Biomedical subjects

Jiong Shi

Publications and source records attributed to Jiong Shi.

7 recordsLinked to original sources

PubMed2025

Reverse transcription progression and genome length regulate HIV-1 core elasticity and disassembly.

The structural and mechanical properties of the HIV-1 core are critical for successful infection, balancing stability for early replication and controlled disassembly for genome release. Recent studies have highlighted the role of core elasticity in nuclear entry, yet the molecular determinants regulating this property remain poorly understood. Here, atomic force microscopy (AFM) was used to investigate the relationship between reverse transcription progression, genome length, core elasticity, and disassembly. The results demonstrate that reverse transcription induces a gradual loss of elasticity, rendering the core increasingly brittle as DNA synthesis progresses. Cores containing shorter genomes remained highly elastic, whereas those with longer genomes exhibited increased brittleness, structural damage, and a higher degree of disassembly, after 4 hours of reverse transcription. Additionally, cores from an RNase H-deficient HIV-1 mutant retained high elasticity. These findings provide insight into the interplay between genome synthesis, core integrity, and nuclear entry, supporting a model in which reverse transcription-generated mechanical stress facilitates uncoating. Furthermore, early-stage reverse transcription preserved core elasticity, suggesting a temporal window for successful nuclear import before structural destabilization compromises infectivity.

HIV-1↗

PubMed2006

Saturation of TRIM5 alpha-mediated restriction of HIV-1 infection depends on the stability of the incoming viral capsid.

HIV-1 infection is restricted at a post-entry stage in some simian cell lines by species-specific variants of TRIM5 alpha. Restriction targets the viral capsid protein (CA) and results in attenuated reverse transcription. TRIM5 alpha restriction can be inhibited by the addition of noninfectious virus-like particles (VLPs), thus rendering cells permissive for infection by an HIV-1 reporter virus. Through the use of HIV-1 VLPs containing Gag cleavage site substitutions and point mutations in CA which alter the stability of the viral capsid, we demonstrate that saturation of TRIM5 alpha restriction depends on the stability of the capsid in the incoming VLPs. Differences in the requirement for cleavage of the specific sites in Gag were observed between distinct African green monkey cell lines. The results strongly suggest that the mechanism of HIV-1 restriction by TRIM5 alpha involves engagement of the viral capsid by the restriction factor prior to completion of uncoating.

Animals↗

PubMed2005

Structural requirements for recognition of the human immunodeficiency virus type 1 core during host restriction in owl monkey cells.

Human immunodeficiency virus type 1 (HIV-1) infection of simian cells is restricted at an early postentry step by host factors whose mechanism of action is unclear. These factors target the viral capsid protein (CA) and attenuate reverse transcription, suggesting that they bind to the HIV-1 core and interfere with its uncoating. To identify the relevant binding determinants in the capsid, we tested the capacity of viruses containing Gag cleavage site mutations and amino acid substitutions in CA to inhibit restriction of a wild type HIV-1 reporter virus in owl monkey cells. The results demonstrated that a stable, polymeric capsid and a correctly folded amino-terminal CA subunit interface are essential for saturation of host restriction in target cells by HIV-1 cores. We conclude that the owl monkey cellular restriction machinery recognizes a polymeric array of CA molecules, most likely via direct engagement of the HIV-1 capsid in target cells prior to uncoating.

Animals↗

PubMed2005

Relapsing-remitting tumefactive multiple sclerosis.

Tumefactive multiple sclerosis (MS) is a rare form of demyelinating disease. The natural course of the disease has been characterized as presenting with a mass-like demyelinating lesion converting to typical relapsing-remitting disease with future exacerbations. Herein we describe a case of a patient whom over a six-year period developed relapsing-remitting tumefactive MS. The natural course, pathophysiology, prognosis and diagnosis are briefly discussed.

Demyelinating Diseases↗

PubMed2004

Coupling of human immunodeficiency virus type 1 fusion to virion maturation: a novel role of the gp41 cytoplasmic tail.

