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. 2020 Feb 23;3:100054. doi: 10.1016/j.bbih.2020.100054

Prevention and treatment of HIV infection and cognitive disease in mice by innate immune responses

Baojun Dong 1, Alejandra Borjabad 1, Jennifer Kelschenbach 1, Wei Chao 1, David J Volsky 1, Mary Jane Potash 1,∗
PMCID: PMC7375446  NIHMSID: NIHMS1607539  PMID: 32699842

Abstract

HIV associated neurocognitive impairment afflicts roughly half of infected individuals on antiretroviral therapy. This disease currently has no treatment. We have previously shown that type I interferon is induced by and partially controls infection and neuropathogenesis in mice infected by chimeric HIV, EcoHIV. Here we investigate the intentional ligation of the pattern recognition receptor Toll-like receptor 3 (TLR3) by polyinosinic-polycytidylic acid (poly I:C) for its ability to prevent or control infection and associated cognitive disease in EcoHIV infected mice. We tested topical, injection, and intranasal application of poly I:C in mice during primary infection through injection or sexual transmission or in established infection. We measured different forms of HIV DNA and RNA in tissues by real-time PCR and the development of HIV-associated cognitive disease by the radial arm water maze behavioral test. Our results indicate that poly I:C blocks primary EcoHIV infection of mice prior to reverse transcription and reduces established EcoHIV infection. Prevention or control of viral replication by poly I:C prevents or reverses HIV associated cognitive disease in mice. These findings indicate that poly I:C or other innate immune agonists may be useful in control of HIV cognitive disease.

Keywords: HIV, Mouse model, Innate immunity, Cognitive disease

1. Introduction

HIV infection can largely be controlled by existing drugs that target the pol proteins: reverse transcriptase, protease, and integrase (Broder, 2010; Volberding and Deeks, 2010). This generally effective therapy does not affect virus present in macrophages that survive productive infection or latently infected T cells (Richman et al., 2009). Sadly, about half of those infected people on combination antiretrovirals develop cognitive disease that persists for life and worsens with age (Harezlak et al., 2011; Robertson et al., 2007). The continued expression of HIV Tat and gp120, among other viral proteins, in chronically infected cells in the brain is considered to be one driver of neuropathogenesis (Carroll and Brew, 2017; Saylor et al., 2016). Interventions that target HIV expression itself are sorely needed.

Host antiviral responses control and can eliminate many viral infections by targeting cells that express viral proteins or nucleic acid. This has been demonstrated in HIV infection or exposure in humans at the level of adaptive immune responses, chiefly T cell responses (Perreau et al., 2013; Rowland-Jones et al., 1999). In addition, the major innate immune effector, Type I interferon (IFN), appears to pose a partially effective block to HIV replication as illustrated in the evolution of viral genes that antagonize IFN-stimulated proteins, APOBEC3G, tetherin, and Serin3/5 (Dubé et al., 2010; Malim, 2009; Usami et al., 2015). The transmitted-founder HIV species that establish infection after sexual transmission are selected, in part, for IFN-resistance (Fenton-May et al., 2013; Parrish et al., 2013). Type I IFN induced early in SIV infection arrests viral infection and transcription in the brain (Barber et al., 2006; Carnathan et al., 2018) and in analogous studies we have shown that knockout of the Type I interferon receptor in mice permits greater neuropathogenesis caused by the chimeric HIV, EcoHIV, than that observed in wildtype mice (He et al., 2014).

Innate immunity is initiated by ligation of any of several pattern recognition receptors, the first family identified being Toll-like receptors (TLR) mimicking Drosophila receptors that mount responses against bacteria and virus components and limit infection (Valanne et al., 2011). A synthetic TLR3 ligand, polyinosinic-polycytidylic acid (poly I:C), can prevent some viral infections including hepatitis B and herpes simplex virus type 1 in human beings (Boivin et al., 2008; Martinez et al., 1980; Wu et al., 2014). Multiple studies, including our own, have shown that activation of various TLR on human cells in culture and the resulting Type I IFN responses can prevent HIV infection (Tsang et al., 2009; Wang et al., 2011; Zhou et al., 2010). Such antiviral responses span the viral life cycle through DNA synthesis, integration, transcription, and virion export (Urbano VDe Crignis and Re, 2018). Clinical trials indicate that treatment with Type I IFN arrests HIV transcription in T cells in infected people (Morón-López et al., 2016). These findings raise the possibility that induction of innate immune responses can silence HIV expression and its associated cognitive disease, as we test here.

To carry out these studies we exploited our system of EcoHIV infection of conventional mice. This HIV has a replacement of gp120 by ecotropic murine leukemia virus envelope to enter mouse cells but otherwise employs all HIV genes (Potash et al., 2005). EcoHIV infects CD4 positive T cells and F4/80 positive macrophages systemically as well as brain microglia. After an early peak its replication is controlled, at least in part, by adaptive immune responses but chronically infected mice maintain some virus expression in macrophages and demonstrate impaired learning analogous to HIV-infected people on effective antiretroviral treatment (Potash et al., 2005; Gu et al., 2018; Kelschenbach et al., 2019). The continued expression of HIV proteins in EcoHIV infected mice has allowed evaluation of vaccines to prevent infection and drugs to treat infection (Hadas et al., 2007; Im et al., 2011; Liu et al., 2018; Roshorm et al., 2009, 2012; Saini et al., 2007; Tomusange et al., 2016a, 2016b) and the persistence of HIV-associated neurocognitive impairment (HIV–NCI) in this model has allowed studies of some of the routes to pathogenesis and NCI treatment (He et al., 2014; Kelschenbach et al., 2019; Bertrand et al., 2019; Jones et al., 2016; Kim et al., 2019; Nedelcovych et al., 2017, 2019; Olson et al., 2018). Here we employ this experimental infection to test the activity of poly I:C in different administration formats on HIV infection by various routes and its ability to reverse established infection and cognitive disease.

