Retroviral escape by Friendly infected DCs

Friend retrovirus infection of myeloid dendritic cells impairs maturation, prolongs contact with naive T cells, and favors expansion of regulatory T cells.

How retroviruses evade immune surveillance has been a fascinating and important question in basic and clinical immunology. Dendritic cells (DCs) are now well-known as pivotal immunological cells in the induction of immunity to infection and are increasingly being recognized as playing important roles in the induction of immunologic tolerance. DCs are present within virtually all tissue compartments of the body, where they serve an immunosurveillant function. The infection of DCs by retroviruses such as human immunodeficiency virus (HIV) has been well-documented. In light of their pivotal role in immunity, it makes intrinsic sense that viral infection of DCs could be a pathway for immune escape. One of the key sentinels of immune tolerance, the regulatory T (Treg) cell, is now also implicated in this process. The retrovirus may either induce or suppress Treg-cell function. It has been shown previously that HIV infection induces Treg cells in untreated infection,¹  whereas the human T-cell leukemia virus 1 (HTLV-1) protein TAX reduces FOXP3 expression in T cells, promoting disease progression.²  These examples highlight the disconnection between the needs of the virus and the needs of the host.

In this issue of Blood, Balkow and colleagues provide significant insights into the mechanism of retroviral immune evasion involving both DCs and Treg cells. Using the murine Friend retrovirus (FV) complex model, an immunosuppressive retrovirus that induces leukemia in mice, the authors demonstrate that this retrovirus infects myeloid DCs both in vitro and in vivo. Balkow and colleagues show that retroviral infection of murine myeloid DCs (mDCs) interferes with the immunological synapses between DCs and naive T cells, and that the cells emerging after this faulty interaction display classic regulatory phenotype and function based on expression of FOXP3 and suppression.

This important effect on promoting CD4⁺CD25⁺ Treg cells was critically dependent on very long contact between DCs and T cells (see figure). The pathways underlying this prolonged contact remain to be determined. Global expression analysis of infected versus noninfected DCs may reveal key genes involved in this process, the identification of which could lead to novel therapeutic targets for intervention in retroviral infection. Intriguingly, only myeloid and lymphoid DCs in mice were infected by FV, with murine plasmacytoid DCs (pDCs; the principal type-I interferon–producing cells) being spared. This is in contrast to the role of pDCs in other virus infections such as Epstein-Barr virus (EBV)³  and HIV,⁴  in which pDCs drive the interferon-mediated antiviral response. Perhaps the FV has learned to avoid these pDCs?

Understanding this pathway of immune escape is of considerable importance. Future research to determine how retrovirally infected DCs can be matured may potentially allow the development of new strategies to promote retroviral clearance. Conversely, exploiting the promising immunosuppressive properties of retroviral DC infection may allow novel means of inducing antigen-specific immunosuppression for allotransplantation and the therapy of autoimmune disease.