Biology subjects

Gorantla, S.

Publications and source records attributed to Gorantla, S..

8 recordsLinked to original sources

bioRxiv2026

HIV Infection in Humanized Microglial Mice Disrupts Feeding Behavior and Circadian Rhythms with Cortical Neuroinflammation

Although effective antiretroviral therapy (ART) has substantially reduced the severity of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND), the condition remains highly prevalent. Understanding HAND has been a challenge due to the lack of small animal models capable of supporting productive HIV infection in the brain. Recent advances in humanized mouse models with engrafted human glial cells now enable systemic HIV infection that extends to the central nervous system, offering a powerful platform to study HAND pathogenesis. In this study, we investigated behavioral alterations and neuropathological changes associated with HIV infection. Using home-cage monitoring, we observed that HIV-infected mice exhibited reduced feeding efficiency, consuming less food despite spending more time at the feeder, compared to uninfected controls. Additionally, infected animals displayed disrupted circadian rhythms, with a significant correlation between central nervous system viral load and increased locomotor activity during the light cycle. Neuropathological analyses revealed region-specific vulnerability, with the cortex exhibiting pronounced inflammatory and neurodegenerative changes. These findings were supported by transcriptomic profiling, which demonstrated heightened inflammatory and antiviral gene expression in the cortex, along with differentially expressed genes associated with neuropathology and behavioral deficits. Together, these results highlight distinct region-specific responses to HIV infection in the brain and establish this humanized mouse model as a valuable tool for elucidating the mechanisms underlying HAND and its associated behavioral deficits.

neuroscience↗

bioRxiv2026

Accelerated amyloid neurodegeneration in HIV-1-infected APP-KI Alzheimer's disease mice

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSA higher incidence of dementia, including Alzheimer s-like pathology, is observed in aged people living with HIV-1. However, mechanisms linking HIV-1 to Alzheimers disease (AD) pathology remain unclear, due to the lack of animal models that allow for concurrent study. METHODSWe created a novel APP knock-in (KI) AD mouse, NOG/APPKM670,671NL/IL-34 (hNAIL) that permits study of progressive brain HIV-1 replication. The mice harbor human microglia-like cells. Four-month-old CD34+ human cell reconstituted mice infected with the HIV-1ADA strain facilitated studies of HIV-1 replication on AD pathologies. RESULTSHIV-1 replication increased A{beta} levels and reduced synaptic and neuronal integrity. Spatial transcriptomics demonstrated distinct A{beta} and HIV-1 transcriptional patterns, whereas dual diseased combinations amplified AD pathology. Neurons showed highest transcriptional change, with genes linked to neuroinflammation, protein trafficking, and synaptic dysfunction. DISCUSSIONThe hNAIL mice enable interrogation of HIV-AD comorbidities, with a future potential for the development of novel therapeutic interventions.

neuroscience↗

bioRxiv2023

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between progressive HIV infection and cocaine use disorder is likely bidirectional, with cocaine use having direct effects on immune function while HIV infection can alter addiction-related behavior. To better characterized the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilized a humanized mouse model to investigate the outcomes of progressive HIV infection on cocaine-related behaviors in a cocaine conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection did not impact the formation of a cocaine CPP, but did result in resistance to extinction of the CPP. No effects of HIV on yohimbine-primed reinstatement or cocaine seeking under conflict were observed. These behavioral alterations were accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes were observed in both mouse and human markers. Among other targets, this included HIV-induced reductions in mouse IL-1 and G-CSF and human TNF and cocaine-induced alterations in human TNF and mouse GM-CSF such that cocaine exposure increases both cytokines only in the absence of HIV infection. Together these data provide new insights into the unique neurobehavioral processes underlying HIV infection and cocaine use disorders, and further how they interact to effect immune responses.

neuroscience↗

bioRxiv2021

Human microglia extensively reconstitute in humanized BLT mice with human interleukin-34 transgene and support HIV-1 brain infection