2. Results

Previous studies indicate that transmitted-founder HIV clones that establish infection in humans after sexual transmission are selectively Type I IFN-resistant (Fenton-May et al., 2013; Parrish et al., 2013). Using EcoHIV infected male mice mated to uninfected females, we developed a model of genuine HIV sexual transmission (Hadas et al., 2013). In other studies we found that intracranial injection of EcoHIV in Type I IFN receptor knock-out (IFNR-KO) mice permits greater virus expression than in wildtype mice (He et al., 2014). Taking these findings together we reasoned that establishment of EcoHIV infection in mice by sexual transmission may be sensitive to Type I IFN signaling. To test this prediction, C57BL/6 females and isogenic IFNR-KO females were allowed to mate with EcoHIV-infected male nude mice; one week later all females were euthanized with inguinal lymph nodes, spleen, and peritoneal macrophages (PM) collected to measure virus burden (Fig. 1). Fig. 1 shows that Type I IFN signaling clearly reduces virus EcoHIV sexual transmission; in each compartment assayed IFNR-KO mice had significantly more viral DNA or RNA. These observations, like our previous study in IFNR-KO mice (He et al., 2014), indicate that EcoHIV itself induces a protective IFN response analogous to the response observed in humans for selection of IFN-resistant virus (Fenton-May et al., 2013; Parrish et al., 2013). To learn if an exogenous ligand activating innate responses also prevents HIV transmission, female C57BL/6 mice were treated on vaginal surfaces with the TLR3 ligand, poly I:C, or phosphate buffered saline (PBS) prior to mating with EcoHIV-infected nude males. Females were euthanized after one week and EcoHIV gag RNA was measured in PM (Fig. 1D). In this pilot study a single topical application of poly I:C largely prevented EcoHIV sexual transmission.

Fig. 1.

Fig. 1

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Innate immune responses prevent EcoHIV sexual transmission. A-C. EcoHIV burdens were measured in IFNR-KO mice one week after virus sexual transmission. A. EcoHIV gag DNA in inguinal lymph nodes. B. EcoHIV gag DNA in spleen. C. EcoHIV gag RNA in peritoneal cells. D. EcoHIV gag RNA in peritoneal cells was measured in C57BL/6 mice treated topically with poly I:C or PBS one week after virus sexual transmission. Each symbol represents a single mouse and the horizontal bars indicate the means. ∗p ​< ​0.05, ∗∗p ​< ​0.01.

To probe the efficacy of induced systemic innate responses to prevent HIV infection, male mice were poly I:C treated and EcoHIV infected by IP injection, with poly I:C preceding infection by 12 ​h. Groups of mice were euthanized 2 or 19 days later for measurement of tissue virus burden (Fig. 2). Injection of poly I:C potently inhibited EcoHIV infection in mice preventing both DNA and RNA synthesis. PBS-treated mice show a 40-fold increase in genomic RNA in macrophages over time but virus spread was completely blocked in the poly I:C group. The findings in Figs. 1D and 2 indicate that the protective innate antiviral response induced by HIV can be augmented by the response to a TLR3 ligand.

Fig. 2.

Fig. 2

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Systemic poly I:C prevents EcoHIV infection. EcoHIV burdens in mice were measured 2 (panel A–B) or 19 days (panel C) after infection and poly I:C treatment by injection. A. EcoHIV gag DNA in spleen. B–C. EcoHIV vif RNA in peritoneal cells. ∗∗p ​< ​0.01, ∗∗∗p ​< ​0.001.

We reported that prophylaxis with antiretrovirals prevented EcoHIV infection and the development of HIV–NCI in mice (Gu et al., 2018). To test whether virus inhibited by poly I:C retains the ability to cause disease, the experiment shown in Fig. 2 was repeated with additional poly I:C injections weekly after EcoHIV infection. Three weeks after infection, mice were tested for learning and memory in the radial arm water maze (RAWM) test (Fig. 3). EcoHIV-infected mice showed a highly significant defect in learning as indicated in the persistence of 3–4 errors and roughly 50 ​s in locating the hidden platform at the point when uninfected mice displayed fewer than 1 error and only 15 ​s for the task (Fig. 3A-B). In distinct contrast, EcoHIV-infected mice treated with poly I:C were indistinguishable from uninfected mice in learning. Poly I:C itself had no effect in the RAWM. Mice in all groups were similarly able to find and swim to a visible platform indicating no defects in motor function, vision, or intention (Fig. 3C). This study illustrates that prevention of EcoHIV infection by induction of an innate immune response likewise prevents HIV brain disease in mice.

Fig. 3.

Fig. 3

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Systemic poly I:C prevents the development of EcoHIV associated cognitive impairment. EcoHIV infected and uninfected mice treated with poly I:C or PBS were tested for memory and learning in RAWM. A. Errors in finding the hidden platform. B. Time to find the hidden platform. C. Errors in finding the visible platform. EcoHIV vs uninfected ∗∗p ​< ​0.01, ∗∗∗p ​< ​0.001. EcoHIV vs EcoHIV ​+ ​poly I:C ​+ ​p ​< ​0.05, ++ p ​< ​0.01, +++ p ​< ​0.001.

The value and the complexity of innate responses are their breadth. To begin to identify phases in the EcoHIV life cycle affected by Type I IFN responses, we first tested splenic virus burden 24 ​h after EcoHIV infection of wildtype and IFNR-KO mice, a timepoint in which DNA synthesis and integration are the major ongoing processes (Fig. 4). EcoHIV DNA is abundant in spleen in both mouse strains but is significantly greater in IFNR-KO mice (Fig. 4A). Likewise, viral RNA is increased in the absence of IFN responses, a natural consequence of the greater amount of viral DNA available for transcription. This observation indicates that the HIV-induced-IFN response acts at early phases of replication. To extend this analysis to intentional induction of innate responses, BALB/c mice were treated with poly I:C or PBS 6 ​h prior to EcoHIV infection by intravenous injection; this infection route was chosen to minimize carryover from the viral stock into the peritoneal cavity and allow better analysis of the responses of macrophages, a major innate immune effector cell (Fig. 4). The innate response to poly I:C coupled with the response to EcoHIV itself blocked reverse transcription, and viral DNA burden was significantly reduced in peritoneal cells (Fig. 4B). Transcription was reduced below the limit of detection in spleen (Fig. 4C). To complete the early phase life cycle analysis, C57BL/6 mice were pretreated with poly I:C, infected by EcoHIV, and then treated daily with poly I:C for five days prior to euthanasia and collection of spleen and peritoneal cells. We then performed a two-step QPCR method as described (Gu et al., 2018) to quantify integrated viral DNA. As expected from its effects on reverse transcription, poly I:C significantly reduced integrants in peritoneal cells and reduced EcoHIV integrants in spleen below the level of detection, roughly 20 copies per 106 ​cells (Fig. 4D-E). At a minimum, poly I:C prevents reverse transcription by EcoHIV and also impairs nuclear entry of viral DNA or its integration; unambiguous quantitation of its effects upon transcription requires other analysis.

Fig. 4.

