Selective monoaminergic and histaminergic circuit dysregulation following long-term HIV-1 protein exposure

Illenberger

et al. 2021

Viruses

Self Cite

The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to (1) evaluate the HIV-1 mRNA distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat, and (2) validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 h of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results that are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments and synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway and/or neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.

Section: Introductionmentioning

confidence: 99%

Microglial HIV-1 Expression: Role in HIV-1 Associated Neurocognitive Disorders

Illenberger

et al. 2021

Viruses

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“…Alterations in intrinsic excitability have also been observed in CA1 pyramidal neurons from the HIP 66 . Furthermore, prominent alterations in dopaminergic and serotonergic function have been observed in both the mPFC and NAc 36 . Considering the relatively high expression of HIV-1 mRNA observed in the mPFC, NAc and HIP, even when infection is latent (e.g., as in the HIV-1 Tg rat), the presence and persistence of viral reservoirs may lead to synaptic dysfunction and neurotransmitter system alterations.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, brain regions exhibiting high HIV-1 mRNA expression also correspond with neuroanatomical alterations previously observed in the HIV-1 Tg rat. Broadly, the HIV-1 Tg rat exhibits synaptic dysfunction 32,35,44 , neurotransmitter system alterations 68,36 , and neuroinflammation 39 ; deficits which have been implicated in the pathogenesis of HAND. More specifically, profound synaptic dysfunction has been observed in both pyramidal neurons from layers II-III of the mPFC 32 and medium spiny neurons from the NAc 35,44 evidenced by alterations in dendritic branching complexity and synaptic connectivity in HIV-1 Tg animals relative to controls.…”

Section: Ecohiv Infection Forms Viral Reservoirs In Microglia Eight Wmentioning

confidence: 99%

“…First, the HIV-1 Tg rat, a biological system to model latent infection, was utilized to characterize the brain regions, and major cell type, expressing HIV-1 mRNA. The HIV-1 Tg rat, originally reported by Reid et al 34 , resembles HIV-1 seropositive individuals on cART and has been utilized to investigate neurocognitive 30,31,33 and neuroanatomical 32,35, 36 alterations associated with HAND. The functional deletion of gag - and pol -, a reverse transcriptase, precludes viral replication rendering the HIV-1 Tg rat noninfectious.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HIV-1 and microglia: EcoHIV and HIV-1 transgenic rats

Mactutus

et al. 2020

Preprint

Self Cite

The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to 1) evaluate the HIV-1 mRNA neuroanatomical distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat (i.e., under conditions of latent infection), and 2) to validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 hours of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results which are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments, synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway, and neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.

“…Notably, when control animals are treated with SE, an agonist selective for ERβ [31], an increased reinforcing efficacy of, and altered sensitivity to, cocaine is observed ( Supplementary Figure 1A-C). The structure and function of the NAc, however, is altered by chronic HIV-1 viral protein exposure [e.g., [25][26][73][74], which may preclude this untoward side effect (i.e., enhanced drug seeking behavior) in HIV-1 Tg rats treated with SE.…”

Section: Synaptic Dysfunction In Medium Spiny Neurons Of the Nucleus mentioning

confidence: 99%

HIV-1-induced apathy: Mitigation by the gut metabolite, S-Equol

Bertrand

Illenberger

et al. 2021

Preprint

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The persistence of motivational alterations, including apathy, in older HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for apathy, however, has yet to be systematically evaluated. Thus, beginning at approximately seven to nine months of age, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed behavior. First, at the genotypic level, apathetic behavior in older HIV-1 Tg rats treated with vehicle was characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose and enhanced drug seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated alterations in goal-directed behaviors and reduced drug seeking behavior in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited prominent decreases in dendritic branching and a shift towards longer dendritic spines with decreased head diameter; synaptic dysfunction that was partially restored by SE treatment. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.