Regulatory T Cells in HIV-1 Infection: The Good, the Bad, and the Ugly

The notion of a “suppressive” process that is active during inflammation was first introduced in the late 1960s [1, 2]. Research in this field faced a major setback in the early 1980s when DNAbased studies revealed that the genetic locus that was thought to control suppressor T-cell activity in mice (the I-J gene within the major histocompatibility complex region) did not exist [3]. Research in the field was revitalized by Sakaguchi et al [4] in 1995, when it was demonstrated that the adoptive transfer of CD4 T cells depleted of interleukin 2 (IL-2) receptor α-chain–positive (CD25) cells led to a spectrum of autoimmune diseases in immunocompromised mice and that cotransfer of the CD25 cells prevented these diseases. In 2003, the forkhead box protein P3 (FoxP3) was identified as a master control gene for the development and in vivo suppressor activity of these CD4CD25 T cells that have become commonly referred to as regulatory T cells or “Tregs” [5, 6]. A substantial number of reports have been generated in both human and murine systems on the characterization of Tregs and their role in the regulation of the immune response in health and disease. Today, Tregs are widely recognized as a subset of CD4CD25FoxP3 T cells capable of suppressing the activation, proliferation, and function of a wide variety of immune effector cells, including CD4 and CD8 T cells, natural killer (NK) and NKT cells, B cells, and antigen-presenting cells, such as dendritic cells and macrophages [7, 8]. There are at least 2 different types of Tregs present in humans: natural Tregs and induced (or adaptive) Tregs. Both Treg populations are characterized by high levels of expression of CD25 on the cell surface and intracellular expression of FoxP3 [6]. Although natural Tregs arise during the normal process of T-cell development in the thymus and survive in the periphery [9], induced or adaptive Tregs can be converted from extrathymic naive CD4 T cells in vivo by antigen stimulation in mice [10] or in vitro in mouse or human cells by culturing CD4FoxP3 T cells with different cytokines, including transforming growth factor β, IL-2, or interleukin 15 [11–13]. Intermittent in vivo administration of IL2 can lead to an expansion of Treg-like cells (CD4CD45ROCD25 T cells) in patients with human immunodeficiency virus type 1 (HIV-1) infection [14] or hepatitis C virus infection [15]. Although no clinical benefit was seen in a phase III study of IL-2 in patients with HIV-1 infection [16], patients with hepatitis C virus–induced vasculitis had remission of their disease. The immune systems of patients with HIV-1 infection are characterized by inadequate control of HIV-1 replication, progressive loss of CD4 T cells, and chronic generalized immune activation [17–19]. There is increasing evidence that clinical progression of HIV-1 infection is critically linked to the negative consequences of immune activation and that the level of immune activation is directly correlated to the plasma levels of HIV-1. [20]. The importance of immune activation in HIV-1 infection has been reinforced by the strong associations between baseline levels of CD4 and CD8 T cells that express CD38 and HLA-DR [21–23], plasma levels of interleukin 6, D-dimer or soluble CD14, and all-cause mortality [24, 25]. Given their potent suppressive capability, the role of Tregs in HIV-1 infection and, in particular, their impact on the host response to HIV-1 and immune activation have received much attention in recent years. In the context of HIV-1 infection, Tregs can be postulated to be beneficial by dampening excessive immune activation (the good) (Figure 1) or to be harmful by suppressing HIV-1–specific immune responses Received and accepted 7 February 2012; electronically published 28 March 2012. Correspondence: H. Clifford Lane, MD, Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (clane@niaid.nih.gov). The Journal of Infectious Diseases 2012;205:1479–82 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2012. DOI: 10.1093/infdis/jis238