Fig. 4

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Prevention of EcoHIV replication prior to reverse transcription by responses to IFN or poly I:C. A. EcoHIV gag DNA in spleen (left columns) and vif RNA in peritoneal cells (right columns) 24 ​h after IP infection of wildtype or IFNR-KO mice. B–C. EcoHIV burden in BALB/c mice 48h after infection and PBS or poly I:C treatment. B. gag DNA in peritoneal cells. C. gag RNA in spleen. D-E. Integrated EcoHIV DNA five days after EcoHIV infection and daily poly I:C treatment. D. peritoneal cells. E. spleen. ∗p ​< ​0.05, ∗∗∗p ​< ​0.001.

Innate immune activation results in rapid and often short-lived responses. To parse the kinetics of induction of antiviral genes by EcoHIV and poly I:C we employed mouse bone marrow-derived macrophages in culture and measured relevant transcripts by real-time PCR. The values shown represent fold induction compared to control cultures assayed at 0 time (Fig. 5). Most of the transcripts monitored were induced by both EcoHIV and poly I:C but it is notable that IFN-β preceded other factors with poly I:C and virus exposure. In addition, the host restriction factor, Apobec3, was induced to higher levels in infected cells with poly I:C. The inflammatory cytokines, TNF-α and IL-1β, and the chemokine MCP-1 were highly induced in all systems compared to controls.

Fig. 5.

Fig. 5

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Heatmap visualization of gene expression. Quantitative PCR was performed to evaluate expression of antiviral genes. Expression was normalized by the housekeeping gene GAPDH. Relative expression or fold changes were calculated versus a control 0h time point and the direction and extent of the regulation is represented in the heatmap by different colors. Gray regions show no significant differences from control. Other levels of statistical significance: ∗p ​< ​0.05, #p ​< ​0.005, γ ​< ​0.0005, & p ​< ​0.00005, $ p ​< ​0.000005, NS not significant. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Our findings show that poly I:C blocks HIV replication prior to reverse transcription but its reported activity later in infection depends upon the system tested (Tsang et al., 2009; Swaminathan et al., 2012; Trapp et al., 2009). To determine whether poly I:C affects virus expression or activity in established infection, mice were treated with poly I:C by IP injection thrice weekly from 21-35 days after EcoHIV infection; RAWM tests were performed day 28–34 and euthanasia and tissue collection day 35 after infection (Fig. 6). Poly I:C treatment significantly reduced EcoHIV DNA and RNA burden in lymphocytes and viral RNA in macrophages. Having demonstrated the inhibition of chronic EcoHIV infection by poly I:C, we probed whether it also affects ongoing cognitive disease. Fig. 6 illustrates that five weeks after EcoHIV infection, mice suffer impaired learning and memory and that this defect was reversed by poly I:C treatment. Poly I:C itself had no effects upon performance in the RAWM. Our findings suggest that inhibition of chronic HIV expression and spread allows recovery of cognitive function.

Fig. 6.

Fig. 6

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Poly I:C treatment of mice chronically infected by EcoHIV reduces virus burden and reverses cognitive disease. A-E Mice were treated by IP injection of poly I:C, tested in RAWM, and euthanized for tissue collection. A-B. gag burden in spleen A: DNA, B: RNA. C. vif RNA burden in peritoneal cells. ∗p ​< ​0.05, ∗∗p ​< ​0.01, ∗∗∗p ​< ​0.001 D. Errors in finding the hidden platform. E. Time to find the hidden platform. EcoHIV vs uninfected ∗ p ​< ​0.05. EcoHIV vs EcoHIV ​+ ​poly I:C ​+ ​p ​< ​0.05.

A general concern in the use of TLR ligands for HIV treatment is the risk of immune activation as observed in advanced HIV disease when the gut mucosa leaks, allowing bacterial translocation and systemic endotoxin contamination (Klatt et al., 2013). Our working protocol of intermittent poly I:C administration was designed to limit systemic immune activation. We tested the outcome of this approach by repeating the experiment shown in Fig. 6, omitting RAWM tests, and harvested peritoneal macrophages 35 days after infection to measure intracellular chemokines and inflammatory cytokines. Of 45 proteins tested only 15 were detected and expression of none of them was altered by poly I:C treatment. These were CCL5, CCL11, CCL12, CCL21, CX3CL1, CXCL1, CXCL2, CXCL9, IFN-β1, IL-2, IL-9, IL-10, IL-15, IL-16, IP-10, and KC. The concentrations detected in macrophage lysates and a list of the undetected proteins are found in Supplemental Information.

IP injection is not a preferred route for drug administration to human beings. However, pharmaceuticals can be preferentially targeted to the brain and mucosal immune system through intranasal (IN) application and this route is used for drug delivery in people (Calzas and Chevalier, 2019; Hanson and Frey, 2007). Moreover, we have shown that IN administration of insulin, as used for treatment of some cognitive disorders (Freiherr et al., 2013; Novak et al., 2014) reversed NCI in EcoHIV-infected mice (Kim et al., 2019). To determine whether administration of poly I:C through a route relevant to clinical use would also effectively treat EcoHIV infection and disease in mice we repeated the experiment shown in Fig. 6 but replaced IP injection by IN application of poly I:C to mice while awake (Fig. 7). Poly I:C significantly inhibited EcoHIV replication in mouse macrophages and lymphocytes. The compound itself administered IN did not affect behavior but it restored cognitive function to infected mice assayed in the RAWM (Fig. 7). The results presented here recommend further evaluation of TLR ligands for eventual treatment of established HIV infection and mild NCI in patients.

Fig. 7.

Fig. 7

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Intranasal poly I:C treatment of mice chronically infected by EcoHIV reduces virus burden and reverses cognitive disease. A-F Mice were treated by intranasal application of poly I:C, tested in RAWM, and euthanized for tissue collection. A-B. gag burden in spleen A: DNA, B: RNA. C-D. RNA burden in peritoneal cells. C: vif, D: gag. ∗p ​< ​0.05, ∗∗p ​< ​0.01, ∗∗∗p ​< ​0.001 ​E. Errors in finding the hidden platform. F. Time to find the hidden platform. EcoHIV vs uninfected ∗ p ​< ​0.05. EcoHIV vs EcoHIV ​+ ​poly I:C ​+ ​p ​< ​0.05.

3. Discussion

Our findings indicate that innate immune responses to poly I:C can both prevent and control established HIV infection and the cognitive disease it causes in mice. Among our new observations that may have particular relevance to HIV infection of humans are the ability of topical poly I:C to prevent EcoHIV sexual transmission and the efficacy of IN administration of poly I:C to reverse cognitive defects in chronically infected mice.

