Type I Interferons in NeuroHIV

Abstract

Infection with Human Immunodeficiency Virus (HIV)-1 continues to cause HIV-associated neurocognitive disorders despite combined antiretroviral therapy. Interferons (IFNs) are important for any antiviral immune response, but the lasting production of IFNα causes exhaustive activation leading eventually to progression to AIDS. Expression of IFNα in the HIV-exposed central nervous system has been linked to cognitive impairment and inflammatory neuropathology. In contrast, IFNβ exerts anti-inflammatory effects, appears to control, at least temporarily, lentiviral infection in the brain and provides neuroprotection. The dichotomy of type I IFN effects on HIV-1 infection and the associated brain injury will be discussed in this review, because the underlying mechanisms require further investigation to allow harnessing these innate immune factors for therapeutic purposes.

Introduction

Infection with Human Immunodeficiency Virus (HIV)-1 continues to cause HIV-associated neurocognitive disorders (HAND) despite combined antiretroviral therapy (cART) (50,108). HIV-associated dementia (HAD) is the most severe manifestation of the disorders, and there is currently no treatment available for any form of HAND. Several lines of evidence strongly suggest that neurodegeneration occurs as a consequence of HIV-1 infection and neurotoxic immune stimulation of microglia and macrophages (MΦ) in the brain (12,37,39,42,60 –62,85,86,97) and impairment of neurogenesis (44,66,94,111).

Beyond activation of MΦ and microglia, infection with HIV-1 triggers an innate immune response that includes interferons (IFN) (20,22,76,98). While IFNs are important for an antiviral immune response, the lasting production of IFNα and -γ causes an erroneous and exhaustive activation leading eventually to immune suppression and progression to AIDS (22,76,98,104). Moreover, expression of IFNα in the HIV-exposed central nervous system (CNS) has been linked to cognitive impairment and inflammatory neuropathology (7,9,80,106,107). In contrast, IFNβ exerts anti-inflammatory effects (54,55,73), appears to control, at least temporarily, HIV and SIV infection in the brain (8,9,25,38,64,65,83), and to provide neuroprotection (120). However, in HIV-1 infection, expression of IFNβ appears to be transient in contrast to that of IFNα (9,76,80). Transient expression of IFNβ has been observed in the CNS of SIV-infected macaques in association with extended viral control and delayed progression to disease in the brain (3,9) as well as in transgenic (tg) mice expressing in their CNS the viral envelope protein gp120 of the CXCR4-utilizing HIV-1 isolate LAV (121,123). Moreover, treatment of the gp120tg mouse model of HIV-associated brain injury with exogenous recombinant IFNβ resulted in neuroprotection against toxicity of the viral envelope protein (120). The dichotomy of type I IFN effects on HIV-1 infection and the associated brain injury will be discussed in this review because the underlying mechanisms require further investigation to allow harnessing these innate immune factors for therapeutic purposes.

HIV-1 Infection Associated with Neurotoxicity

HIV-1 infects microglia/MΦ and T cells through the chemokine receptors CCR5 and CXCR4, which, in conjunction with CD4, function as coreceptors for the virus (6,15,23,24,30,32). Interestingly, in the absence of intact virus, the HIV-1 envelope protein gp120 of CCR5-preferring, CXCR4-preferring, and dual-tropic viral strains all can trigger macrophage neurotoxicity and induce injury and apoptosis, in vitro and in vivo, in both primary human and rodent neurons (17,43,52,61,62,68,69,72,86 –88,112,114,121). Moreover, in MΦ, HIV-1 infection and exposure to just the viral proteins gp120 or Tat seems to initiate a similar neurotoxic phenotype (42,43,74,117). Although HIV-1 primarily infects macrophages and microglia in the CNS, the virus and its envelope protein also cause impairment of neurogenesis by interfering with the proliferation of neural progenitor cells (44,66,94,111).

Neuropathology of HIV-1 Infection

The neuropathology associated with HIV-1 infection in the CNS is characterized by astrocytosis, myelin pallor, infiltration of MΦ, increased number of resident microglia and multinucleated giant cells, diminished synaptic and dendritic density, and selective neuronal loss (18,78,79,92). However, the increased number of microglia and MΦ, decreased synaptic and dendritic density, evidence of excitotoxins, and selective neuronal loss are the pathological hallmarks most closely associated with the clinical signs of HAND/HAD. Many regions of the brain can be affected, including frontal cortex, hippocampus, substantia nigra, putamen, basal ganglia and cerebellum, and HAND/HAD is associated with evidence of neuronal apoptosis (reviewed in (11,34,60,63,71)).

Interferons

IFNs were identified over 50 years ago and were characterized for their ability to “interfere” with viral replication (57). These cytokines are produced and secreted in response to pathogenic host invasion and inflammation by a variety of nucleated cells both in the CNS and the periphery, including astrocytes, microglia, neurons, macrophages, and T lymphocytes (29). These cytokines play critical roles in immunomodulatory activities that affect both the innate and adaptive immune responses (51). IFNs are separated into three different families based on the receptor type used. The type I IFN family encodes 13 IFNα subtypes in humans (14 in mice), a single IFNβ gene, IFNω, IFNκ, and IFNɛ, which together signal through the IFN-α/β receptor (IFNAR) that is composed of IFNAR1 and IFNAR2 subunits (110). In contrast, the type II IFN family consists solely of IFNγ, which is produced primarily by T cells and natural killer cells, whereas the type III group is composed of IFNλ1, IFNλ2, IFNλ3, and the recently discovered IFNλ4 (21,100).

