Autoantibodies to TNFα in HIV-1 infection: prospects for anti-cytokine vaccine therapy

Tumor necrosis factor alpha (TNFα) is a proinflammatory cytokine principally involved in the activation of lymphocytes in response to viral infection. TNFα also stimulates the production of other cytokines, activates NK cells and potentiates cell death and/or lysis in certain models of viral infection. Although TNFα might be expected to be a protective component of an antiviral immune response, several lines of evidence suggest that TNFα and other virally-induced cytokines actually may contribute to the pathogenesis of HIV infection. Based on the activation of HIV replication in response to TNFα, HIV appears to have evolved to take advantage of host cytokine activation pathways. Antibodies to TNFα are present in the serum of normal individuals as well as in certain autoimmune disorders, and may modulate disease progression in the setting of HIV infection. We examined TNFα-specific antibodies in HIV-infected non-progressors and healthy seronegatives; anti-TNFα antibody levels are significantly higher in GRIV seropositive slow/non-progressors (N = 120, mean = 0.24), compared to seronegative controls (N = 12, mean = 0.11). TNFα antibodies correlated positively with viral load, (P = 0.013, r = 0.282), and CD8+ cell count (P = 0.03, r = 0.258), and inversely with CD4+ cell count (P = 0.003, r = – 0.246), percent CD4+ cells (P = 0.008, r = –0.306), and CD4 :CD8 ratio (P = 0.033, r = – 0.251). TNFα antibodies also correlated positively with antibodies to peptides corresponding to the CD4 binding site of gp160 (P = 0.001, r = 0.384), the CD4 identity region (P = 0.016, r = 0.29), the V3 loop (P = 0.005, r = 0.34), and the amino terminus of Tat (P = 0.001, r = 0.395); TNFα antibodies also correlated positively with antibodies to Nef protein (P = 0.008, r = 0.302). The production of anti-TNFα antibodies appears to be an adaptive response to HIV infection and suggests the potential utility of modified cytokine vaccines in the treatment of HIV infections as well as AIDS-related and unrelated autoimmune and CNS disorders.