EcoHIV infection of wildtype mice compared to IFNR-KO mice was employed to illustrate two points: virus infection itself induces an immediate, innate response and this antiviral response is partially protective. When competent for IFN signaling, mice restrict EcoHIV infection by sexual transmission with higher virus burdens obtained in IFNR-KO mice; this mechanism is imposed on the first day of virus exposure (Fig. 1). Having demonstrated the scope of the endogenous response, we amplified it by adding a TLR agonist yielding a highly effective block (Fig. 1, Fig. 2). It is noteworthy that infection by both injection and sexual transmission was affected suggesting that cells in the peritoneal cavity and the reproductive mucosa mount protective antiviral responses (Fig. 1, Fig. 2). Innate antiviral responses can act throughout virus replication (Urbano VDe Crignis and Re, 2018) but the first phase blocked by poly I:C in mice precedes reverse transcription (Fig. 4). This finding echoes our report of HIV infection of human cells in culture, where the TLR ligand response was seen after efficient virus entry and before DNA synthesis (Wang et al., 2011).

EcoHIV infection of mice not only reproduces much of the life cycle of HIV in vivo but it also provides a model of HIV–NCI. The virus replicates in macrophages and microglia as well as T cells and establishes an active reservoir in macrophages refractory to antiretroviral treatment (Potash et al., 2005; Gu et al., 2018; Kelschenbach et al., 2019). Infection in the brain reduces expression of certain synaptic function genes, reduces synaptic activity in generating long term potentiation in hippocampal slices tested ex vivo, and drives dendritic dearborization in the hippocampus but not neuronal death (Kelschenbach et al., 2019; Kim et al., 2019). As shown in RAWM and fear conditioning behavioral tests, EcoHIV impairs visuospatial learning and working, contextual, and associative fear memory (Gu et al., 2018; Kelschenbach et al., 2019; Kim et al., 2019). Here we link these injuries to viral replication at the levels of both prophylaxis of primary infection and treatment of chronic infection. Poly I:C prevention of EcoHIV infection also prevented its associated cognitive disease but the compound itself did not affect behavior (Fig. 3). This finding is consistent with our previous report that virologically effective antiretroviral therapy also prevents HIV–NCI in mice (Gu et al., 2018). However, antiretroviral treatment failed to alter EcoHIV burdens or HIV–NCI in chronically infected mice (Gu et al., 2018) while poly I:C was effective at both levels (Fig. 6, Fig. 7). These results suggest that HIV–NCI in mice is sensitive to treatment at the transcriptional level, presumably in virus expressing macrophage reservoirs. Previous studies indicate that HIV persists in an expressed state in the central nervous system of HIV-infected persons on effective antiretroviral therapy (Heaton et al., 2011; Gelman et al., 2013), likely contributing to the observed chronic cognitive disease they suffer. There is currently no treatment for HIV–NCI and multiple observations show that the disease worsens with age (Brouillette et al., 2016; Goodkin et al., 2017), overlapping and potentially synergizing with cognitive aging and age-related neurological diseases (Hategan et al., 2017, 2019).

The effects of poly I:C just prior to and during virus infection extended to extensive changes in cellular gene expression (Fig. 5). A suite of IFN related genes was activated in several systems but relevant to HIV infection and control are the host restriction factor Apobec3 and host integration co-factor LEDGF (Engelman and Singh, 2018). Given the imposition of blocks to EcoHIV replication before reverse transcription and integration are completed, LEDGF may be important in this response. Recent studies indicate the significance of DNA sensing in the endogenous innate response to HIV and implicate cGas (Siddiqui et al., 2019). In addition, key inflammatory genes TNF-α and IL-1β were highly induced in bone marrow macrophages by both EcoHIV and poly I:C. These genes respond to NFκB promotion of transcription, a pro-inflammatory signaling series activated by TLR3 ligation (Funami et al., 2008) separable from the Stat-1 pathway. Further studies will be needed to identify the poly I:C induced genes that function to block infection.

Cognitive disease accompanying established EcoHIV infection is not affected by reverse transcription or integration inhibitors (Gu et al., 2018) but the ability of poly I:C to inhibit late phases of virus replication (Sang et al., 2014) suggested that it can treat HIV–NCI. As shown in Fig. 6, intermittent poly I:C injection reduced virus expression and reversed existing HIV–NCI in mice. We also limited systemic exposure to poly I:C by IN administration and found that it preserved its antiviral and neuroprotective function (Fig. 7). A safety evaluation of injected poly I:C conducted five weeks after infection revealed that it did not affect inflammatory cytokine or chemokine proteins expressed by peritoneal macrophages indicating that excessive immune activation (Klatt et al., 2013) does not occur, possibly because exposure to the TLR agonist was limited.

The question arises how this experimental treatment in mice can be translated to potential clinical applications. It is fascinating to note that HIV infection in human beings is already subject to control by TLR3 agonists, presumably present in HIV, as revealed in genetic studies. A polymorphism in the TLR3 gene is associated with a reduced frequency of HIV transmission during intravenous drug use in multiple cohorts (Huik et al., 2013; Sironi et al., 2012). Other human studies indicate that IFN responses in reproductive mucosa limit sexual transmission of HIV (Nazli et al., 2019; Shey et al., 2016) recommending evaluation of poly I:C or other innate immune triggers to enhance this response (Fig. 1) and reduce or prevent this major route of infection. Poly I:C is already investigated clinically for various purposes. A modified poly I:C has been shown to be safe in Phase I trials in HIV-infected people on antiretroviral therapy (Saxena et al., 2019). Also in clinical trial, a proprietary poly I:C vaccine administered IN was found to be effective in prevention of infection by rhinovirus and influenza A (Malcolm et al., 2018). IN administration is preferred for some vaccines, eliciting better responses than intramuscular injection in some cases (Hoft et al., 2017). The IN route is also employed to target interventions to the brain (Hanson and Frey, 2007). IN insulin is used for treatment of certain cognitive disorders (Freiherr et al., 2013; Novak et al., 2014) and we found it effective against HIV–NCI in mice (Kim et al., 2019), an approach currently in trials in humans in NCT03081117.

In conclusion, poly I:C can prevent experimental EcoHIV transmission and control established infection in mice. Once EcoHIV infection is silenced, its impairment of cognitive function is reversed. Interventions that control HIV expression in chronically infected cells, like poly I:C, may help to alleviate progression of HIV–NCI with age and address the growing public health concern in aging HIV-infected individuals on antiretroviral therapy (Brown et al., 2014).