HIV-1 Infection and IFNs

HIV appears to invade the CNS soon after peripheral infection, but severe neurological symptoms do often not present until later stages of disease progression (82). This delay in clinical manifestations can be explained by the host's ability to mount an antiviral immune response, which results in viral control during the acute stages of infection (3). In the periphery, HIV triggers a rapid nonspecific activation of the innate immune system, followed by a slower, but antigen-specific, adaptive immune response (84). In the brain, the blood–brain barrier restricts access of T and B cells, and therefore shifts the burden of HIV control to local innate immune defense mechanisms (115). IFNs are a major component of the first line of host defense against HIV and critical mediators of the immune response in the brain (47). Important for the periphery and the brain, IFNα, -β and -γ all can inhibit HIV-1 infection of MΦ and CD4⁺ T cells (45,75,89,113).

During HIV infection, Type I IFN induction and secretion can be activated by several different mechanisms and the extent of induction depends on cell type and viral structure available for recognition by cellular Pattern Recognition Receptors (2). Intracellular sensing of HIV infection includes the Toll-like receptors (TLRs), of which TLR-7 is responsible for recognition of viral single-stranded (ss) RNA in endosomes. Cytosolic DNA sensors include the enzyme cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (c-GAS) and IFNγ-inducible protein 16 (IFI16), which detects HIV reverse-transcribed DNA products, and retinoic acid-inducible gene-1 (RIG-1), which senses viral RNA (31).

Plasmacytoid dendritic cells (pDC) are major producers of type I IFN/IFNα in the periphery and can be activated by free HIV particles as well as virus-infected CD4⁺ T cells (70). When HIV is taken up by pDC through endocytosis, TLR7 detects endosomally delivered ssRNA and activates the myeloid differentiation primary response gene 88 (MYD88) signaling pathway. This signaling cascade leads to activation of IFN Regulatory Factor 7 (IRF7) and activation of the nuclear factor-κB (NF-κB) transcription factor to promote robust production of IFNs, specifically IFNα (10,14,70). In conventional Dendritic Cells (cDCs) and macrophages, HIV cDNA can be detected by c-GAS or IFI16 that can activate stimulator of IFN genes (STING) in the endoplasmic reticulum and induce IFN production through IRF3 and NF-κB. Finally, cytosolic RIG-1 can detect genomic viral RNA and trigger a STING-dependent immune response and the activation of IRF3 (2,31).

Because of its pronounced antiviral activity, IFNα has been investigated for HIV-1 treatment in several settings: before the introduction of cART, as part of a structured treatment interruption strategy, in acute HIV infection, as a component of salvage therapy and most recently, in attempts of eradication of viral reservoirs (102,122). Early attempts of treating established HIV infection had been disappointing or inconclusive, perhaps in part because under chronic conditions, IFNα eventually suppresses the function of the immune system, which then facilitates viral persistence and progression to AIDS (122). Therefore, it may not be surprising that one recent study suggested that blocking type I IFN signaling during chronic HIV infection–in this case with an antibody against IFNAR2–facilitates the restoration of immune function (127). However, other recent investigations related to HIV eradication suggest that IFNα in combination with cART and viral reactivation agents may support the elimination of HIV-1 reservoirs (41,56,93,105,116). The CNS is a HIV-1 reservoir and as such presents a major challenge for viral eradication (35,46,91). Given that IFNα clearly has a temporary antiviral effect on HIV-1, timing of IFNα treatment, time of onset and length of application, may be critical factors for successful eradication.

Type I IFN Signaling and IFN-Stimulated Genes

Both IFNα and IFNβ exert their effects by signaling in an autocrine and paracrine manner through the JAK/STAT pathway to activate transcription of antiviral genes that are known collectively as IFN-stimulated genes (ISGs) (31,109). IFN signaling induces dimerization of its cell surface receptors, IFNAR1 and IFNAR2, and activates the receptor-associated protein tyrosine kinases Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2). These signaling events lead to phosphorylation, dimerization, and nuclear translocation of cytoplasmic signal transducer and activator of transcription (STAT) molecules. The IFN-stimulated factor 3 (ISGF3) complex, which consists of a STAT1-STAT2 heterodimer and the cytoplasmic protein IFN-regulatory factor 9 (IRF9), binds to IFN-stimulated response elements (ISRE) in the promoters of most ISGs and activates a classical antiviral response. On the other hand, STAT1 homodimers bind gamma-activated sequences (118) and induce proinflammatory ISGs (58).

Altogether, these pathways result in an induction of numerous antiviral factors that restrict or interfere with HIV/SIV replication at different stages of the viral life cycle. HIV restriction and resistance factors include: tripartite motif-containing protein 5α (TRIM5α), sterile α motif domain and histidine aspartic acid (HD) domain 1 (SAMHD1), apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3), tetherin, IFN-induced transmembrane (IFITM) proteins, schlafen 11 (SLFN11), and MX2. Furthermore, some of these restriction factors can enhance the expression of an antiviral response by sensing viral particles (31,109).

