An idiotypic network model of AIDS immunopathogenesis.

Abstract

Considerations from a network theory of the immune system suggest that human immunodeficiency virus and allogeneic stimuli may act synergistically to cause AIDS. The immune responses to these stimuli include two components that are directed against each other. In some AIDS risk groups other antigens that mimic major histocompatibility complex antigens may substitute for allogeneic stimuli. Implications for the prevention of AIDS are discussed.The idea that human immunodeficiency virus (HIV) is the sole cause of AIDS (without any cofactors) and is directly responsible for the depletion of CD4-bearing T cells is currently being questioned by many researchers for several reasons. A surprisingly low number of T cells are infected with HIV in AIDS (1), and immunosuppression occurs prior to depletion of CD4 cells (2). Furthermore, immunity against HIV does not protect against AIDS; AIDS patients have high quantities of anti-HIV antibodies in their sera (3) and generate a strong anti-HIV cytotoxic T-cell response (4) but are not protected. In fact, people tend to become seriously ill only after they make anti-HIV antibodies. In spite of intensive research, a detailed mechanism explaining T-cell depletion in vivo, only on the basis of HIV infection, has not been characterized.An alternative possibility being considered by several groups of researchers is that HIV induces a deleterious immune response that attacks the immune system itself (5-15). In this paper, we describe an immunological process that could lead to AIDS. Network RegulationThe recognition of variable (V) regions by lymphocytes and vice versa is widely believed to be a central aspect of the specific regulation of the immune system (16). The relative levels ofpopulations oflymphocytes and the topology oftheir interactions are then key aspects of a description of the system. Some lymphocyte populations recognize an invading antigen, and some have V regions that functionally resemble the antigen in that they have complementarity to the V regions of antigen-specific clones. Specific interactions between these populations are believed to regulate the immune response. An explicit network model accounts for a considerable range of phenomena, including memory, separate roles for IgM and IgG, helper T cells, suppressor T cells, and specific T-cell factors (10,11,(17)(18)(19)(20)(21).The theory we describe here emerges from that model. An important component of the theory is the concept of network focusing, which refers to the ability of the network to select clones that are images of particular antigens, including self antigens. A second component is the idea that there is a major axis of specificities in the immune system, bounded by self class I and class II major histocompatibility complex (MHC) antigens. We suggest AIDS is a consequence of a destabilization of the system after excessive stimulation along its major axis.T (Fig. 1). Each suppressor T cell is idiotypically connected to a large number of helper T cells and the suppressor T cells are said ...

Anti-lymphocyte antibodies in plasma of HIV-1–infected patients preferentially react with MHC class Il-negative T cells and are linked to antibodies against gp41

“…Anti-idiotype phenomena as a cause of immune system destabitization in the pathogenesis of AIDS were first suggested by Ziegler & Stitcs [26]. Hoffmann and co-workers [5] presented a network model of AIDS pathogenesis which includes idiotypicinduced autoantibodies. These, possibly, react with the MHC class II image of T cell receptors.…”

“…Anti-lymphocyte antibodies are able to induce helper cell defects in vitro [16], and an association of helper cell defects to anti-CD4 cell antibodies in vivo has been demonstrated [34]. The network model presented by Hoffmann et al [5] especially focuses on autoimmune reactivity against regulatory suppressor (CD8 *) T cells. Therefore, the induction of defects in helper and suppressor cells could be a major mechanism of anti-lymphocyte antibody activity.…”

Correlation between expression of antibodies to histone H2B and clinical activity in HIV-infected individuals

“…Indeed, Habeshaw et al have advanced the hypothesis that gp120 mimics a portion of an MHC-like protein, and thus can further potentiate an autoimmune GVHD-like reaction [43]. A variation of this hypothesis has been advanced by Hoffmann and colleagues [44,45], who have used the observation that patients with HIV infection have high levels of anti-collagen antibodies as evidence for a GVHD reaction [46].…”

On the benefits of sin

“…Indeed, the gp120 component of the HIV Env has the potential to mimic major histocompatibility complex class II. 66 As such, it is foreseeable that the idiotypic cascade induced after the initiation of the anti-HIV humoral immune response includes anti-HIV Abs that mimic CD4, as well as anti-anti-HIV Abs that mimic MHC II and bind CD4 mimicking anti-HIV Abs or CD4 itself. Several investigators have independently demonstrated the presence of anti-CD4 Abs in HIV-infected individuals, and some reports have linked these Abs with progression toward AIDS.…”