Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2020)

Human immunodeficiency virus type-1 (HIV-1) is a global pandemic that has infected millions across the globe and is the precursor to acquired immunodeficiency syndrome (AIDS). Antiretroviral therapy (ART) allows HIV-1 infected individuals to live a full life; however, ART does not remove HIV-1 infected cells, allowing infected cells to become latent. These latent HIV-1 reservoirs cannot only reactivate once ART administration ends, but these latent HIV-1 reservoirs despite producing no replication competent virus can produce chronic inflammation in an individual leading to an assortment of other health conditions. A strategy to eradicate latent reservoirs is designed to reactivate HIV-1 from latently infected cells and kill the virus prior to it infecting uninfected bystander cells (often called “shock and kill”). Here, we identify Tat-Vpu peptide as a potential “shock” in the “shock and kill” cure strategy. We show that Tat-Vpu is able to increase HIV-1 viral release in infected macrophages through the LVEM66 amino acid sequence that is not observed in the tat-scramble. To analyze the inflammatory pathway induced by HIV-1, we used a GU-rich single stranded RNA (RNA40) derived from the long terminal repeat (LTR) region of HIV-1. We identified that TLR8 is critical in causing “bystander” CD4+ T cells to elicit IL-1β production. We also show a lack of cell death in RNA40 stimulated macrophages, and identify that caspase-8 and RIPK3 are involved in efficient IL-1β release suggesting the involvement of an alternative inflammasome. We also show that potassium efflux is essential in producing an inflammatory response in RNA40 stimulated macrophages. The involvement of TLR8, no pyroptosis, potassium efflux, and involvement of proteins in the alternative inflammasome indicate that a novel inflammatory pathway is involved with the induction of IL-1β by RNA40.

    Cover page: Tat-Vpu Peptide Inducing a Shock Effect on Human Immunodeficiency Virus Type-1 Infected Primary Macrophage Cells and Understanding a Novel NLRP3 Inflammasome Activation Induced by GU-rich Human Immunodeficiency Virus Type-1 ssRNA
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2021)
    Macrophages promote an early host response to infection by releasing pro-inflammatory cytokines such as interleukin-1β (IL-1β), TNF, and IL-6. The bioactivity of IL-1β is classically dependent on NLRP3 inflammasome activation, which culminates in caspase-1 activation and pyroptosis. Recent studies suggest a role for NLRP3 inflammasome activation in lung inflammation and fibrosis in both COVID-19 and SARS, and there is evidence of NLRP3 involvement in HIV-1 disease. Here, we show that GU-rich single-stranded RNA (GU-rich RNA) derived from SARS-CoV-2, SARS-CoV-1, and HIV-1 trigger a TLR8-dependent pro-inflammatory cytokine response from human macrophages in the absence of pyroptosis, with GU-rich RNA from the SARS-CoV-2 spike protein triggering the greatest inflammatory response. Using genetic and pharmacological inhibition, we show that the induction of mature IL-1β is through a non-classical pathway dependent on caspase-1, caspase-8, the NLRP3 inflammasome, potassium efflux, and autophagy while being independent of TRIF (TICAM1), vitamin D3, and pyroptosis.
      Cover page: SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2023)
      Background Complex percutaneous coronary intervention (PCI) is increasingly performed in older adults (age ≥75 years) with stable ischemic heart disease. However, little is known about clinical outcomes. Methods and Results We derived a cohort of older adults undergoing elective PCI for stable ischemic heart disease across a large health system. We compared 12-month event-free survival (freedom from all-cause death, nonfatal myocardial infarction, stroke, and major bleeding), all-cause death, target lesion revascularization, and bleeding events for patients receiving complex versus noncomplex PCI and derived risk estimates with Cox regression models. We included 513 patients (mean age, 81±5 years). Patients receiving complex PCI versus noncomplex PCI did not significantly differ across a host of clinical characteristics including cardiovascular disease features, noncardiac comorbidities, guideline-directed medical therapy use, and frailty. Patients receiving complex PCI versus noncomplex PCI experienced worse event-free survival (80.4% versus 86.8%), which was not significant in adjusted analyses (hazard ratio [HR], 1.38 [95% CI, 0.88-2.16]). All-cause death at 1 year for patients undergoing complex PCI was nearly double that seen for patients receiving noncomplex PCI (10.2% versus 5.9%), and the risk was significant in models adjusted for clinical characteristics (HR, 1.97 [95% CI, 1.02-3.79]). Target lesion revascularization risk was lower for patients receiving complex PCI (2.2% versus 3.5%, adjusted HR), but bleeding events were not statistically different between groups (25.3% versus 20.5%; P=0.19). Conclusions Complex PCI in older adults with stable ischemic heart disease was associated with lower risk of target lesion revascularization but higher all-cause death compared with noncomplex PCI.
        Cover page: Complex Percutaneous Coronary Intervention Outcomes in Older Adults.
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2020)
        Therapeutic strategies that provide effective and broad-spectrum neutralization against HIV-1 infection are highly desirable. Here, we investigate the potential of nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP) to neutralize a broad range of HIV-1 strains. TNP displayed outstanding neutralizing breadth and potency; they neutralized all 125 HIV-1-pseudotyped viruses tested, including global subtypes/recombinant forms, and transmitted/founder viruses, with a geometric mean 80% inhibitory concentration (IC80) of 819 μg ml-1 (range, 72 to 8,570 μg ml-1). TNP also selectively bound to and induced autophagy in HIV-1-infected CD4+ T cells and macrophages, while having no effect on uninfected cells. This TNP-mediated autophagy inhibited viral release and reduced cell-associated HIV-1 in a dose- and phospholipase D1-dependent manner. Genetic or pharmacological inhibition of autophagy ablated this effect. Thus, we can use TNP as therapeutic agents to neutralize cell-free HIV-1 and to target HIV-1 gp120-expressing cells to decrease the HIV-1 reservoir.IMPORTANCE HIV-1 is a major global health challenge. The development of an effective vaccine and/or a therapeutic cure is a top priority. The creation of vaccines that focus an antibody response toward a particular epitope of a protein has shown promise, but the genetic diversity of HIV-1 hinders this progress. Here we developed an approach using nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP). Not only do TNP effectively neutralize all strains of HIV-1, but they also selectively bind to infected cells and decrease the release of HIV-1 particles through an autophagy-dependent mechanism with no drug-induced off-target or cytotoxic effects on bystander cells.
          Cover page: CD4+ T Cell-Mimicking Nanoparticles Broadly Neutralize HIV-1 and Suppress Viral Replication through Autophagy
          Top