Type I IFNs in the Normal and HIV-Infected CNS

A mouse model with genetic depletion of endogenous IFNβ signaling develops a Parkinson's Disease-like phenotype with motor and cognitive learning deficiencies, a significant reduction in dopaminergic neurons, impaired neuronal autophagy, and presence of α-synuclein-containing Lewy bodies in the brain (33). Interestingly, when these animals were treated with IFNβ, neuronal growth, branching, autophagy flux, and α-synuclein degradation in neurons were restored (33). This study revealed the critical role of physiological IFNβ signaling for normal brain homeostasis and function. Similarly, we detected impairment of spatial learning and memory in the absence of IFNAR1 (Hina Singh, Amanda Roberts, and Marcus Kaul, unpublished results). These findings are also in line with the observation in the normal brain of low-level baseline expression of IFNα and–β, which seems to be required for an effective type I IFN response in case of a viral infection (1,120).

Several studies have been published on the antiviral and neuromodulatory activities of type I IFNs in the CNS, yet the question of whether these cytokines hinder or facilitate HIV disease and HAND progression over time remains controversial (122). Of note, whereas IFNAR1-signaling of type I IFNs is critical for antiviral immunity, IFNα and IFNβ promote different additional biological responses in the CNS (47) in that IFNβ expression is associated with an anti-inflammatory response in the brain and IFNα is linked to increased neurocognitive dysfunction and inflammatory neuropathology (47).

Mice lacking functional IFNAR1 show increased susceptibility to fatal disease in most experimental RNA-virus infections of the CNS (19,36,47,90,103). For example, one study investigating the role of IFNAR1-mediated responses in antiviral control involved chimeric HIV-1 (EcoHIV), wherein gp80 of the ecotropic murine leukemia virus replaces HIV-1 gp120 to permit productive infection of mice (99). In this model, IFNAR1 knockout (KO) mice infected with EcoHIV presented with enhanced virus infiltration into the brain and inflammatory pathology, thus implicating type I IFN responses in control of HIV neuropathogenesis (49). However, since this model lacks expression of HIV gp120 in the brain, which is a critical component associated with HIV neurotoxicity, the role of IFNAR1 responses is not yet known in the context of gp120-induced neuronal injury.

Increased production of IFNα in the brain is a double-edged sword that provides antiviral protection, but also promotes inflammatory neuropathology and cognitive impairment. Transgenic mice that chronically produce IFNα in astrocytes show decreased susceptibility to neurotropic viral infection, but develop progressive inflammatory encephalopathy, gliosis, and neurodegeneration (4).

In humans, elevated IFNα expression in the CNS is associated with neurodegenerative disorders, such as Aicardi–Goutieres syndrome and Cree encephalitis (26,125). Moreover, antiviral therapy with IFNα in patients infected with hepatitis C and herpes virus is known to have side effects such as cognitive slowing, amnesia, and impaired executive functions (28,106,124). In the context of HIV infection, three separate studies showed that HIV patients with dementia have significantly higher levels of IFNα in the CSF compared with those without dementia (67,96,101). Moreover, elevated IFNα levels in the CNS correlate with increased atrophy in the frontal cortex of HAD patients and severity of dementia (80,96,101). In addition, a recent study found that IFNα in the CSF also correlates with milder forms of neurocognitive impairment and soluble neurofilament light chain (NFL), a marker of neuronal injury (7). These observations suggest that IFNα is involved in the pathogenesis of HAND before the development of dementia and in the presence of cART. Finally, under certain chronic conditions, IFNα can suppress the function of the immune system, which then promotes viral persistence and progression to AIDS (122).

The role of IFNα in the CNS has also been characterized in a SCID mouse model. Experiments where HIV-infected human macrophages were injected into the SCID mouse brains demonstrated that HIV infection causes significant increases in IFNα expression in the brain, which strongly correlated with cognitive deficits (107). Furthermore, blocking IFNα with neutralizing antibodies significantly improved cognitive impairment and decreased microgliosis in these animals (106).

In contrast to IFNα, IFNβ exerts anti-inflammatory effects and appears to be able to control HIV and SIV infection in the brain. Studies of SIV-infected macaques show that IFNβ is the main type I IFN that is produced by the brain during acute infection and its expression is associated with viral control in the brain (9). Previous studies showed that obstruction of endogenous IFNβ signaling in an experimental autoimmune encephalomyelitis mouse model produced more severe and chronic neurological symptoms, as well as increased microglial activation that can contribute to extensive tissue damage in the brain (119).

In the classical model of type I IFN signaling, IFNβ production leads to induction of IFNα (53). However, during SIV infection brains induce protective antiviral responses through the production of IFNβ, without production of IFNα (5). Meanwhile, in the periphery acute infection with SIV results in significant IFNα increases (5). This differential regulation during SIV infection in the brain depends on CCL2, which is predominantly produced by astrocytes upon viral infection (126). CCL2 binds to the CCR2 receptor on macrophages to selectively suppress IFNα expression without altering expression of IFNβ and antiviral ISGs, such as MX1 (128). Several SIV studies strongly suggested that tight temporal regulation of the type I IFN response, in particular of IFNα expression, is critical to the avoidance of pathogenic lentiviral infection (16,48,59).

