Pathogenesis of Hivaidsassociated autoimmunity

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In viral diseases, after an acute infection some viruses undergo a prolonged latency period in the host, whereas other agents directly produce chronic infections following the primary stage. The mechanisms whereby these infections produce arthritis are diverse and still poorly understood, but are influenced by both host and viral factors [70].

HIV-1 specifically infects CD4+ T lymphocytes, especially those expressing the chemokine receptor CCR5, which serves as a co-receptor for HIV-1. In acute HIV infections, there is a massive expansion of HIV that massively depletes CD4+ cells, particularly in extra lymphoid tissues that contain the majority of CCR5+ T cells and the majority of effector and memory T cells. As CD4+ T cells include several functional populations [71], their depletion can result in a variety of immune alterations. Clearly, depletion of the Th1-type of CD4+ cells favors infections by viruses and intracellular pathogens and predisposes to allergy, whereas depletion of Th2-type cells could increase overall T cells responses and susceptibility to parasitic infections. Whereas depletion of these cells can account for the increased susceptibility to infectious complications of AIDS, it is unlikely that it can contribute to the increased autoimmunity and autoimmune syndromes seen in AIDS.

A subset of CD4+ T cells that constitutively express CD25 and the transcription factor FoxP3 has regulatory functions of immune responses [72]. Expression of the x-chromosome-linked FoxP3 gene is actively involved in the acquisition of the immunoregulatory phenotype of these cells, and genetic defects of FoxP3 cause severe autoimmunity leading to death within the first two years of life in males affected. It has recently been shown that CD4 + /CD25+ T cells (TREG) express CCR5 and can be infected by HIV-1. Although the levels of TREG in HIV-positive individuals with autoimmune manifestations have not been reported, it seems plausible to propose that preferential depletion of TREG in some individuals could account for the increased autoimmune phenomena in some AIDS patients.

The caprine arthritis encephalitis virus Vif protein is necessary for a productive infection of susceptible goat cells. The vif gene is conserved among all primate and most nonprimate lentiviruses. Nevertheless, one study reported in vitro interactions between different Vif proteins and nucleocapsid domains of heterologous Gag precursors, supporting the notion that species specificity of lentiviral infection is not caused by molecular interactions between Vif and viral components [73]. There is some similarity in the sequences of a portion of the HIV-1 envelope glycoprotein 120 and several types of human collagen and collagen-like molecules. This observation led to the suggestion that the antibodies against the third hypervariable region (V3) of HIV-1 glycoprotein 120 (V3-specific antibodies) could play a role in the autoimmune phenomena occurring in HIV-infected patients. Such V3-reactive antibodies purified by affinity chromatography are highly specific for the V3-peptide. Moreover, there is cross-reactivity with the separate chains of the human Clq and with the chicken collagen type VI [74].

The chemokine receptor-5 mediates chemotaxis by CC chemokines and is expressed by Th1-type lymphocytes and monocyte-macrophages. In these diseases chemokine receptor-5 is expressed by most T cells and monocytes in the inflammatory infiltrates of rheumatoid arthritis (RA) and multiple sclerosis, but not on RA and multiple sclerosis peripheral blood leukocytes. Moreover, chemokine receptor-5 is the major coreceptor for M-tropic HIV-1 strains [75]. A 32-base pair deletion in chemokine receptor-5 (chemokine receptor-5S 32 allele) abolishes receptor expression in homozygotes, whereas chemokine receptor-5S 32 carriers express less receptor than wild-type homozygotes. This polymorphism is related to the resistance to HIV-1 infection and progression towards AIDS [76]. Polymorphisms of the chemokine receptor-2 gene (CCR2-64I) and the chemokine receptor-5 promoter (pCCR5-59029G) have also been correlated with slower progression of HIV-1 disease [77].

The mechanisms of host-virus interactions leading to rheumatic disease continue to be studied in HIV-positive patients with a host-response HIV-1 infection characterized by circulating and tissue infiltrative CD8 T-cell lymphocytosis, termed ''diffuse infiltrative lymphocytosis syndrome.'' This syndrome primarily occurs in the salivary glands, lungs, renal interstitium, and gastrointestinal tract [78]. It differs from Sjogren's syndrome in the degree of salivary gland enlargement, high frequency of extraglandular manifestations, paucity of autoantibodies, and distinct immunogenetic associations, although anti-52-kd Ro/SSA positive has been reported [79]. Salivary gland B-cell lymphoma is a complication common to both conditions. The circulating CD8 T cells in diffuse infiltrative lymphocytosis syndrome have a memory phenotype. Dense infiltrates of CD8+, potentially antiviral killer cells, are characteristically found in the salivary glands of patients who express a certain HLA genotype and who are, typically, long-term survivors of the disease [80]. Tissue cell damage seems to be a consequence of the host immune response to viral proteins present within macrophages in the target tissues. Because similar mechanisms seem to be involved in polymyositis associated with human T-cell lymphotropic virus type I infection, studies into a primate model of polymyositis induced by human T-cell lymphotropic virus type I may be particularly informative. Intra-cisternal A-type particles, antigenically related to HIV, have been reported in H9 cells co-cultured with homogenates of salivary glands obtained from patients with Sjogren's syndrome and with synovial fluid of patients with RA [81]. Human A-type retroviral particles reverse transcriptase activity and anti-human A-type retroviral particle autoantibodies have been detected in patients with Sjogren's syndrome. A second type of a human intra-cisternal A-type retrovirus, human A-type retroviral particle-II, was detected in a subset of patients with idiopathic CD4 lymphocytopenia, an AIDS-like immunodeficiency disease. Most human A-type retroviral parti-cle-II positive patients were also antinuclear antibodies positive [82]. Anti-human A-type retroviral particles and anti-HIV p24 autoantibodies are seen in SLE, primary biliary cirrhosis, and multiple sclerosis [83].

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