Humanized bone marrow-liver-thymic (hu-BLT) mice develop a functional immune system in periphery but have a limited reconstitution of human myeloid cells, especially microglia, in CNS. Further, whether bone marrow derived hematopoietic stem and progenitor cells (HSPCs) can enter the brain and differentiate into microglia in adults remains controversial. To close these gaps, in this study we unambiguously demonstrated that human microglia in CNS were extensively reconstituted in adult NOG mice with human interleukin-34 transgene (hIL34 Tg) from circulating CD34+ HSPCs but no in hu-BLT NOG mice, providing strong evidence that human CD34+ HSPCs can enter adult brain and differentiate into microglia in CNS in the presence of hIL34. Further, the human microglia in the CNS of hu-BLT-hIL34 NOG mice robustly supported HIV-1 infection reenforcing the notion that microglia are the most important target cells of HIV-1 in CNS and demonstrating its great potential as an in vivo model for studying HIV-1 pathogenesis and evaluating curative therapeutics in both periphery and CNS compartments.

microbiology↗

bioRxiv2020

Elucidating the pathogenic mechanisms of AD brain-derived tau-containing extracellular vesicles: Highly transmissible and preferential propagation to GABAergic neurons

Extracellular vesicles (EVs) propagate tau pathology for Alzheimers disease (AD). How EV transmission influences AD are, nonetheless, poorly understood. To these ends, the physicochemical and molecular structure-function relationships of human brain-derived EVs, from AD and prodromal AD (pAD), were compared to non-demented controls (CTRL). AD EVs were shown to be significantly enriched in epitope-specific tau oligomers versus pAD or CTRL EVs assayed by dot-blot and atomic force microscopy tests. AD EVs were efficiently internalized by murine cortical neurons and transferred tau with higher aggregation potency than pAD and CTRL EVs. Strikingly, inoculation of tau-containing AD EVs into the outer molecular layer of the dentate gyrus induced tau propagation throughout the hippocampus. This was seen in 22 months-old C57BL/6 mice at 4.5 months post-injection by semiquantitative brain-wide immunohistochemistry tests with multiple anti-phospho-tau (p-tau) antibodies. Inoculation of the equal amount of tau from CTRL EVs or as oligomer or fibril-enriched fraction from the same AD donor showed little propagation. AD EVs induced tau accumulation in the hippocampus as oligomers or sarkosyl-insoluble proteins. Unexpectedly, p-tau cells were mostly GAD67+ GABAergic neurons and to a lesser extent, GluR2/3+ excitatory mossy cells, showing preferential EV-mediated GABAergic neuronal tau propagation. Whole-cell patch clamp recording of Cornu Ammonis (CA1) pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+GABAergic neurons and GAD67+ GABAergic neuronal puncta surrounding pyramidal neurons in the CA1 region confirming reduced interneuronal projections. Our study posits a novel tau-associated pathological mechanism for brain-derived EVs.

neuroscience↗

bioRxiv2019

Proteomic Profiling and Biological Characterization of Extracellular Vesicles Isolated from Human Alzheimer’s Disease Brain Tissues

IntroductionExtracellular vesicles (EVs) from human Alzheimers disease (AD) biospecimens contain amyloid-{beta} peptide (A{beta}) and tau. While AD EVs are known to affect brain disease pathobiology, their biochemical and molecular characterizations remain ill defined.\n\nMethodsEVs were isolated from the cortical grey matter of 20 AD and 18 control brains. Tau and A{beta} levels were measured by immunoassay. Differentially expressed EV proteins were assessed by quantitative proteomics and machine learning.\n\nResultsLevels of pS396 tau and A{beta} were significantly elevated in AD EVs. High levels of neuron- and glia- specific factors are detected in control and AD EVs, respectively. Machine learning identified ANXA5, VGF, GPM6A and ACTZ in AD EV compared to controls. They distinguished AD EVs from controls in the test sets with 88% accuracy.\n\nDiscussionIn addition to A{beta} and tau, ANXA5, VGF, GPM6A and ACTZ are new signature proteins in AD EVs.