Similar to the observation in the SIV-infected macaques, we detected transiently increased IFNβ mRNA expression in the brains of HIVgp120tg mice at 1.5, but not 3 or 6 months of age (120). These tg mice express the viral gp120 of the HIV-1 isolate LAV under the control of a modified GFAP promotor in astrocytes in their CNS and recapitulate key features of brain damage seen in HIV/AIDS patients (121). As such, HIVgp120tg mice display a decrease of synaptic and dendritic density, an increased number of activated microglia, and pronounced astrocytosis (121). HIVgp120tg mice also develop significant behavioral changes, such as impaired spatial learning and memory at 8–9 months (81) and reduced swimming velocity at 12 months of age (27). Moreover, HIVgp120tg mouse brains share a significant number for differentially expressed genes with human HIV and HIV encephalitis (HIVE) patients, including evidence of an endogenous IFN response (40,81). However, while CCL2 expression was significantly elevated, IFNα remained at baseline level in HIVgp120tg mouse brains. Similar to the SIV model, the absence of an increase in IFNα in association with significantly elevated IFNβ in the brains of HIVgp120tg mice at 1.5 months might be due to upregulated CCL2.

As an antiviral therapeutic tool, IFNβ seems to cause less adverse side effects than IFNα (95). Moreover, due to its immunomodulatory effect, IFNβ is FDA approved for the treatment of multiple sclerosis, which is an inflammatory neurodegenerative autoimmune disease (77,95). IFNβ can also induce expression of factors that have neuroprotective activities, such as nerve growth factor (13), and the CCR5 ligands, CCL4 and CCL5 (65,121). In fact, using mixed neuronal–glial cerebrocortical cell cultures, we recently showed that IFNβ confers neuronal protection against the toxicity of HIVgp120. Moreover, treatment of HIV gp120tg mice with exogenous recombinant IFNβ through intranasal delivery resulted in neuroprotection, including neuronal dendrites and presynaptic terminals in cortex and hippocampus (120). Figure 1 summarizes in a schematic model the effects of IFNα and IFNβ in the HIV-infected brain and HAND.

FIG. 1.

Schematic model of the effects of IFNα and IFNβ in the HIV-infected brain and HAND. HIV-1 reaches the brain apparently soon after peripheral infection and resides in perivascular MΦ and microglia. These cell types are the primary sites of productive viral infection in the CNS, although all neural cell types can express the HIV coreceptors, CCR5 and CXCR4. HIV-infected and uninfected stimulated MΦ and microglia produce neurotoxins that damage neurons presumably engaging various receptors and mechanisms, all culminating in synaptic and dendritic injury and eventually neuronal apoptosis. HIV-infected MΦ and microglia may, at least temporarily, produce IFNα and IFNβ. CCL2 released by astrocytes, however, can suppress IFNα production by MΦ and microglia. IFNα and IFNβ can interact with all cells in the CNS since all express the two IFNAR subunits. Stimulation with IFNα and IFNβ generally induces ISGs and an antiviral state in all cell types. However, the spectrum of ISGs induced may be different for each type I IFN. IFNα seems to promote inflammatory processes and directly and/or indirectly compromise neuronal function and thus may contribute to the development of HAND. In contrast, IFNβ seems to overall limit inflammatory processes and contribute to neuroprotection by counteracting injurious mechanisms. In vivo, exogenous IFNβ can be delivered to the brain through intranasal application. CNS, central nervous system; HAND, HIV-associated neurocognitive disorder; IFN, interferon; IFNAR, IFN-α/β receptor; ISG, IFN-stimulated gene; MΦ, macrophages.

In summary, based on the available data, it seems highly reasonable to further investigate whether IFNβ as part of the innate antiviral immune response, or if therapeutically administered, can provide a beneficial effect in controlling chronic HIV-1 infection and delay or prevent the development of HAND and its most severe manifestation, HAD.

Footnotes

Acknowledgment

This work was supported by NIH grants R01 MH087332, MH104131, MH105330 (to M.K.), and P50 DA026306 (Project 5 to M.K.).

Author Disclosure Statement

No competing financial interests exist.

References

Abt

, Osborne

, Monticelli

, et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity, 2012; 37:158–170.

Acchioni

, Marsili

, Perrotti

, et al. Type I IFN—a blunt spear in fighting HIV-1 infection. Cytokine Growth Factor Rev, 2015; 26:143–158.

Akhtar

, Qin

, Muldowney

, et al. Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages. J Immunol, 2010; 185:2393–2404.

Akwa

, Hassett

, Eloranta

, et al. Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. J Immunol, 1998; 161:5016–5026.

Alammar

, Gama

, and Clements

. Simian immunodeficiency virus infection in the brain and lung leads to differential type I IFN signaling during acute infection. J Immunol, 2011; 186:4008–4018.

Alkhatib

, Combadiere

, Broder

, et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science, 1996; 272:1955–1958.

