Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

Abstract

Approximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we know about viral immunity comes from studies using mouse models. Experiments using the Friend virus (FV) model have been particularly informative in defining highly complex anti-retroviral mechanisms of the intrinsic, innate and adaptive arms of immunity. FV studies have unraveled fundamental principles about how the immune system controls both acute and chronic viral infections. They led to a more complete understanding of retroviral immunity that begins with cellular sensing, production of type I interferons, and the induction of intrinsic restriction factors. Novel mechanisms have been revealed, which demonstrate that these earliest responses affect not only virus replication, but also subsequent innate and adaptive immunity. This review on FV immunity not only surveys the complex host responses to a retroviral infection from acute infection to chronicity, but also highlights the many feedback mechanisms that regulate and counter-regulate the various arms of the immune system. In addition, the discovery of molecular mechanisms of immunity in this model have led to therapeutic interventions with implications for HIV cure and vaccine development.

Keywords: Friend retrovirus; adaptive immunity; immunotherapy; innate immunity; intrinsic immunity; mouse model.

Figure 1.

Sensing of FV and induction of intrinsic and innate immunity. After virus entry, a number of different viral nucleic acid products can be sensed and IFN I responses are initiated. Although the IFN I response is limited by FV due to an unknown viral mechanisms, it induces the expression and activity of the restriction factors APOBEC3 and Tetherin as well as anti-viral NK cell responses. Complement binding can directly lead to virus lysis or increase virus uptake leading to cellular degradation and improved antigen presentation.

Figure 2.

Kinetics of adaptive immune responses during FV infection. Virus-infected DCs and B cells prime CD4+ and CD8+ effector T cells, but infected DCs can also initiate Treg responses. Membrane-bound TNFα-positive CD8+ T cells and GITR expressing B cells expand Tregs. Effector T cells as well as antibody-producing B cells control acute virus replication in a complex immune response. Cytotoxic CD8+ T cells are especially effective in restricting virus spread, but become exhausted via Tregs and inhibitory receptors during the transition phase between acute and chronic infection. Infected B cells upregulate ligands for inhibitory receptors and subsequently escape from CTL killing, suppress CD8+ T cell functions and form a persisting viral reservoir. During chronic infection most CD8+ T cells, except a few SIRPα-positive ones, are dysfunctional and virus replication is kept in check by cytotoxic CD4+ T cells and most likely neutralizing antibodies.

Figure 3.

The complex interplay of innate and adaptive immunity in FV infection. Virus sensing initiates IFN I responses, which stimulate and activate NK cells, CD8+ T cells and DCs. CD4+ and CD8+ T cell priming by FV-infected DCs is more efficient when complement-opsonized virus was taken up by the DCs, but IgG-opsonized virus inhibits T cell induction. Infected B cells can also initiate CD8+ T cell responses, which is also more efficient after infection with complement opsonized virus. The expression of APOBEC3 after virus sensing augments B cell/antibody responses, whereas the expression of Tetherin facilitates CD4+ and CD8+ T cell responses by enhancing antigen presentation. Effector CD8+ T cell responses can be suppressed by virus-activated NK cells, Tregs as well as gMDSCs.