Antifibrotic Therapy in Simian Immunodeficiency Virus Infection Preserves CD4+ T-Cell Populations and Improves Immune Reconstitution With Antiretroviral Therapy

Normal T-cell homeostasis and immune system function depend on the organized structure of the paracortical T-cell zone (TZ) of secondary lymph nodes (LNs). Here, the fibroblastic reticular cell network (FRCn) provides a highly organized framework where T cells and antigen-presenting cells interact by rolling along the exterior surface of the FRCn, directed in their movement via interaction of cell-associated L-selectin adhesion molecules with peripheral LN node addressins on the FRCn [1–5]. These hollow FRCn fibers also form a conduit system for delivery of soluble antigen and cytokines, and provide a source and access to growth factors critical for T-cell survival and proliferation such as interleukin 7 (IL-7) [1, 6–10]. Human immunodeficiency virus (HIV) infection significantly damages the FRCn, which leads to T-cell depletion and limits immune reconstitution with antiretroviral treatment (ART). Regulatory T cells are recruited into lymphoid tissues where the virus is replicating and produce transforming growth factor β (TGF-β) [11]. While TGF-β moderates the immunopathologic consequences of immune activation, it also induces fibroblasts to produce collagen and other extracellular matrix proteins that eventually replace the FRCn, resulting in loss of the important T-cell survival cytokine IL-7 [11–13] and leading to naive T-cell depletion [14]. Given the key roles of collagen in CD4+ T-cell loss before initiation of ART [15, 16] and immune reconstitution with ART [17] and the key role of TGF-β in driving lymphoid tissue fibrosis, we reasoned that interfering with this process could preserve and restore CD4+ T-cell populations. We investigated the potential benefit of the antifibrotic drug pirfenidone (5-methyl-1-phenylpyridin-2-one), which is a pyridone molecule that inhibits TGF-β–signaling pathways [18–20]. Pirfenidone has been effective in preventing or reversing fibrosis in several experimental models of fibrosis [21–26]. We used a nonhuman primate model of simian immunodeficiency virus (SIV) infection, having previously shown that the lymphoid tissue fibrosis seen in HIV-infected humans is recapitulated in SIV-infected rhesus macaques [12, 14]. Our experiments were designed to determine whether antifibrotic therapy limits loss of CD4+ T cells in lymphoid tissues and improves immune reconstitution. We show that SIV-infected animals treated with pirfenidone have significantly less TZ collagen and significantly greater numbers of CD4+ T cells in peripheral blood and LNs than untreated controls and that pirfenidone in combination with ART significantly improves restoration of CD4+ T-cell populations. These data provide a rationale for testing antifibrotic drugs as adjunctive treatment in HIV infection to slow progression of disease and improve immune reconstitution.