Anderson

, Lennox

, Mulligan

, et al. Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals. J Neurovirol, 2017; 23:106–112.

Barber

, Gama

, Dudaronek

, et al. Mechanism for the establishment of transcriptional HIV latency in the brain in a simian immunodeficiency virus-macaque model. J Infect Dis, 2006; 193:963–970.

Barber

, Herbst

, Bullock

, et al. Innate immune responses and control of acute simian immunodeficiency virus replication in the central nervous system. J Neurovirol, 2004; 10 Suppl 1:15–20.

10.

Beignon

, McKenna

, Skoberne

, et al. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest, 2005; 115:3265–3275.

11.

Bell

JE.

An update on the neuropathology of HIV in the HAART era. Histopathology, 2004; 45:549–559.

12.

Bezzi

, Domercq

, Brambilla

, et al. CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci, 2001; 4:702–710.

13.

Biernacki

, Antel

, Blain

, et al. Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch Neurol, 2005; 62:563–568.

14.

Blasius

, and Beutler

. Intracellular toll-like receptors. Immunity, 2010; 32:305–315.

15.

Bleul

, Farzan

, Choe

, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature, 1996; 382:829–833.

16.

Bosinger

, Li

, Gordon

, et al. Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. J Clin Invest, 2009; 119:3556–3572.

17.

Brenneman

, Westbrook

, Fitzgerald

, et al. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature, 1988; 335:639–642.

18.

Budka

Multinucleated giant cells in brain: a hallmark of the acquired immune deficiency syndrome (AIDS). Acta Neuropathol (Berl), 1986; 69:253–258.

19.

Byrnes

, Durbin

, and Griffin

. Control of Sindbis virus infection by antibody in interferon-deficient mice. J Virol, 2000; 74:3905–3908.

20.

Capobianchi

, Ameglio

, Cordiali

, et al. Coordinate induction of interferon alpha and gamma by recombinant HIV-1 glycoprotein 120. AIDS Res Hum Retroviruses, 1993; 9:957–962.

21.

Chelbi-Alix

, and Wietzerbin

. Interferon, a growing cytokine family: 50 years of interferon research. Biochimie, 2007; 89:713–718.

22.

Cho

, Astgen

, Hendel

, et al. Homeostasis of chemokines, interferon production and lymphocyte subsets: implications for AIDS pathogenesis. Biomed Pharmacother, 1997; 51:221–229.

23.

Choe

, Farzan

, Sun

, et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell, 1996; 85:1135–1148.

24.

Clapham

PR.

HIV and chemokines: ligands sharing cell-surface receptors. Trends Cell Biol, 1997; 7:264–268.

25.

Cocchi

, Devico

, Garzino-Demo

, et al. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV- suppressive factors produced by CD8+ T cells. Science, 1995; 270:1811–1815.

26.

Crow

, Black

, Ali

, et al. Cree encephalitis is allelic with Aicardi-Goutieres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism. J Med Genet, 2003; 40:183–187.

27.

D'hooge

, Franck

, Mucke

, et al. Age-related behavioural deficits in transgenic mice expressing the HIV-1 coat protein gp120. Eur J Neurosci, 1999; 11:4398–4402.

28.

Dafny

Is interferon-alpha a neuromodulator?. Brain Res Brain Res Rev, 1998; 26:1–15.

29.

Dafny

, and Yang

. Interferon and the central nervous system. Eur J Pharmacol, 2005; 523:1–15.

30.

Doranz

, Rucker

, Yi

, et al. A dual-tropic primary HIV-1 isolate that uses fusin and the beta- chemokine receptors CKR5, CKR3, and CKR2b as fusion cofactors. Cell, 1996; 85:1149–1158.

31.

Doyle

, Goujon

, and Malim

. HIV-1 and interferons: who's interfering with whom?. Nat Rev Microbiol, 2015; 13:403–413.

32.

Dragic

, Litwin

, Allaway

, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature, 1996; 381:667–673.

33.

Ejlerskov

, Hultberg

, Wang

, et al. Lack of Neuronal IFN-beta-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia. Cell, 2015; 163:324–339.

34.

Ellis

, Langford

, and Masliah

. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci, 2007; 8:33–44.

35.

Ellis

, and Letendre

. Update and new directions in therapeutics for neurological complications of HIV infections. Neurotherapeutics, 2016; 13:471–476.

36.

Fiette

, Aubert

, Muller

, et al. Theiler's virus infection of 129Sv mice that lack the interferon alpha/beta or interferon gamma receptors 156. J Exp Med, 1995; 181:2069–2076.

37.

Gartner

HIV infection and dementia. Science, 2000; 287:602–604.

38.

Garzino-Demo

, DeVico

, Cocchi

, et al. Beta-chemokines and protection from HIV type 1 disease. AIDS Res Hum Retroviruses, 1998; 14 Suppl 2:S177–S184.

39.

Gelbard

, Dewhurst

, Maggirwar

, et al. Rebuilding synaptic architecture in HIV-1 associated neurocognitive disease: a therapeutic strategy based on modulation of mixed lineage kinase. Neurotherapeutics, 2010; 7:392–398.

40.

