Abstract
In the past decade, evidence has accumulated that human immunodeficiency virus (HIV)-induced chronic immune activation drives progression to AIDS. Studies among different monkey species have shown that the difference between pathological and non-pathological infection is determined by the response of the immune system to the virus, rather than its cytopathicity. Here we review the current understanding of the various mechanisms driving chronic immune activation in HIV infection, the cell types involved, its effects on HIV-specific immunity, and how persistent inflammation may cause AIDS and the wide spectrum of non-AIDS related pathology. We argue that therapeutic relief of inflammation may be beneficial to delay HIV-disease progression and to reduce non-AIDS related pathological side effects of HIV-induced chronic immune stimulation.
Highlights
CHRONIC IMMUNE ACTIVATION IS THE PRIMARY DRIVER IN HIV PATHOGENESIS Upon discovery of the virus that causes AIDS, the name human immunodeficiency virus (HIV) was coined because the virus eventually causes severe immune deficiency
A striking difference between the two viral subtypes is that the level of immune activation is lower in HIV-2 compared to HIV-1 infection, expression patterns and prognostic values for immune activation markers were found to be similar when patients with HIV-1 or HIV-2 infection were matched for CD4+ T-cell depletion levels [35, 36] These observations were paralleled by insights from simian immunodeficiency virus (SIV) infection in sooty mangabeys (SMs) and African green monkeys (AGMs)
And similar to what is observed in SIV-infected SMs [102, 104] and AGMs [83], chronically HIV-infected individuals who do not progress to AIDS despite their high viral loads turned out to have very low levels of proliferating and activated T cells [117] correlating with relatively low levels of IFN-stimulated genes (ISGs) and immune activation gene expression in CD8+ T cells [118]
Summary
CHRONIC IMMUNE ACTIVATION IS THE PRIMARY DRIVER IN HIV PATHOGENESIS Upon discovery of the virus that causes AIDS, the name human immunodeficiency virus (HIV) was coined because the virus eventually causes severe immune deficiency This was based on the clinical symptoms with which end-stage HIV-infected patients presented and on the gradual decline of CD4+ T-cell numbers in the blood, which is still considered a hallmark of HIV-disease progression. HIV induces strong cellular immune responses, both with respect to magnitude and breadth [7,8,9,10,11], and even in progressive HIV infection, high avidity HIV-specific CD8+ T cells are being induced [12] Both CD4+ and CD8+ T cells are more activated in acute and chronic HIV infection, and proliferate rapidly and have a short half life. These observations have gradually shifted the paradigm from the classical hypothesis that viral cytopathicity is the primary driver of CD4+ T-cell depletion and immune deficiency, to the hypothesis that chronic immune activation is the cause of T-cell depletion and immune deficiency [35, 39]
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