Retrovirus particles are not infectious until they undergo proteolytic maturation to form a functional core. Here we report a link between human immunodeficiency virus type 1 (HIV-1) core maturation and the ability of the virus to fuse with target cells. Using a recently developed reporter assay of HIV-1 virus-cell fusion, we show that immature HIV-1 particles are 5- to 10-fold less active for fusion with target cells than are mature virions. The fusion of mature and immature virions was rendered equivalent by truncating the gp41 cytoplasmic domain or by pseudotyping viruses with the glycoprotein of vesicular stomatitis virus. An analysis of a panel of mutants containing mutated cleavage sites indicated that HIV-1 fusion competence is activated by the cleavage of Gag at any site between the MA and NC segments and not as an indirect consequence of an altered core structure. These results suggest a mechanism by which binding of the gp41 cytoplasmic tail to Gag within immature HIV-1 particles inhibits Env conformational changes on the surface of the virion that are required for membrane fusion. This "inside-out" regulation of HIV-1 fusion could play an important role in the virus life cycle by preventing the entry of immature, noninfectious particles.

Cell Fusion↗

PubMed2002

Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice.

We have studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD brain biopsy, human short postmortem brain tissues, and yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5 kb deleted, and mouse mtDNA was performed, along with immunocytochemistry using antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8-OHG), and cytochrome c oxidase (COX). There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC, and C57B6/SJL Tg (+) mice compared to age-matched controls. In addition, vessels with more severe lesions showed immunopositive staining for APP and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells (EC). Significantly more mitochondrial abnormalities were seen in human AD, YAC, and C57B6/SJL Tg (+) mouse microvessels where lesions occurred. In situ hybridization using wild and chimera (5 kb) mtDNA probes revealed positive signals in damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels close to regions of large amyloid deposition. These features were absent in undamaged regions of human AD tissues, YAC and C57B6/SJL Tg (+) mouse tissues, and in age-matched control subjects. In addition, vessels with atherosclerotic lesions revealed endothelium and perivascular cells possessing clusters of wild and deleted mtDNA positive probes. These mtDNA deletions were accompanied by increased amounts of immunoreactive APP, 8-OHG, and COX in the same cellular compartment. Our observations demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress-induced damage.

Alzheimer Disease↗

PubMed2002

Labeling of cerebral amyloid beta deposits in vivo using intranasal basic fibroblast growth factor and serum amyloid P component in mice.

UNLABELLED: There is currently no method for noninvasive imaging of amyloid beta (Abeta) deposition in Alzheimer's disease (AD). Because Abeta plaques are characteristic of AD and Abeta deposits contain abundant heparan sulfate proteoglycans that can bind basic fibroblast growth factor (bFGF) and serum amyloid P component (SAP), we investigated a novel route of ligand delivery to the brain to assess Abeta deposition in a transgenic (Tg) mouse model overexpressing Abeta-protein precursor. METHODS: The biodistribution of bFGF injected intranasally was studied using (125)I-bFGF in Tg and wild-type control mice and by unlabeled bFGF and SAP immunocytochemistry with light and electron microscopy. RESULTS: Three- to 5-fold higher amounts of (125)I-bFGF were found in the brain of Tg mice than that of wild-type mice (P < 0.05). bFGF or SAP given intranasally labeled cerebral Abeta plaques in the cortex and microvessels of Tg mice but not in wild-type mice. Weak bFGF staining and no SAP staining were detected in Tg mice without intranasal injection of the ligands. bFGF and SAP stained neurons around the rim of Abeta deposits and throughout the cortex in Tg mice. There was only weak staining of neurons in Tg mice without intranasal injection of bFGF and no staining of SAP in Tg mice without intranasal injection of SAP. No bFGF or SAP staining was evident in wild-type control mice. CONCLUSION: We report a novel noninvasive method for labeling Abeta plaques. This method may be modified for human studies using intranasal injection of radiolabeled ligands and imaging with SPECT or PET.

Administration, Intranasal↗