biochemistry↗

bioRxiv2018

Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection

BackgroundThe use of immunodeficient mice transplanted with human hematopoietic stem cells is an accepted approach to study human-specific infectious diseases, like HIV-1, and to investigate multiple aspects of human immune system development. However, mouse and human are different in sialylation patterns of proteins due to evolutionary mutations of the CMP-N-acetylneuraminic acid hydroxylase (CMAH) gene that prevent formation of N-glycolylneuraminic acid from N-acetylneuraminic acid. How changes of mouse glycoproteins chemistry will affect phenotype and function of transplanted human hematopoietic stem cells and mature human immune cells in the course of HIV-1 infection is not known.\n\nResultsWe mutated mouse CMAH on the most widely human cells transplantation strain NOD/scid-IL2R{gamma} c-/- (NSG) mouse background using the CRISPR/Cas9 system. The new strain provides a better environment for human immune cells. Transplantation of human hematopoietic stem cells leads to broad B cells repertoire, higher sensitivity to HIV-1 infection, and enhanced proliferation of transplanted peripheral blood lymphocytes. The mice showed low effects on the clearance of human immunoglobulins and enhanced transduction efficiency of recombinant adeno-associated viral vector rAAV2/DJ8.\n\nConclusionNSG-cmah-/- mice expand the mouse models suitable for human cells transplantation and this new model has advantages in generating a human B cell repertoire. This strain is suitable to study different aspects of the human immune system development, might provide advantages in patient-derived tissue and cell transplantation, and could allow studies of viral vectors and infectious agents that are sensitive to human-like sialylation of mouse glycoproteins.

immunology↗

bioRxiv2017

Systemic HIV-1 Infection Produces a Unique Glial Footprint in Humanized Mouse Brains

Studies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are hindered by the availability of relevant small-animal models. To overcome this hindrance, a mouse model reconstituted with humanized brain and immune systems was created. Newborn NOD/SCID/IL2R{gamma}c-/- mice of both sexes were transplanted with human neuroglial progenitors (NPC) and hematopoietic stem cells. Intraventricular injection of NPC yielded an anatomical symmetrical glia (human astrocyte and oligodendrocyte) repopulation of the mouse brain. The human glia were observed in periventricular areas, white matter tracts, the olfactory bulb and brain stem. HIV-1 infection of these dual humanized mice led to meningeal and perivascular human leukocyte infiltration into brain. The species-specific viral-neuroimmune interactions in the infected animals were identified by deep RNA sequencing. In the corpus callosum and hippocampus overlapping human-specific transcriptional alterations were seen for interferon type 1 and 2 signaling pathways (STAT1, 2, IRF9, ISG15, IFI6) and a range of host antiviral responses (MX1, OAS1, RSAD2, BST2, SAMHD1) in infected animals. Glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG and ZNF488) were downregulated. The data sets were confirmed by real-time PCR. The viral defense signaling patterns observed in these mice parallels the neuroimmune communication networks present in the HIV-1 infected human brain. In this manner, the new mouse model can facilitate discovery of therapeutics, viral eradication targets for virus induced nervous system diseases, and simplify HIVCure research approaches.\n\nSummary StatementWe created mice with both a humanized brain and an immune system. The animals were used to investigate glial responses to HIV-1 infection. At a transcriptional level we defined the interactions between human glia and immune cells in the presence of the systemic HIV-1 infection. Noticeably, altered transcriptional changes were human specific. At five weeks after viral infection humanized mouse brain displayed potent interferon-mediated antiviral innate immune responses and alteration of neuronal progenitors differentiation and myelination. This model can be used to tests both diagnostic and therapeutic interventions for cure HIV-associated brain impairment.

neuroscience↗