Gelman

, Chen

, Lisinicchia

, et al. The National NeuroAIDS Tissue Consortium brain gene array: two types of HIV-associated neurocognitive impairment. PLoS One, 2012; 7:e46178.

41.

George

, and Mattapallil

. Interferon-alpha subtypes as an adjunct therapeutic approach for human immunodeficiency virus functional cure. Front Immunol, 2018; 9:299.

42.

Giulian

, Vaca

, and Noonan

. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science, 1990; 250:1593–1596.

43.

Giulian

, Wendt

, Vaca

, et al. The envelope glycoprotein of human immunodeficiency virus type 1 stimulates release of neurotoxins from monocytes. Proc Natl Acad Sci U S A, 1993; 90:2769–2773.

44.

Gorantla

, Liu

, Sneller

, et al. Copolymer-1 induces adaptive immune anti-inflammatory glial and neuroprotective responses in a murine model of HIV-1 encephalitis. J Immunol, 2007; 179:4345–4356.

45.

Goujon

, and Malim

. Characterization of the alpha interferon-induced postentry block to HIV-1 infection in primary human macrophages and T cells. J Virol, 2010; 84:9254–9266.

46.

Gray

, Cowley

, Welsh

, et al. CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies. Mol Psychiatry, 2016; 21:574–584.

47.

Griffin

DE.

Immune responses to RNA-virus infections of the CNS. Nat Rev Immunol, 2003; 3:493–502.

48.

Harris

, Tabb

, Sodora

, et al. Downregulation of robust acute type I interferon responses distinguishes nonpathogenic simian immunodeficiency virus (SIV) infection of natural hosts from pathogenic SIV infection of rhesus macaques. J Virol, 2010; 84:7886–7891.

49.

, Sharer

, Chao

, et al. Enhanced human immunodeficiency virus Type 1 expression and neuropathogenesis in knockout mice lacking Type I interferon responses. J Neuropathol Exp Neurol, 2014; 73:59–71.

50.

Heaton

, Clifford

, Franklin

Jr ., et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology, 2010; 75:2087–2096.

51.

Hertzog

, O'Neill

, and Hamilton

. The interferon in TLR signaling: more than just antiviral. Trends Immunol, 2003; 24:534–539.

52.

Hesselgesser

, Taub

, Baskar

, et al. Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 alpha is mediated by the chemokine receptor CXCR4. Curr Biol, 1998; 8:595–598.

53.

Honda

, Takaoka

, and Taniguchi

. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity, 2006; 25:349–360.

54.

Hua

, and Lee

. Distinct patterns of stimulus-inducible chemokine mRNA accumulation in human fetal astrocytes and microglia. Glia, 2000; 30:74–81.

55.

Hua

, Liu

, Brosnan

, et al. Selective inhibition of human glial inducible nitric oxide synthase by interferon-beta: implications for multiple sclerosis. Ann Neurol, 1998; 43:384–387.

56.

Hua

, Vigano

, Tse

, et al. Pegylated Interferon-alpha-induced natural killer cell activation is associated with human immunodeficiency virus-1 DNA decline in antiretroviral therapy-treated HIV-1/Hepatitis C Virus-Coinfected Patients. Clin Infect Dis, 2018; 66:1910–1917.

57.

Isaacs

, and Lindenmann

. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci, 1957; 147:258–267.

58.

Ivashkiv

, and Donlin

. Regulation of type I interferon responses. Nat Rev Immunol, 2014; 14:36–49.

59.

Jacquelin

, Mayau

, Targat

, et al. Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest, 2009; 119:3544–3555.

60.

Kaul

, Garden

, and Lipton

. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature, 2001; 410:988–994.

61.

Kaul

, and Lipton

. Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci U S A, 1999; 96:8212–8216.

62.

Kaul

, Ma

, Medders

, et al. HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection. Cell Death Differ, 2007; 14:296–305.

63.

Kaul

, Zheng

, Okamoto

, et al. HIV-1 infection and AIDS: consequences for the central nervous system. Cell Death Differ, 2005; 12 Suppl 1:878–892.

64.

Kim

, Si

, Zhou

, et al. Interferon-beta activates multiple signaling cascades in primary human microglia. J Neurochem, 2002; 81:1361–1371.

65.

Kitai

, Zhao

, Zhang

, et al. Role of MIP-1beta and RANTES in HIV-1 infection of microglia: inhibition of infection and induction by IFNbeta. J Neuroimmunol, 2000; 110:230–239.

66.

Krathwohl

, and Kaiser

. HIV-1 promotes quiescence in human neural progenitor cells. J Infect Dis, 2004; 190:216–226.

67.

Krivine

, Force

, Servan

, et al. Measuring HIV-1 RNA and interferon-alpha in the cerebrospinal fluid of AIDS patients: insights into the pathogenesis of AIDS Dementia Complex. J Neurovirol, 1999; 5:500–506.

68.

Kruman

, Nath

, and Mattson

. HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol, 1998; 154:276–288.

69.

Lannuzel

, Lledo

, Lamghitnia

, et al. HIV-1 envelope proteins gp120 and gp160 potentiate NMDA [Ca2+]i increase, alter [Ca2+]i homeostasis and induce neurotoxicity in human embryonic neurons. Eur J Neurosci, 1995; 7:2285–2293.