4. Materials and methods

Poly I:C source and administration. Poly I:C was purchased from Sigma-Aldrich, catalogue number P1530. It was prepared as a solution in PBS for all uses with a final dose of 50 ​μg per mouse administration or 5 ​μg per ml in culture. For topical administration, it was applied to outer vaginal surfaces of lightly sedated supine females in a volume of 10–20 ​μl. Mouse hindquarters were slightly elevated for 15–30 ​min to allow liquid to enter the vaginal cavity. For intranasal administration it was applied to both nostrils of awake mice as described (Kim et al., 2019). Otherwise it was injected IP.

Mice. All animal studies were conducted with the approval of the Icahn School of Medicine Institutional Animal Care and Use Committee, protocol IACUC-2014-0124, and in full compliance with NIH guidelines. Adult male and female C57BL/6 mice, male BALB/c and nude C57BL/6 mice, and male and female IFNR-KO mice on a C57BL/6 background were purchased from Jackson Labs. Except where specified in the text, studies were conducted in male C57BL/6 mice.

Virus preparation and infection. EcoHIV/NDK was propagated and administered by IP or IV injection to mice as described (Potash et al., 2005). For EcoHIV sexual transmission, individual female mice were housed overnight with an individual EcoHIV-infected male nude mouse and then housed separately as described (Hadas et al., 2013).

Cells. Bone marrow was obtained from adult mouse femurs and BMM were differentiated and infected as described (Gu et al., 2018).

Tissue isolation and measurement of virus burden. At times indicated in the text, mice were euthanized by carbon dioxide asphyxiation and spleen, peritoneal cells, and inguinal lymph nodes collected. Tissues and cells were prepared and subjected to quantitative PCR for measurement of EcoHIV gag DNA and RNA and vif RNA as described (Hadas et al., 2007). Measurement of integrated EcoHIV DNA was conducted as described (Gu et al., 2018).

Cellular gene expression. Peritoneal cells or BMM were harvested at the times indicated in the text and subjected to quantitative PCR as described (He et al., 2014; Kim et al., 2019).

RAWM. At times indicated in the text, the RAWM was conducted as described (Gu et al., 2018) with the exception that C57BL/6 and not 129X1 mice were used here and uninfected C57BL/6 mice achieved 1 or no errors after 5–7 days of testing at which point the assay was completed.

Declaration of competing interest

The authors of the manuscript, “Prevention and treatment of HIV infection and cognitive disease in mice by innate immune responses”, Dong, Borjabad, Kelschenbach, Chao, Volsky, and Potash declare they have no conflicts of interest regarding any element of this manuscript.

Acknowledgments

The authors wish to thank Ilene Totillo for expert manuscript preparation and our laboratory members for support and good nature. This work was supported by US National Institutes of Health grants R01 NS 94146 (MJP), R01 MH 104145 (DJV), and R01 DA 37611 (DJV).

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.bbih.2020.100054.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1
mmc1.docx (15.3KB, docx)

