Biology subjects

Midkiff, C.

Publications and source records attributed to Midkiff, C..

6 recordsLinked to original sources

bioRxiv2025

Neuroinvasion by Simian Immunodeficiency Virus Triggers Glial Senescence and Accelerated Neurodegeneration

Virus-induced accelerated aging has emerged as a potential contributor to HIV-associated neurocognitive disorders (HAND), despite widespread implementation of combination antiretroviral therapy (cART). Although evidence of accelerated aging in people living with HIV (PLWH) has been reported, most investigations of acute infection rely on in vitro systems or small animal models, leaving a critical gap in understanding early neuropathological events. To address this, we analyzed formalin-fixed, paraffin-embedded (FFPE) brain tissues from rhesus macaques acutely infected with simian immunodeficiency virus (SIV). We focused on two key aging-related proteins: the cellular senescence marker p16INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). We hypothesized that accelerated aging phenotypes would be detectable during acute infection, manifesting as increased p16 expression and altered SIRT1 levels, correlating with neurodegeneration. Consistent with this hypothesis, we observed marked upregulation of GFAP and p16, along with evidence of neurodegeneration, across multiple brain regions - including the frontal lobe, caudate, putamen, thalamus, hippocampus, and cerebellum - by 21 days post-infection. These findings suggest that aging-related and senescence pathways are activated almost immediately following HIV infection, highlighting the potential importance of astrocyte- or CNS-specific therapeutic strategies to mitigate early neuropathology.

neuroscience↗

bioRxiv2025

Resolving Inflammation: The Impact of Antiretroviral Therapy on Macrophage Traffic In and Out of the CNS.

The effect of antiretroviral therapy (ART) and therapy interruption on myeloid cell traffic out of the central nervous system (CNS) with human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection are understudied. Using intracisternal (i.c.) injection of dual-colored fluorescent superparamagnetic iron oxide nanoparticles (SPION) in SIV-infected macaques early (12-14 dpi) and late (30 days before sacrifice) we studied CNS macrophage viral infection, turnover, and traffic out. SPION are preferentially taken up by perivascular, meningeal, and choroid plexus macrophages. In non-infected macaques, SPION+ macrophages can traffic out of the CNS to the periphery (deep cervical lymph node (dcLN), spleen, and dorsal root ganglia (DRG)), but accumulate in the CNS with SIV infection. ART reduces the accumulation of CNS SPION+ perivascular macrophages but not meningeal or choroid plexus macrophages. ART interruption does not affect the number of SPION+ perivascular and choroid plexus but the number of SPION+ meningeal macrophages increase. ART eliminates SIV-RNA perivascular macrophages, but few scattered RNA+ macrophages in the meninges and choroid plexus remain. With ART interruption, perivascular macrophages remain SIV-but scattered SIV+ meningeal and choroid plexus macrophages exist. In non-infected animals SPION+ macrophages traffic to dcLN, spleen, and DRG at a rate that is decreased with SIV infection and AIDS. SIV- RNA+ SPION+ macrophages that traffic out of the CNS are eliminated by ART and do not rebound with ART interruption. Using two different colored SPION to study the establishment of CNS SIV viral reservoirs, we find greater numbers of early SPION+ macrophages within and outside of the CNS with SIVE, ART, and ART interruption. These data are consistent with SIV-infected perivascular macrophages establishing an early viral reservoir, and continual viral seeding of the meninges and choroid plexus during infection. These findings are consistent with ART reducing traffic of infected macrophages out of the CNS, clearing the CNS perivascular macrophage viral reservoir but not SIV-RNA+ macrophages in meninges and choroid plexus that can rebound with ART interruption.

immunology↗

bioRxiv2023

Immune Correlates of Hyperglycemia and Vaccination in a Non-human Primate Model of Long-COVID

Hyperglycemia, and exacerbation of pre-existing deficits in glucose metabolism, are major manifestations of the post-acute sequelae of SARS-CoV-2 (PASC). Our understanding of lasting glucometabolic disruptions after acute COVID-19 remains unclear due to the lack of animal models for metabolic PASC. Here, we report a non-human primate model of metabolic PASC using SARS-CoV-2 infected African green monkeys (AGMs). Using this model, we have identified a dysregulated chemokine signature and hypersensitive T cell population during acute COVID-19 that correlates with elevated and persistent hyperglycemia four months post-infection. This persistent hyperglycemia correlates with elevated hepatic glycogen, but there was no evidence of long-term SARS-CoV-2 replication in the liver and pancreas. Finally, we report a favorable glycemic effect of the SARS-CoV-2 mRNA vaccine, administered on day 4 post-infection. Together, these data suggest that the AGM metabolic PASC model exhibits important similarities to human metabolic PASC and can be utilized to assess therapeutic candidates to combat this syndrome.