70.

Lepelley

, Louis

, Sourisseau

, et al. Innate sensing of HIV-infected cells. PLoS Pathog, 2011; 7:e1001284.

71.

Lindl

, Marks

, Kolson

, et al. HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities. J Neuroimmune Pharmacol, 2010; 5:294–309.

72.

Liu

, Jones

, Hingtgen

, et al. Uptake of HIV-1 Tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands. Nat Med, 2000; 6:1380–1387.

73.

, Riley

, Babcock

, et al. Interferon (IFN) beta acts downstream of IFN-gamma-induced class II transactivator messenger RNA accumulation to block major histocompatibility complex class II gene expression and requires the 48-kD DNA-binding protein, ISGF3-gamma. J Exp Med, 1995; 182:1517–1525.

74.

Maggirwar

, Tong

, Ramirez

, et al. HIV-1 Tat-mediated activation of glycogen synthase kinase-3beta contributes to Tat-mediated neurotoxicity. J Neurochem, 1999; 73:578–586.

75.

Malim

, and Bieniasz

. HIV Restriction Factors and Mechanisms of Evasion. Cold Spring Harb Perspect Med, 2012; 2:a006940.

76.

Mandl

, Barry

, Vanderford

, et al. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med, 2008; 14:1077–1087.

77.

Markowitz

CE.

Interferon-beta: mechanism of action and dosing issues. Neurology, 2007; 68:S8–S11.

78.

Masliah

, Achim

, Ge

, et al. Spectrum of human immunodeficiency virus-associated neocortical damage. Ann Neurol, 1992; 32:321–329.

79.

Masliah

, Ge

, Achim

, et al. Selective neuronal vulnerability in HIV encephalitis. J Neuropathol Exp Neurol, 1992; 51:585–593.

80.

Masliah

, Roberts

, Langford

, et al. Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis. J Neuroimmunol, 2004; 157:163–175.

81.

Maung

, Hoefer

, Sanchez

, et al. CCR5 knockout prevents neuronal injury and behavioral impairment induced in a transgenic mouse model by a CXCR4-using HIV-1 glycoprotein 120. J Immunol, 2014; 193:1895–1910.

82.

McArthur

, Haughey

, Gartner

, et al. Human immunodeficiency virus-associated dementia: an evolving disease. J Neurovirol, 2003; 9:205–221.

83.

McManus

, Liu

, Hahn

, et al. Differential induction of chemokines in human microglia by type I and II interferons. Glia, 2000; 29:273–280.

84.

McMichael

, Borrow

, Tomaras

, et al. The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol, 2010; 10:11–23.

85.

Medders

, and Kaul

. Mitogen-activated protein kinase p38 in HIV infection and associated brain injury. J Neuroimmune Pharmacol, 2011; 6:202–215.

86.

Medders

, Sejbuk

, Maung

, et al. Activation of p38 MAPK is required in monocytic and neuronal cells for HIV glycoprotein 120-induced neurotoxicity. J Immunol, 2010; 185:4883–4895.

87.

Meucci

, Fatatis

, Simen

, et al. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc Natl Acad Sci U S A, 1998; 95:14500–14505.

88.

Meucci

, and Miller

. Gp120-induced neurotoxicity in hippocampal pyramidal neuron cultures: protective action of TGF-beta1. J Neurosci, 1996; 16:4080–4088.

89.

Meylan

, Guatelli

, Munis

, et al. Mechanisms for the inhibition of HIV replication by interferons-alpha, -beta, and -gamma in primary human macrophages. Virology, 1993; 193:138–148.

90.

Muller

, Steinhoff

, Reis

, et al. Functional role of type I and type II interferons in antiviral defense. Science, 1994; 264:1918–1921.

91.

Nath

Eradication of human immunodeficiency virus from brain reservoirs. J Neurovirol, 2015; 21:227–234.

92.

Navia

, Cho

, Petito

, et al. The AIDS dementia complex: II. Neuropathology. Ann Neurol, 1986; 19:525–535.

93.

Noel

, Jacquelin

, Huot

, et al. Interferon-associated therapies toward HIV control: the back and forth. Cytokine Growth Factor Rev, 2018; 40:99–112.

94.

Okamoto

, Kang

, Brechtel

, et al. HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cell-cycle withdrawal and G1 arrest. Cell Stem Cell, 2007; 1:230–236.

95.

Paul

, Ricour

, Sommereyns

, et al. Type I interferon response in the central nervous system. Biochimie, 2007; 89:770–778.

96.

Perrella

, Carreiri

, Perrella

, et al. Transforming growth factor beta-1 and interferon-alpha in the AIDS dementia complex (ADC): possible relationship with cerebral viral load?. Eur Cytokine Netw, 2001; 12:51–55.

97.

Persidsky

, Limoges

, McComb

, et al. Human immunodeficiency virus encephalitis in SCID mice. Am J Pathol, 1996; 149:1027–1053.

98.

Poli

, Biswas

, and Fauci

. Interferons in the pathogenesis and treatment of human immunodeficiency virus infection. Antiviral Res, 1994; 24:221–233.

