Protective versus pathogenic anti-CD4 immunity: insights from the study of natural resistance to HIV infection

HIV-1 exposure causes several dramatic unbalances in the immune system homeostasis. Here, we will focus on the paradox whereby CD4 specific autoimmune responses, which are expected to contribute to the catastrophic loss of most part of the T helper lymphocyte subset in infected patients, may display the characteristics of an unconventional protective immunity in individuals naturally resistant to HIV-1 infection. Reference to differences in fine epitope mapping of these two oppositely polarized outcomes will be presented, with particular reference to partially or totally CD4-gp120 complex-specific antibodies. The fine tuning of the anti-self immune response to the HIV-1 receptor may determine whether viral exposure will result in infection or, alternatively, protective immunity

Autoimmune T-cell response to the CD4 molecule in HIV-infected patients

In a previous study, we demonstrated that by downregulating plasma membrane CD4 and increasing its processing, human immunodeficiency (HIV)-1-gp120 unveils hidden CD4 epitopes, inducing an in vitro anti-CD4-specific T-cell response. We report herein that this mechanism may potentially have important implications in HIV immunopathogenesis, because it could take part in the severe depletion of CD4(+) cells that characterizes acquired immune deficiency syndrome (AIDS) and be related to disease progression. Freshly isolated peripheral blood lymphocytes (PBMC) from about 1/4 of a conspicuous cohort of HIV-infected patients responded to CD4 and this response was correlated with beta(2)-microglobulin levels, widely recognized as marker for progression of HIV infection. Moreover, we provide evidence that a CD4-specific T cell priming can occur in vivo, following a gp120 or anti-CD4 monoclonal antibody (mAb)-mediated CD4 molecule downregulation on antigen-presenting cells (APC). To our knowledge, this is the first study indicating that an autoimmune T-cell response is linked to HIV infection and that it could have an important impact on the immunopathogenesis of this disease