Immune Activation and AIDS Pathogenesis

Donald L Sodora; Guido Silvestri

Disclosures

AIDS. 2008;22(4):439-446. 

In This Article

Why is the HIV-induced immune activation so disruptive to the immune system?

In considering this issue, it should be noted from the outset that although many lines of evidence indicate that chronic immune activation is a key determinant of immunodeficiency in HIV-infected individuals, the exact mechanisms by which this phenomenon induces CD4 T-cell depletion and disease progression are still largely unknown, and in fact may vary in different classes of patients. The possibilities discussed below are largely hypothetical.

Since HIV is known to replicate more efficiently in activated CD4 T lymphocytes,[78] chronic immune activation is probably instrumental in sustaining viral replication by providing available targets for HIV replication. In this context, the preferential activation, infection and killing of HIV-specific CD4 T cells[79] is probably detrimental as it results in the loss of CD4 T-cell help, potentially contributing to the exhaustion/failure of CD8-mediated cytotoxic T lymphocytes responses to the virus. Another consequence of HIV-associated chronic immune activation that may have negative consequences in the long term is the expansion of activated 'effector' T (TE) cells of both CD4 and CD8 lineages.[9,13,16] The expansion of a pool of fast-replicating but short-lived CD4 TE cells may indirectly facilitate CD4 T-cell depletion. First, the expansion of CD4 TE cells may come at the expense of the naive and memory T-cell pools. A continuous drain from these pools could, in turn, result in a reduced capacity of the immune system to generate primary and anamnestic responses to antigens. Chronic immune activation may also result in the proliferative senescence of the T-cell pool, particularly at the level of CD4 TCM cells,[46] thus supporting the interesting concept of AIDS as a disease characterized by a prematurely ageing immune system.[80] Second, expansion of activated TE cells may be accompanied by the production of pro-inflammatory and pro-apoptotic cytokines that complete the vicious cycle sustaining the generalized immune activation associated with pathogenic HIV/SIV infections. Third, the chronic pro-inflammatory environment has also multiple suppressive effects at different levels. It interferes with the function of several immune cell types, such as B cells, NK, ? d T-cells, dendritic cells, and monocytes,[81,82,83,84,85,86] and may impair the regenerative capacity of the immune system at the levels of bone marrow, thymus, and lymph nodes.[87,88,89,90] Interestingly, the increase in CD4 T cell counts that follows ART appears to be better correlated, at least in certain situations, with the favorable effect of ART on reducing immune activation and apoptosis rather than with its direct suppressive effect on HIV replication.[91,92,93,94]

In summary, the hypothetical mechanisms by which T-cell immune activation causes disease progression in HIV-infected individuals can be grouped in three main classes: (i) stimulation of naive and memory CD4 T-cell activation, proliferation and differentiation, leading to increased CCR5 expression that renders these cells more susceptible to infection; (ii) alterations of long-term homeostasis of the naive and memory T-cell pools that lead to their gradual depletion and that interfere with the capacity of the host to effectively mount adaptive immune responses; (iii) induction of inflammation and fibrosis, likely destroying secondary lymphoid tissue niches required for the production and homeostasis of CD4 T cells.

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