Immunological abnormalities in the natural history of HIV infection: mechanisms and clinical relevance.

Abstract

Infection with the human immunodeficiency virus (HIV) ultimately results in profound immunodeficiency characterized by severe depletion of CD4+ T helper cells. In symptomatic infection a general perturbance of immune function is observed. Here recent insights in the sequence of events in progression to AIDS is reviewed. Following seroconversion a rapid persistent loss of inducible B cell function is observed. In addition, in long term infection, antigen-presenting cell functions of monocytes and dendritic cells are increasingly affected. T-cell non-responsiveness, preceding CD4 cell loss, appears to be induced through several different, sequential mechanisms. In early infection, the in-vivo deletion of memory cells can account for the in-vitro decreased responsiveness. Later on in infection, when the balance between memory and naive T cells is normalized, both CD4 and CD8 cells are non-responsive to nominal antigen and low dose anti-CD3 monoclonal antibodies. This anergy is at the level of IL-2 gene expression since early signal transduction events following CD2 and CD2 receptor occupancy are normal. This state of anergy, probably due to inappropriate activation in vivo, may be related to programmed cell death (PCD) observed in vitro for both CD8 and CD4 cells reflecting a systemic interference with maturation and differentiation of T cells. In progression to symptomatic infection, the proportion of non-responsive CD8 cells with immature or activated phenotypes increases and in about fifty percent of the cases, CD4 cell decline may accelerate in association with emergence of syncytium-inducing HIV variants. During this progressive stage, anti-CD3 reactivity is severely decreased, and alloantigen reactivity and finally the capacity to respond to phytohemagglutinin (PHA) are affected. These functional parameters appear useful for staging of HIV-infected individuals and for evaluation of anti-viral therapy.