immunology↗

bioRxiv2021

The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over four million people worldwide as of July 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.

immunology↗

bioRxiv2021

Clinicopathologic features of a feline SARS-CoV-2 infection model parallel acute COVID-19 in humans

The emergence and ensuing dominance of COVID-19 on the world stage has emphasized the urgency of efficient animal models for the development of therapeutics and assessment of immune responses to SARS-CoV-2 infection. Shortcomings of current animal models for SARS-CoV-2 include limited lower respiratory disease, divergence from clinical COVID-19 disease, and requirements for host genetic modifications to permit infection. This study validates a feline model for SARS-CoV-2 infection that results in clinical disease and histopathologic lesions consistent with severe COVID-19 in humans. Intra-tracheal inoculation of concentrated SARS-CoV-2 caused infected cats to develop clinical disease consistent with that observed in the early exudative phase of COVID-19. A novel clinical scoring system for feline respiratory disease was developed and utilized, documenting a significant degree of lethargy, fever, dyspnea, and dry cough in infected cats. In addition, histopathologic pulmonary lesions such as diffuse alveolar damage, hyaline membrane formation, fibrin deposition, and proteinaceous exudates were observed due to SARS-CoV-2 infection, imitating lesions identified in people hospitalized with ARDS from COVID-19. A significant correlation exists between the degree of clinical disease identified in infected cats and pulmonary lesions. Viral loads and ACE2 expression were quantified in nasal turbinates, distal trachea, lung, and various other organs. Natural ACE2 expression, paired with clinicopathologic correlates between this feline model and human COVID-19, encourage use of this model for future translational studies. Author SummaryIdentifying an ideal animal model to study COVID-19 has been difficult, and current models come with challenges that restrict their potential in translational studies. Few lab animals naturally express the receptors necessary for viral infection (ACE2), and many fail to manifest clinical signs or pathology similar to that seen in humans. Other models (non-human primates, mink) are ideal for disease and transmission studies, but are restricted by cost, husbandry challenges, and scarce availability. Alternatively, cats naturally express ACE2 receptors, are naturally infected with SARS-CoV-2 and can transmit virus from cat-to-cat. Prior to this study, cats infected by oral/nasal routes have not displayed significant clinical disease or lung pathology. However, we demonstrate that direct inoculation of concentrated SARS-CoV-2 virus in the trachea of cats induces analogous clinical and pathologic features to hospitalized patients with acute COVID-19. Our results show that infected cats exhibit significant clinical signs during experimental infection (coughing, increased respiratory effort, lethargy, and fever) and exhibit extensive lung lesions that mimic severe COVID-19 pathology such as diffuse alveolar damage and hyaline membrane formation - highlighting the immeasurable potential for this feline model to address translational approaches for COVID-19 and to better understand the role of cats in transmission and disease.

microbiology↗

bioRxiv2017

Polyclonal HIV envelope-specific breast milk antibodies limit founder SHIV acquisition and cell-associated virus loads in infant rhesus monkeys.

Vertical HIV-1 transmission via breastfeeding is the predominant contributor to pediatric infections that are ongoing in this era of highly effective antiretroviral therapy (ART). Remarkably, only ~10% of infants chronically exposed to the virus via breastfeeding from untreated HIV-infected mothers become infected, suggesting the presence of naturally protective factors in breast milk. HIV-specific maternal antibodies are obvious candidates as potential contributors to this protection. This study assessed the protective capacity of common HIV envelope-specific non-broadly neutralizing antibodies isolated from breast milk of HIV-infected women in an infant rhesus monkey (RM), tier 2 SHIV oral challenge model. Prior to oral SHIV challenge, infant RMs were i.v. infused with either a single weakly-neutralizing monoclonal antibody (mAb), a tri-mAb cocktail with neutralizing and ADCC functionalities, or an anti-influenza HA control mAb. Of these groups, the fewest tri-mAb-treated infants developed plasma viremia (2/6, 3/6, and 6/8 animals viremic in tri-mAb, single-mAb, and control mAb groups, respectively). Tri-mAb-treated infants demonstrated significantly fewer transmitted/founder SHIV variants in plasma and decreased peripheral CD4+ T cell proviral loads at 8 week post-challenge compared to control mAb-treated infants. Abortive infection was observed as detectable CD4+ T cell provirus in non-viremic control mAb- and single-mAb-, but not tri-mAb-treated animals. Taken together, these results support the potential viability of maternal or infant vaccine strategies that elicit non-broadly neutralizing antibodies to prevent vertical transmission of HIV through breastfeeding.

immunology↗