CONSEQUENCES OF IMMUNE ACTIVATION

A heightened state of chronic immune activation is expected to be deleterious to the host on many fronts. In a prospective cohort of acutely infected adults, Deeks et al. demonstrated that an immu­nologic activation set point is established early in the natural history of HIV disease and that this set point determines the rate at which CD4 T cells are lost over time.³⁹ In chronic HIV infection, increased T cell activation is associated with shorter duration of viral suppression, frequent low- level viremia, and lower nadir CD4⁺ T cell counts.⁴⁰ Immune activation accelerates viral replication⁷ and leads to depletion of naive cells and exhaustion of the memory T cell pool,^41-45 rendering the host unable to generate new primary immune responses.

Another consequence of generalized immune activation is to dampen antigen-specific immune responses to HIV and other antigens.

The hallmark of HIV disease is the progressive loss of CD4 T cells. One of the important mechanisms that contributes to this CD4 loss is lymphocyte apoptosis, and immune activation is a major underlying cause of the increased lymphocyte apoptosis.⁵² Increased lymphocyte apoptosis is believed to involve not only CD4 T cells but also CD8 T cells and possibly other cells, such as γδ T cells, B cells, and NK cells.^38-40 In persons infected with HIV, both infected and uninfected cells undergo accelerated apoptosis. Apoptosis of cells directly infected with HIV results in only a small percentage of the apoptosis observed, as the vast majority of cells undergoing apoptosis are uninfected.^53,54 One of the mechanisms proposed to mediate apoptosis of uninfected cells in HIV is AICD. Normally, AICD is a physiological process of cell death that occurs in a controlled manner for the central and peripheral deletion of cells in the context of tolerance and homeostasis.⁵⁵ In HIV infection, lymphocyte AICD is exaggerated because of the heightened state of immune activation.

Supportive evidence that apoptosis contributes to loss of CD4 T cells in HIV-1 infection of humans comes from the normal levels of apoptosis in apathogenic lentivirus infections of nonhuman primates, including HIV-1 infection of chimpanzees.^56-58 Chimpanzees infected with the LAI∕LAV-1b strain of HIV develop progressive loss of CD4 T cells with high viral burdens and increased levels of CD4 T cell apoptosis, both in vitro and in vivo.⁵⁹ In contrast, SIV-infected chimpanzees do not lose CD4 T cells and have no increases in apoptosis compared with control groups.

Spontaneous apoptosis is greater in patients with progressive HIV disease than in long-term nonprogressors (LTNPs). The frequency of T cells exhibiting loss of mitochondrial transmembrane potential and increased reactive oxygen species (ROS) production is also lower in LTNPs.⁶⁰ These findings indicate that the degree of apoptosis correlates inversely with CD4 T cell depletion and suggest that apoptosis contributes to HIV-induced immunodeficiency.