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

Tumor necrosis factor alpha (TNF alpha) is a proinflammatory cytokine princ ipally involved in the activation of lymphocytes in response to viral infec tion. TNF alpha also stimulates the production of other cytokines, activate s NK cells and potentiates cell death and/or lysis in certain models of vir al infection. Although TNF alpha might be expected to be a protective compo nent of an antiviral immune response, several lines of evidence suggest tha t TN alphaF( and other virally-induced cytokines actually may contribute to the pathogenesis of HIV infection. Based on the activation of HIV replicat ion in response to TNF alpha, HIV appears to have evolved to take advantage of host cytokine activation pathways. Antibodies to TNF alpha are present in the serum of normal individuals as well as in certain autoimmune disorde rs, and may modulate disease progression in the setting of HIV infection. W e examined TNF alpha -specific antibodies in HIV-infected non-progressors a nd healthy seronegatives; anti-TNF alpha antibody levels are significantly higher in HIV seropositive slow/non-progressors (N = 120, mean = 0.24), com pared to seronegative controls (N = 12, mean = 0.11). TNF alpha antibodies correlated positively with viral load, (P = 0.013, r = 0.282), and CD8+ cel l count (P = 0.03, r = 0.258), and inversely with CD4+ cell count (P = 0.00 3, r = -0.246), percent CD4+ cells (P = 0.008, r = -0.306), and CD4 :CD8 ra tio (P = 0.033, r = - 0.251). TNF alpha antibodies also correlated positive ly with antibodies to peptides corresponding to the CD4 binding site of gp1 60 (P = 0.001, r = 0.384), the CD4 identity region (P = 0.016, r = 0.29), t he V3 loop (P = 0.005, r = 0.34), and the amino terminus of Tat (P = 0.001, r = 0.395); TNF alpha antibodies also correlated positively with antibodie s to Nef protein (P = 0.008, r = 0.302). The production of anti-TNF alpha a ntibodies 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 disord ers. (C) 2801 Editions scientifiques et medicates Elsevier SAS