References

  1. Barber S.A., Gama L., Dudaronek J.M., Voelker T., Tarwater P.M., Clements J.E. 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. doi: 10.1086/500983. [DOI] [PubMed] [Google Scholar]
  2. Bertrand L., Méroth F., Tournebize M., Leda A.R., Sun E., Toborek M. Targeting the HIV-infected brain to improve ischemic stroke outcome. Nat. Commun. 2019;10:2009. doi: 10.1038/s41467-019-10046-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boivin N., Sergerie Y., Rivest S., Boivin G. Effect of pretreatment with toll-like receptor agonists in a mouse model of herpes simplex virus type 1 encephalitis. J. Infect. Dis. 2008;198:664–672. doi: 10.1086/590671. [DOI] [PubMed] [Google Scholar]
  4. Broder S. The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antivir. Res. 2010;85:1–18. doi: 10.1016/j.antiviral.2009.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brouillette M.-J., Yuen T., Fellows L.K., Cysique L.A., Heaton R.K., Mayo N.E. Identifying neurocognitive decline at 36 months among HIV-positive participants in the CHARTER Cohort using group-based trajectory analysis. PloS One. 2016;11 doi: 10.1371/journal.pone.0155766. e0155766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brown L.A.M., Scarola J., Smith A.J., Sanberg P.R., Tan J., Giunta B. The role of tau protein in HIV-associated neurocognitive disorders. Mol. Neurodegener. 2014;9:40. doi: 10.1186/1750-1326-9-40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Calzas C., Chevalier C. Innovative mucosal vaccine formulations against Influenza A virus infections. Front. Immunol. 2019;10:1605. doi: 10.3389/fimmu.2019.01605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carnathan D., Lawson B., Yu J., Patel K., Billingsley J.M., Tharp G.K., Delmas O.M., Dawoud R., Wilkinson P., Nicolette C., Cameron M.J., Sekaly R.P., Bosinger S.E., Silvestri G., Vanderford T.H. Reduced chronic lymphocyte activation following interferon alpha blockade during the acute phase of simian immunodeficiency virus infection in rhesus macaques. J. Virol. 2018;92 doi: 10.1128/JVI.01760-17. e01760-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Carroll A., Brew B. HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment. F1000Res. 2017;6:312. doi: 10.12688/f1000research.10651.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dubé M., Bego M.G., Paquay C., Cohen É.A. Modulation of HIV-1-host interaction: role of the Vpu accessory protein. Retrovirology. 2010;7:114. doi: 10.1186/1742-4690-7-114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Engelman A.N., Singh P.K. Cellular and molecular mechanisms of HIV-1 integration targeting. Cell. Mol. Life Sci. 2018;75:2491–2507. doi: 10.1007/s00018-018-2772-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fenton-May A.E., Dibben O., Emmerich T., Ding H., Pfafferott K., Aasa-Chapman M.M., Pellegrino P., Williams I., Cohen M.S., Gao F., Shaw G.M., Hahn B.H., Ochsenbauer C., Kappes J.C., Borrow P. Relative resistance of HIV-1 founder viruses to control by interferon-α. Retrovirology. 2013;10:146. doi: 10.1186/1742-4690-10-146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Freiherr J., Hallschmid M., Frey W.H., 2nd, Brünner Y.F., Chapman C.D., Hölscher C., Craft S., De Felice F.G., Benedict C. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs. 2013;27:505–514. doi: 10.1007/s40263-013-0076-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Funami K., Sasai M., Oshiumi H., Seya T., Matsumoto M. Homo-oligomerization is essential for Toll/interleukin-1 receptor domain-containing adaptor molecule-1-mediated NF-kappaB and interferon regulatory factor-3 activation. J. Biol. Chem. 2008;283:18283–18291. doi: 10.1074/jbc.M801013200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gelman B.B., Lisinicchia J.G., Morgello S., Masliah E., Commins D., Achim C.L., Fox H.S., Kolson D.L., Grant I., Singer E., Yiannoutsos C.T., Sherman S., Gensler G., Moore D.J., Chen T., Soukup V.M. Neurovirological correlation with HIV-associated neurocognitive disorders and encephalitis in a HAART-era cohort. J. Acquir. Immune Defic. Syndr. 2013;62:487–495. doi: 10.1097/QAI.0b013e31827f1bdb. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goodkin K., Miller E.N., Cox C., Reynolds S., Becker J.T., Martin E., Selnes O.A., Ostrow D.G., Sacktor N.C., Study M.A.C. Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study. Lancet HIV. 2017;4:e411–e422. doi: 10.1016/S2352-3018(17)30098-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gu C.J., Borjabad A., Hadas E., Kelschenbach J., Kim B.H., Chao W., Arancio O., Suh J., Polsky B., McMillan J., Edagwa B., Gendelman H.E., Potash M.J., Volsky D.J. EcoHIV infection of mice establishes latent viral reservoirs in T cells and active viral reservoirs in macrophages that are sufficient for induction of neurocognitive impairment. PLoS Pathog. 2018;14 doi: 10.1371/journal.ppat.1007061. e1007061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hadas E., Borjabad A., Chao W., Saini M., Ichiyama K., Potash M.J., Volsky D.J. Testing antiretroviral drug efficacy in conventional mice infected with chimeric HIV-1. AIDS. 2007;21:905–909. doi: 10.1097/QAD.0b013e3281574549. [DOI] [PubMed] [Google Scholar]
  19. Hadas E., Chao W., He H., Saini M., Daley E., Saifuddin M., Bentsman G., Ganz E., Volsky D.J., Potash M.J. Transmission of chimeric HIV by mating in conventional mice: prevention by pre-exposure antiretroviral therapy and reduced susceptibility during estrus. Dis Model Mech. 2013;6:1292–1298. doi: 10.1242/dmm.012617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hanson L.R., Frey W.H., 2nd Strategies for intranasal delivery of therapeutics for the prevention and treatment of neuroAIDS. J. Neuroimmune Pharmacol. 2007;2:81–86. doi: 10.1007/s11481-006-9039-x. [DOI] [PubMed] [Google Scholar]
  21. Harezlak J., Buchthal S., Taylor M., Schifitto G., Zhong J., Daar E., Alger J., Singer E., Campbell T., Yiannoutsos C., Cohen R., Navia B. Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS. 2011;25:625–633. doi: 10.1097/QAD.0b013e3283427da7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hategan A., Bianchet M.A., Steiner J., Karnaukhova E., Masliah E., Fields A., Lee M.-H., Dickens A.M., Haughey N., Dimitriadis E.K., Nath A. HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity. Nat. Struct. Mol. Biol. 2017;24:379–386. doi: 10.1038/nsmb.3379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hategan A., Masliah E., Nath A. HIV and Alzheimer’s disease: complex interactions of HIV-Tat with amyloid β peptide and Tau protein. J. Neurovirol. 2019 doi: 10.1007/s13365-019-00736-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. He H., Sharer L.R., Chao W., Gu C.J., Borjabad A., Hadas E., Kelschenbach J., Ichiyama K., Do M., Potash M.J., Volsky D.J. 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. doi: 10.1097/NEN.0000000000000026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Heaton R.K., Franklin D.R., Ellis R.J., McCutchan J.A., Letendre S.L., Leblanc S., Corkran S.H., Duarte N.A., Clifford D.B., Woods S.P., Collier A.C., Marra C.M., Morgello S., Mindt M.R., Taylor M.J., Marcotte T.D., Atkinson J.H., Wolfson T., Gelman B.B., McArthur J.C., Simpson D.M., Abramson I., Gamst A., Fennema-Notestine C., Jernigan T.L., Wong J., Grant I. