Suppression of Transforming Growth Factor β Receptor 2 and Smad5 Is Associated with High Levels of MicroRNA miR-155 in the Oral Mucosa during Chronic Simian Immunodeficiency Virus Infection

Abstract

C hronic human immunodeficiency virus (HIV) infection is characterized by a significant increase in generalized immune activation (1, 2) and in mucosal inflammatory conditions such as periodontitis and gingivitis (3-6). Some studies have reported an increased migration of inflammatory cells into the oral mucosa (7), whereas others have shown that levels of proinflammatory cytokines such as interleukin-6 (IL-6) (8-10) were significantly elevated during HIV infection. Interestingly, chronic immune activation and mucosal inflammation occurs in the presence of transforming growth factor ␤ (TGF␤), a highly immunosuppressive cytokine (11, 12) that has been shown to deactivate mononuclear phagocytes (13), reduce IL-2 receptor expression on T cells, and inhibit IL-2-induced T cell proliferation (14,15).Numerous studies have shown that TGF␤ levels were elevated during HIV infection and were associated with disease progression (16-18). Titers of plasma TGF␤ were shown to be sufficient to induce cellular responses in vitro (16). Likewise, simian immunodeficiency virus (SIV)-infected rhesus macaques were found to have persistently increased levels of TGF␤ in the plasma during chronic infection (19).Why immune activation and chronic inflammation persist even in the presence of high levels of immunosuppressive cytokines is not clear. Ploquin et al. (20) reported that the failure of TGF␤ to resorb virus-driven inflammation and activation during pathogenic HIV type 1 (HIV-1) and SIV infections may be due to increased unresponsiveness to TGF␤ that was associated with altered signaling. The exact mechanisms for this unresponsiveness are still not clear.TGF␤ binds to and signals through its high-affinity type I and type II serine/threonine kinase receptors TGF␤ receptor 1 (TGF␤-R1) and TGF␤-R2, which are expressed on a variety of cell types (21,22). Binding of TGF␤ to TGF␤-R2 phosphorylates and activates TGF␤-R1, which in turn recruits and phosphorylates a number of receptor-activated Smad proteins such as Smad1 to Smad5 (23). We hypothesized that the inability of TGF␤ to suppress immune activation may be associated with the dysregulated expression of its receptors in the oral mucosa. The loss of TGF␤ receptors has been shown to mediate resistance to TGF␤ in cell lines (22,24). We used the rhesus macaque model of HIV infection to address this question.Seventeen rhesus macaques (Macaca mulatta) of Indian origin (n ϭ 17) were used in this study. Ten animals were chronically infected with pathogenic SIVmac251, whereas the rest (n ϭ 7) were uninfected. The animals were housed in accordance with the guidelines of the American Association for Accreditation of Laboratory Animal and were seronegative for SIV, simian retrovirus (SRV), and simian T-cell leukemia virus (STLV) type 1 prior to SIV challenge.Peripheral blood and oropharyngeal tissue samples were collected at the time of sacrifice. Plasma and peripheral blood mononuclear cells (PBMC) were isolated and cryopreserved along with the oropharyngeal tissue samples. PBMC were isolated...

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