immune activation, and T-cell turnover. First, CD8 T-cells, which are not directly targeted by the virus, also show increased rates of activation and proliferation.[7,15,33] Second, suppression of virus replication by antiretroviral therapy (ART) is followed by a rapid decline of proliferating CD4 T-cells at a time when the absolute number of these cells is still low.[27] Finally, the majority of CD4 T-cell death involves uninfected cells.[42] The currently prevailing view is that these cells die as a consequence of their previous activation, that their death is not directly responsible for the slow depletion of CD4 T-cells and that other consequences of chronic immune activation drive the pathogenic process leading to AIDS.[9,10,11,12,13,14,15,16,17] Grossman and colleagues also proposed that the heightened turnover of T cells during chronic HIV infection largely consists of overlapping bursts of proliferation and differentiation in response to T-cell receptor mediated stimuli and inflammation.[13,17,43,44] Direct support for the hypothesis that T-cell turnover is antigen driven has been provided by studies performed in SIVmac239-infected rhesus macaques using extensive in vivo labeling of dividing cells with BrdU and tracing the kinetics of labeled T cells in blood and in lymphoid and nonlymphoid tissues.[45,46]

Homeostatic pressure on the T-cell regenerative compartment likely occurs during pathogenic HIV/SIV infection, mainly as a consequence of the progressive depletion of naive and central memory T cells that are known to be subject to strict homeostatic regulation. Depletion of these cells, in turn, appears to be caused in large part by the chronic immune activation rather than the direct cytopathic effect of the virus. Furthermore, homeostatic proliferation (i.e., occurring in response to depletion) and classical immune activation-related proliferation (i.e., antigen-specific T-cell responses) are not necessarily distinct phenomena, but, rather, may overlap significantly. For instance, a scenario could be envisioned where a pro-inflammatory environment favors the activation of certain T-cell clones that may then become particularly prone to respond to homeostatic stimuli such as interleukin (IL)-7, IL-15 and others. Of note, linking 'homeostatic proliferation' to 'immune activation' in this way, within the framework of an immune activation oriented approach to the pathogenesis of HIV/SIV disease progression, bears no resemblance to a pathogenic model of HIV/SIV infection whereby CD4 T-cells are progressively depleted simply because their 'homeostatic' replication in response to viral killing collapses over time.

Another interesting question is how tissue-specific CD4 T-cell homeostasis (particularly in the mucosa associated lymphoid tissue, MALT) is maintained under normal circumstances and, in the context of HIV/SIV, whether and to what extent an increased homing of activated/memory CD4 T-cells in the MALT may compensate for the early loss of mucosal CD4CCR5 T cells. This point is important as the loss of mucosal CD4 T effector-memory (TEM) cells appears to be a critical determinant of progression to AIDS during both early and chronic phases of SIV infection of Indian rhesus macacques.[45,46] However, it is still unclear whether, in this model, the failure of reconstituting the mucosal CD4 TEM pool is primarily related to events occurring at the level of MALT (due to excessive virus-mediated cell destruction) as opposed to an upstream collapse of the CD4 central memory T (TCM) cell pool from which these CD4 TEM cells originate. A recent analysis of the dynamics of the input of CD4 T cells from the pool of lymph node-based TCM cells to that of MALT-based TEM cells during SIV infection supported the second view, although a defect in recruiting and/or retaining long-lived CD4 TEM cells in MALT due to the indirect effect of viral replication has also been implicated.[46]

A better understanding of how CD4 T-cell homeostasis is regulated in the face of immune activation and how this regulation affects the physiologic events of CD4 T-cell activation, proliferation, and migration to effector tissues will help us elucidate the mechanisms of AIDS pathogenesis and hopefully pave the way to novel therapeutic approaches aimed directly at replenishing the CD4 T-cell pool in HIV-infected individuals.


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