99.

Potash

, Chao

, Bentsman

, et al. A mouse model for study of systemic HIV-1 infection, antiviral immune responses, and neuroinvasiveness. Proc Natl Acad Sci U S A, 2005; 102:3760–3765.

100.

Prokunina-Olsson

, Muchmore

, Tang

, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet, 2013; 45:164–171.

101.

Rho

, Wesselingh

, Glass

, et al. A potential role for interferon-alpha in the pathogenesis of HIV-associated dementia. Brain Behav Immun, 1995; 9:366–377.

102.

Rivero-Juarez

, Frias

, and Rivero

. Current views on interferon therapy for HIV. Expert Opin Biol Ther, 2016; 16:1135–1142.

103.

Ryman

, Klimstra

, Nguyen

, et al. Alpha/beta interferon protects adult mice from fatal Sindbis virus infection and is an important determinant of cell and tissue tropism. J Virol, 2000; 74:3366–3378.

104.

Sandler

, Bosinger

, Estes

, et al. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature, 2014; 511:601–605.

105.

Sandstrom

, Ranganath

, and Angel

. Impairment of the type I interferon response by HIV-1: potential targets for HIV eradication. Cytokine Growth Factor Rev, 2017; 37:1–16.

106.

Sas

, Bimonte-Nelson

, Smothers

, et al. Interferon-alpha causes neuronal dysfunction in encephalitis. J Neurosci, 2009; 29:3948–3955.

107.

Sas

, Bimonte-Nelson

, and Tyor

. Cognitive dysfunction in HIV encephalitic SCID mice correlates with levels of Interferon-alpha in the brain. AIDS, 2007; 21:2151–2159.

108.

Saylor

, Dickens

, Sacktor

, et al. HIV-associated neurocognitive disorder—pathogenesis and prospects for treatment. Nat Rev Neurol, 2016; 12:234–248.

109.

Schoggins

, Wilson

, Panis

, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature, 2011; 472:481–485.

110.

Schreiber

, and Piehler

. The molecular basis for functional plasticity in type I interferon signaling. Trends Immunol, 2015; 36:139–149.

111.

Schwartz

, and Major

. Neural progenitors and HIV-1-associated central nervous system disease in adults and children. Curr HIV Res, 2006; 4:319–327.

112.

Shi

, De

, He

, et al. Apoptosis induced by HIV-1 infection of the central nervous system. J Clin Invest, 1996; 98:1979–1990.

113.

Shirazi

, and Pitha

. Alpha interferon inhibits early stages of the human immunodeficiency virus type 1 replication cycle. J Virol, 1992; 66:1321–1328.

114.

Singh

, El-Hage

, Campbell

, et al. Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons. Neuroscience, 2005; 135:781–790.

115.

Speth

, Dierich

, and Sopper

. HIV-infection of the central nervous system: the tightrope walk of innate immunity. Mol Immunol, 2005; 42:213–228.

116.

Sugawara

, Thomas

, and Balagopal

HIV-1 infection and type 1 interferon: navigating through uncertain waters. AIDS Res Hum Retroviruses, 2018 [Epub ahead of print]; DOI: 10.1089/AID.2018.0161.

117.

Sui

, Fan

, Sniderhan

, et al. Inhibition of mixed lineage kinase 3 prevents HIV-1 Tat-mediated neurotoxicity and monocyte activation. J Immunol, 2006; 177:702–711.

118.

Takaoka

, and Yanai

. Interferon signalling network in innate defence. Cell Microbiol, 2006; 8:907–922.

119.

Teige

, Treschow

, Teige

, et al. IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis. J Immunol, 2003; 170:4776–4784.

120.

Thaney

, O'Neill

, Hoefer

, et al. IFNβ protects neurons from damage in a murine model of HIV-1 associated brain injury. Sci Rep, 2017; 7:46514.

121.

Toggas

, Masliah

, Rockenstein

, et al. Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature, 1994; 367:188–193.

122.

Utay

, and Douek

. Interferons and HIV infection: the good, the bad, and the ugly. Pathog Immun, 2016; 1:107–116.

123.

Valentin

, Trivedi

, Lu

, et al. CXCR4 mediates entry and productive infection of syncytia-inducing (X4) HIV-1 strains in primary macrophages. Virology, 2000; 269:294–304.

124.

Valentine

, Meyers

, Kling

, et al. Mood and cognitive side effects of interferon-alpha therapy. Semin Oncol, 1998; 25:39–47.

125.

van Heteren

, Rozenberg

, Aronica

, et al. Astrocytes produce interferon-alpha and CXCL10, but not IL-6 or CXCL8, in Aicardi-Goutieres syndrome. Glia, 2008; 56:568–578.

126.

Zaritsky

, Gama

, and Clements

. Canonical type I IFN signaling in simian immunodeficiency virus-infected macrophages is disrupted by astrocyte-secreted CCL2. J Immunol, 2012; 188:3876–3885.

127.

Zhen

, Rezek

, Youn

, et al. Targeting type I interferon-mediated activation restores immune function in chronic HIV infection. J Clin Invest, 2017; 127:260–268.