Simian Immunodeficiency Virus Infection in the Brain and Lung Leads to Differential Type I IFN Signaling during Acute Infection

Abstract

Using an accelerated and consistent SIV pigtailed macaque model of HIV-associated neurologic disorders, we have demonstrated that virus enters the brain during acute infection. However, neurologic symptoms do not manifest until late stages of infection, suggesting that immunological mechanisms exist within the CNS that control viral replication and associated inflammation. We have shown that IFN-β, a type I IFN central to viral innate immunity, is a major cytokine present in the brain during acute infection and is responsible for limiting virus infection and inflammatory cytokine expression. However, the induction and role of IFN-α in the CNS during acute SIV infection has never been examined in this model. In the classical model of IFN signaling, IFN-β signals through the IFN-α/β receptor, leading to expression of IFN-α. Surprisingly, although IFN-β is upregulated during acute SIV infection, we found that IFN-α is downregulated. We demonstrate that this downregulation is coupled with a suppression of signaling molecules downstream of the IFN receptor, namely tyrosine kinase 2, STAT1, and IFN regulatory factor 7, as indicated by either lack of protein phosphorylation, lack of nuclear accumulation, or transcriptional and/or translational repression. In contrast to brain, IFN-α is upregulated in lung and accompanied by activation of tyrosine kinase 2 and STAT1. These data provide a novel observation that during acute SIV infection in the brain, there is differential signaling through the IFN-α/β receptor that fails to activate expression of IFN-α in the brain.

Distinct Patterns of Tryptophan Maintenance in Tissues during Kynurenine Pathway Activation in Simian Immunodeficiency Virus-Infected Macaques

“…For example, macrophages and microglia are thought to be the major producers of IDO1 in the brain (41), whereas mDCs may express the highest level of IDO1 in the spleen (data shown here) and lymph nodes (2) during HIV/SIV infection. Conversely, IFNα subtypes are known to differ in different tissue sites; such differences could modulate the induction of IDO1 or IDO1 modulators (63). Future studies will be necessary in order to examine the cell-specific requirements of IDO and other KP enzyme induction in other peripheral tissue sites and during acute vs. chronic infection.…”

Current views on interferon therapy for HIV

“…Antiretroviral drug penetration into tissues that may be reservoirs of HIV infection, such as the central nervous system, gastrointestinal tract and lymph nodes, is variable [39,40]. Conversely, IFN-alpha has shown good penetration into the liver, kidney, gastrointestinal tract, pancreas, spleen, and lung in models involving mice [41], and into the central nervous system in SIV-infected pigtailed macaque models [42]. IFN-alpha can also eradicate HCV from the liver even when chronic infection has been established, indicating its excellent penetration into this tissue [11].…”

Canonical Type I IFN Signaling in Simian Immunodeficiency Virus-Infected Macrophages Is Disrupted by Astrocyte-Secreted CCL2

“…Our group has made the novel discovery that type I IFN signaling in the central nervous system (CNS) in response to SIV infection occurs in a more complex, noncanonical manner (2). Using an accelerated, consistent pigtailed macaque SIV model of HIV associated neurological disease, we have shown that while IFNβ is induced during acute SIV infection in brain, IFNα is simultaneously down regulated and associated with a suppression of signaling modulators downstream of the IFN receptor, including Tyk2, STAT1 and IRF7.…”