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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Riverside Electronic Theses and Dissertations (2024)

Human immunodeficiency virus-1 (HIV-1) is a retrovirus that can infiltrate and infect the central nervous system (CNS) leading to HIV-associated neurocognitive disorders (HAND). HAND is a condition behaviorally characterized by cognitive and neurological impairments, and pathologically characterized by rampant inflammation and loss of synaptic integrity. Although therapeutics exist to increase the lifespan of people living with HIV, the overall prevalence of HAND and the presence of HIV induced neuronal damage remains unchanged. Understanding the mechanisms underlying the neuropathology in HIV will guide the development of more efficacious therapeutics.One hallmark response to HIV is the type I interferon antiviral response. HIV-1, and an HIVgp120 transgenic (HIVgp120tg) mouse model, both activate the innate immune system, including the production of type 1 interferons (IFNs) α and β, and induction of IFN-stimulated genes (ISG). In this dissertation, we characterize IFNβ’s role in HIVgp120tg induced neuroHIV using an IFNβKO mouse model. The neuropathology observed in HIVgp120tg is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, IFNβKO results in an amelioration of neuronal presynaptic terminal damage but no protection of neuronal dendrites in the hippocampal CA1 region of HIVgp120tg mice. Additionally, female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in the cortex and hippocampus. IFNβKO abrogates or diminishes the induction of type I interferon related genes including MX1, DDX58, IRF7, and IRF9 in HIVgp120tg brains. Additionally, the effects of IFNβKO on MAPK activities with a pronounced reduction of active ERK1/2 and active p38 in the HIVgp120tg brain. In summary, these findings show that IFNβ’s absence in the presence of HIVgp120, is partially protective when assessing hippocampal pre-synaptic terminals and microglial counts, but partially damaging based on cortical dendritic assessment. Moreover, IFNβ plays a vital role in mediating the gp120 induced type I interferon response, expression of pro-inflammatory markers, and MAPK signaling. Additionally, we highlight the activation of ephrin-B/EphB in the CNS of people living with HIV driven, at least in part, by gp120 viral envelope protein and type I interferon, IFNβ. Furthermore, EphB2 mediated ephrin-B reverse signaling onto microglia induces a prominent pro-inflammatory and antiviral signature with the capacity for this microglial specific pro-inflammatory secretome profile to induce non-contact dependent neurotoxicity. Finally, knockdown of microglial ephrin-B1, a binding partner for EphB2, shows a partial alleviation of the microglial pro-inflammatory signature and resulting neurotoxicity. Elevated EphB2 and its signaling onto microglia may present as a novel mechanism of neuroinflammation, and mediator of neurotoxicity, seen in the context of neuroHIV and potentially other neurodegenerative diseases.

    Cover page: Implications of IFNβ and EphB2 mediated Ephrin-B Reverse Signaling on Inflammation, Antiviral Response and Neurotoxicity in HIVCreative Commons 'BY' version 4.0 license
    • Article
    • Peer Reviewed
    UC Riverside Previously Published Works (2024)
    Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNβKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNβ-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNβKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNβ on multiple components with more pronounced changes in IFNβKO females. In contrast, the effects of IFNβKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNβ impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNβ plays a vital role in maintaining neuronal homeostasis and memory function.
      Cover page: Interferon-β deficiency alters brain response to chronic HIV-1 envelope protein exposure in a transgenic model of NeuroHIV
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2020)
      People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex. However, the question if LCN2 contributes to HIV-associated neurotoxicity or is part of a protective host response required further investigation. We found that the knockout of LCN2 in transgenic mice expressing HIVgp120 in the brain (HIVgp120tg) abrogates behavioral impairment, ameliorates neuronal damage, and reduces microglial activation in association with an increase of the neuroprotective CCR5 ligand CCL4. In vitro experiments show that LCN2 neurotoxicity also depends on microglia and p38 MAPK activity. Genetic ablation of CCR5 in LCN2-deficient HIVgp120tg mice restores neuropathology, suggesting that LCN2 overrides neuroprotection mediated by CCR5 and its chemokine ligands. RNA expression of 168 genes involved in neurotransmission reveals that neuronal injury and protection are each associated with genotype- and sex-specific patterns affecting common neural gene networks. In conclusion, our study identifies LCN2 as a novel factor in HIV-associated brain injury involving CCR5, p38 MAPK and microglia. Furthermore, the mechanistic interaction between LCN2 and CCR5 may serve as a diagnostic and therapeutic target in HIV patients at risk of developing brain pathology and neurocognitive impairment.
        Cover page: Lipocalin-2 mediates HIV-1 induced neuronal injury and behavioral deficits by overriding CCR5-dependent protection
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