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J. Neurovirol. 2011;17:3–16. doi: 10.1007/s13365-010-0006-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hoft D.F., Lottenbach K.R., Blazevic A., Turan A., Blevins T.P., Pacatte T.P., Yu Y., Mitchell M.C., Hoft S.G., Belshe R.B. Comparisons of the humoral and cellular immune responses induced by live attenuated influenza vaccine and inactivated influenza vaccine in adults. Clin. Vaccine Immunol. 2017;24:e00414–e00416. doi: 10.1128/CVI.00414-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Huik K., Avi R., Pauskar M., Kallas E., Jõgeda E.L., Karki T., Marsh K., Des Jarlais D., Uusküla A., Lutsar I. Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users. Infect. Genet. Evol. 2013;20:78–82. doi: 10.1016/j.meegid.2013.08.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Im E.-J., Hong J.P., Roshorm Y., Bridgeman A., Létourneau S., Liljeström P., Potash M.J., Volsky D.J., McMichael A.J., Hanke T. Protective efficacy of serially up-ranked subdominant CD8 T cell epitopes against virus challenges. PLoS Pathog. 2011;7 doi: 10.1371/journal.ppat.1002041. e1002041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jones L.D., Jackson J.W., Maggirwar S.B. Modeling HIV-1 induced neuroinflammation in mice: role of platelets in mediating blood-brain barrier dysfunction. PloS One. 2016;11 doi: 10.1371/journal.pone.0151702. e0151702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kelschenbach J., He H., Kim B.H., Borjabad A., Gu C.J., Chao W., Do M., Sharer L.R., Zhang H., Arancio O., Potash M.J., Volsky D.J. Efficient expression of HIV in immunocompetent mouse brain reveals a novel nonneurotoxic viral function in hippocampal synaptodendritic injury and memory impairment. mBio. 2019;10 doi: 10.1128/mBio.00591-19. e00591-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kim B.-H., Kelschenbach J., Borjabad A., Hadas E., He H., Potash M.J., Nedelcovych M.T., Rais R., Haughey N.J., McArthur J.C., Slusher B.S., Volsky D.J. Intranasal insulin therapy reverses hippocampal dendritic injury and cognitive impairment in a model of HIV-associated neurocognitive disorders in EcoHIV-infected mice. AIDS. 2019;33:973–984. doi: 10.1097/QAD.0000000000002150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Klatt N.R., Chomont N., Douek D.C., Deeks S.G. Immune activation and HIV persistence: implications for curative approaches to HIV infection. Immunol. Rev. 2013;254:326–342. doi: 10.1111/imr.12065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Liu W., Wong Y.C., Chen S.M.Y., Tang J., Wang H., Cheung A.K.L., Chen Z. DNA prime/MVTT boost regimen with HIV-1 mosaic Gag enhances the potency of antigen-specific immune responses. Vaccine. 2018;36:4621–4632. doi: 10.1016/j.vaccine.2018.06.047. [DOI] [PubMed] [Google Scholar]
  34. Malcolm B.A., Aerts C.A., Dubois K.J., Geurts F.J., Marien K., Rusch S., Van Dijck A.H., Verloes R., Vingerhoets J. PrEP-001 prophylactic effect against rhinovirus and influenza virus - RESULTS of 2 randomized trials. Antivir. Res. 2018;153:70–77. doi: 10.1016/j.antiviral.2018.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Malim M.H. APOBEC proteins and intrinsic resistance to HIV-1 infection. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2009;364:675–687. doi: 10.1098/rstb.2008.0185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Martinez D., Lynch R.J., Meeker J.B., Field A.K. Macrophage dependence of polyriboinosinic acid-polyribocytidylic acid-induced resistance to herpes simplex virus infection in mice. Infect. Immun. 1980;28:147–153. doi: 10.1128/iai.28.1.147-153.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Morón-López S., Gómez-Mora E., Salgado M., Ouchi D., Puertas M.C., Urrea V., Navarro J., Jou A., Pérez M., Tural C., Clotet B., Montaner L.J., Blanco J., Crespo M., Martinez-Picado J. Short-term treatment with interferon alfa diminishes expression of HIV-1 and reduces CD4+ T-cell activation in patients coinfected with HIV and Hepatitis C virus and receiving antiretroviral therapy. J. Infect. Dis. 2016;213:1008–1012. doi: 10.1093/infdis/jiv521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Nazli A., Dizzell S., Zahoor M.A., Ferreira V.H., Kafka J., Woods M.W., Ouellet M., Ashkar A.A., Tremblay M.J., Bowdish D.M., Kaushic C. Interferon-β induced in female genital epithelium by HIV-1 glycoprotein 120 via Toll-like-receptor 2 pathway acts to protect the mucosal barrier. Cell. Mol. Immunol. 2019;16:178–194. doi: 10.1038/cmi.2017.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nedelcovych M.T., Tenora L., Kim B.-H., Kelschenbach J., Chao W., Hadas E., Jančařík A., Prchalová E., Zimmermann S.C., Dash R.P., Gadiano A.J., Garrett C., Furtmüller G., Oh B., Brandacher G., Alt J., Majer P., Volsky D.J., Rais R., Slusher B.S. N-(pivaloyloxy)alkoxy-carbonyl prodrugs of the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) as a potential treatment for HIV associated neurocognitive disorders. J. Med. Chem. 2017;60:7186–7198. doi: 10.1021/acs.jmedchem.7b00966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Nedelcovych M.T., Kim B.H., Zhu X., Lovell L.E., Manning A.A., Kelschenbach J., Hadas E., Chao W., Prchalová E., Dash R.P., Wu Y., Alt J., Thomas A.G., Rais R., Kamiya A., Volsky D.J., Slusher B.S. Glutamine antagonist JHU083 normalizes aberrant glutamate production and cognitive deficits in the EcoHIV murine model of HIV-associated neurocognitive disorders. J. Neuroimmune Pharmacol. 2019;14:391–400. doi: 10.1007/s11481-019-09859-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Novak V., Milberg W., Hao Y., Munshi M., Novak P., Galica A., Manor B., Roberson P., Craft S., Abduljalil A. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care. 2014;37:751–759. doi: 10.2337/dc13-1672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Olson K.E., Bade A.N., Namminga K.L., Potash M.J., Mosley R.L., Poluektova L.Y., Volsky D.J., Gendelman H.E. Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. J. Neurovirol. 2018;24:398–410. doi: 10.1007/s13365-018-0629-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Parrish N.F., Gao F., Li H., Giorgi E.E., Barbian H.J., Parrish E.H., Zajic L., Iyer S.S., Decker J.M., Kumar A., Hora B., Berg A., Cai F., Hopper J., Denny T.N., Ding H., Ochsenbauer C., Kappes J.C., Galimidi R.P., West A.P., Jr., Bjorkman P.J., Wilen C.B., Doms R.W., O’Brien M., Bhardwaj N., Borrow P., Haynes B.F., Muldoon M., Theiler J.P., Korber B., Shaw G.M., Hahn B.H. Phenotypic properties of transmitted founder HIV-1. Proc. Natl. Acad. Sci. U.S.A. 2013;110:6626–6633. doi: 10.1073/pnas.1304288110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Perreau M., Levy Y., Pantaleo G. Immune response to HIV. Curr. Opin. HIV AIDS. 2013;8:333–340. doi: 10.1097/COH.0b013e328361faf4. [DOI] [PubMed] [Google Scholar]
  45. Potash M.J., Chao W., Bentsman G., Paris N., Saini M., Nitkiewicz J., Belem P., Sharer L., Brooks A.I., Volsky D.J. 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. doi: 10.1073/pnas.0500649102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Richman D.D., Margolis D.M., Delaney M., Greene W.C., Hazuda D., Pomerantz R.J. The challenge of finding a cure for HIV infection. Science. 2009;323:1304–1307. doi: 10.1126/science.1165706. [DOI] [PubMed] [Google Scholar]
