HIV-induced Autoimmunity - Grouppe Kurosawa

Autoimmunity and Its Role in AIDS Pathogenesis

Substantial evidence supports the hypothesis that autoimmunity plays a fundamental role in establishing the clinical syndrome of AIDS. The HIV viral membrane protein gp160 includes multiple sequences found on MHC class I and II molecules, T cell receptors, and the constant regions of various IgG subtypes.

Allogenic activation of T cells by anti-MHC II antigens represents an autoimmune phenomenon resembling chronic graft-versus-host disease (GVHD). HIV preferentially infects activated T cells, while naive, quiescent T cells remain resistant. The extensive T cell activation and sensitivity to apoptosis observed in HIV infections have not been adequately explained. One possible explanation is an autoimmune reaction initiated by antibodies targeting specific domains of the gp160 protein.

Recent findings enhance the plausibility of this hypothesis. Homology between gp120 and MHC II molecules extends beyond sequence similarity to three-dimensional conformations. The gp120 molecule contains a broadly specific peptide binding site, which could activate T cell receptors similarly to MHC II molecules.

Similarities Between GVHD and HIV-Related Conditions

A wide range of clinical features is shared between GVHD and HIV disease, as outlined in Habeshaw, J. et al., Immunology Today 13:207, 1992:

Activation of T cells
Antigen-specific dysfunction
B cell hyperactivity leading to hypergammaglobulinemia and autoreactive antibodies
Changes in CD8 T cells, in both total and relative number
Suppressor cells selective for CD4 T cells
Cytotoxicity for autologous cells
Scaly skin lesions resembling eczema or psoriasis
Gastrointestinal symptoms or diseases
Lymphadenopathy
Opportunistic infections
High-grade lymphomas
Angiodysplastic-like lesions
Hypersecretion of cytokines, including TNF-α and IL-6

AIDS-Like Disease Induced by Alloimmune Stimuli in Mice

A study published in Nature Medicine (Ter-Grigorov, VS. Nature Medicine 3:37, 1997) demonstrated that alloimmune stimuli in mice induced a condition resembling AIDS. The condition involved chronic lymphoproliferation, severe depletion of CD4 cells, progressive immune impairment, Kaposi’s sarcoma-like tumors, and terminal B cell lymphomas.

This experimental condition was induced by repeated mating of BALB/C female mice with C57BL/6 males (seven to ten allogenic pregnancies), followed by immunization with paternal lymphocytes. The resulting clinical course closely resembled AIDS. The condition was found to be sexually and vertically transmissible, transferable via cell-free plasma, and associated with autoimmune reactions to major histocompatibility complex antigens and CD4 cells. Since mice cannot be infected with HIV, the disease must result from an autoimmune or GVHD-like immune reaction.

Immunological Concerns Regarding gp160-Based Vaccines

The gp160 membrane protein is an inappropriate immunological target for vaccine development. Few conserved sites exist on this protein across different HIV strains, and many regions cross-react with sequences found in normal proteins, particularly histocompatibility antigens.

Autoimmune responses against the viral gp160 protein likely contribute significantly to the development of AIDS. Vaccines utilizing gp160 or its gp120 fragment as immunogens may sensitize the immune system, potentially triggering a GVHD-like reaction upon HIV exposure. While such vaccines might offer short-term protection against select viral strains, they could ultimately initiate a slow-progressing GVHD disease that may take years to fully develop.

Autoantibodies and Persistent Immune Dysfunction

Notably, when researchers successfully suppressed viral titers to nearly undetectable levels for extended periods, immune recovery—especially CD4 count restoration—remained incomplete. One explanation involves the permanent damage to lymphoid tissues. Another possible cause is the persistence of autoimmune antibodies following the cessation of viral replication.

Lymphoid tissue germinal centers harbor large amounts of viral proteins, particularly gp160/gp120. These proteins may continue to stimulate autoimmune antibody production even after viral synthesis stops. Over time, in the absence of active viral replication, the autoimmune antibody levels may eventually decline. However, given the abundance of HIV proteins retained in lymphoid tissue as immune complexes, such a decrease is unlikely to occur quickly.

The proposed autoimmune or alloimmune model suggests some individuals may continue to experience disease progression—even without detectable viral RNA. The primary concern shifts from the presence of active, infectious viruses to the immune response targeting gp160/gp120 proteins embedded in immune complexes throughout the body.