  47. Robertson K.R., Smurzynski M., Parsons T.D., Wu K., Bosch R.J., Wu J., McArthur J.C., Collier A.C., Evans S.R., Ellis R.J. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS. 2007;21:1915–1921. doi: 10.1097/QAD.0b013e32828e4e27. [DOI] [PubMed] [Google Scholar]
  48. Roshorm Y., Hong J.P., Kobayashi N., McMichael A.J., Volsky D.J., Potash M.J., Takiguchi M., Hanke T. Novel HIV-1 clade B candidate vaccines designed for HLA-B(∗)5101(+) patients protected mice against chimaeric ecotropic HIV-1 challenge. Eur. J. Immunol. 2009;39:1831–1840. doi: 10.1002/eji.200939309. [DOI] [PubMed] [Google Scholar]
  49. Roshorm Y., Cottingham M.G., Potash M.J., Volsky D.J., Hanke T. T cells induced by recombinant chimpanzee adenovirus alone and in prime-boost regimens decrease chimeric EcoHIV/NDK challenge virus load. Eur. J. Immunol. 2012;42:3243–3255. doi: 10.1002/eji.201242624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Rowland-Jones S.L., Dong T., Dorrell L., Ogg G., Hansasuta P., Krausa P., Kimani J., Sabally S., Ariyoshi K., Oyugi J., MacDonald K.S., Bwayo J., Whittle H., Plummer F.A., McMichael A.J. Broadly cross-reactive HIV-specific cytotoxic T-lymphocytes in highly-exposed persistently seronegative donors. Immunol. Lett. 1999;66:9–14. doi: 10.1016/s0165-2478(98)00179-5. [DOI] [PubMed] [Google Scholar]
  51. Saini M., Hadas E., Volsky D.J., Potash M.J. Vaccine-induced protection from infection of mice by chimeric human immunodeficiency virus type 1, EcoHIV/NL4-3. Vaccine. 2007;25:8660–8663. doi: 10.1016/j.vaccine.2007.10.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sang M., Liu J.B., Dai M., Wu J.G., Ho W.Z. Toll-like receptor 3 signaling inhibits simian immunodeficiency virus replication in macrophages from rhesus macaques. Antivir. Res. 2014;112:103–112. doi: 10.1016/j.antiviral.2014.10.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Saxena M., Sabado R.L., La Mar M., Mohri H., Salazar A.M., Dong H., Correa Da Rosa J., Markowitz M., Bhardwaj N., Miller E. Poly-ICLC, a TLR3 agonist, induces transient innate immune responses in patients with treated HIV-infection: a randomized double-blinded placebo controlled trial. Front. Immunol. 2019;10:725. doi: 10.3389/fimmu.2019.00725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Saylor D., Dickens A.M., Sacktor N., Haughey N., Slusher B., Pletnikov M., Mankowski J.L., Brown A., Volsky D.J., McArthur J.C. HIV-associated neurocognitive disorder − pathogenesis and prospects for treatment. Nat. Rev. Neurol. 2016;12:234–248. doi: 10.1038/nrneurol.2016.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Shey M.S., Maharaj N., Archary D., Ngcapu S., Garrett N., Abdool Karim S., Passmore J.A. Modulation of female genital tract-derived dendritic cell migration and activation in response to inflammatory cytokines and toll-like receptor agonists. PloS One. 2016;11 doi: 10.1371/journal.pone.0155668. e0155668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Siddiqui M.A., Saito A., Halambage U.D., Ferhadian D., Fischer D.K., Francis A.C., Melikyan G.B., Ambrose Z., Aiken C., Yamashita M. A novel phenotype links HIV-1 capsid stability to cGAS-Mediated DNA sensing. J. Virol. 2019;93:e00706–e00719. doi: 10.1128/JVI.00706-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Sironi M., Biasin M., Cagliani R., Forni D., De Luca M., Saulle I., Lo Caputo S., Mazzotta F., Macías J., Pineda J.A., Caruz A., Clerici M. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J. Immunol. 2012;188:818–823. doi: 10.4049/jimmunol.1102179. [DOI] [PubMed] [Google Scholar]
  58. Swaminathan G., Rossi F., Sierra L.J., Gupta A., Navas-Martín S., Martín-García J. A role for microRNA-155 modulation in the anti-HIV-1 effects of Toll-like receptor 3 stimulation in macrophages. PLoS Pathog. 2012;8 doi: 10.1371/journal.ppat.1002937. e1002937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tomusange K., Wijesundara D., Gummow J., Garrod T., Li Y., Gray L., Churchill M., Grubor-Bauk B., Gowans E.J. A HIV-Tat/C4-binding protein chimera encoded by a DNA vaccine is highly immunogenic and contains acute EcoHIV infection in mice. Sci. Rep. 2016;6:29131. doi: 10.1038/srep29131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Tomusange K., Wijesundara D., Gummow J., Wesselingh S., Suhrbier A., Gowans E.J., Grubor-Bauk B. Mucosal vaccination with a live recombinant rhinovirus followed by intradermal DNA administration elicits potent and protective HIV-specific immune responses. Sci. Rep. 2016;6:36658. doi: 10.1038/srep36658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Trapp S., Derby N.R., Singer R., Shaw A., Williams V.G., Turville S.G., Bess J.W., Jr., Lifson J.D., Robbiani M. Double-stranded RNA analog poly(I:C) inhibits human immunodeficiency virus amplification in dendritic cells via type I interferon-mediated activation of APOBEC3G. J. Virol. 2009;83:884–895. doi: 10.1128/JVI.00023-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Tsang J., Chain B.M., Miller R.F., Webb B.L., Barclay W., Towers G.J., Katz D.R., Noursadeghi M. HIV-1 infection of macrophages is dependent on evasion of innate immune cellular activation. AIDS. 2009;23:2255–2263. doi: 10.1097/QAD.0b013e328331a4ce. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Urbano V D., De Crignis E., Re M.C. Host restriction factors and human immunodeficiency virus (HIV-1): a dynamic interplay involving all phases of the viral life cycle. Curr. HIV Res. 2018;16:184–207. doi: 10.2174/1570162X16666180817115830. [DOI] [PubMed] [Google Scholar]
  64. Usami Y., Wu Y., Göttlinger H.G. SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef. Nature. 2015;526:218–223. doi: 10.1038/nature15400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Valanne S., Wang J.H., Ramet M. The Drosophila Toll signaling pathway. J. Immunol. 2011;186:649–656. doi: 10.4049/jimmunol.1002302. [DOI] [PubMed] [Google Scholar]
  66. Volberding P.A., Deeks S.G. Antiretroviral therapy and management of HIV infection. Lancet. 2010;376:49–62. doi: 10.1016/S0140-6736(10)60676-9. [DOI] [PubMed] [Google Scholar]
  67. Wang X., Chao W., Saini M., Potash M.J. A common path to innate immunity to HIV-1 induced by Toll-like receptor ligands in primary human macrophages. PloS One. 2011;8 doi: 10.1371/journal.pone.0024193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Wu J., Huang S., Zhao X., Chen M., Lin Y., Xia Y., Sun C., Yang X., Wang J., Guo Y., Song J., Zhang E., Wang B., Zheng X., Schlaak J.F., Lu M., Yang D. Poly(I:C) treatment leads to interferon-dependent clearance of hepatitis B virus in a hydrodynamic injection mouse model. J. Virol. 2014;88:10421–10431. doi: 10.1128/JVI.00996-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Zhou Y., Wang X., Liu M., Hu Q., Song L., Ye L., Zhou D., Ho W. A critical function of toll-like receptor-3 in the induction of anti-human immunodeficiency virus activities in macrophages. Immunology. 2010;131:40–49. doi: 10.1111/j.1365-2567.2010.03270.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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