21 results on '"Carole Harbison"'
Search Results
2. Contributors
- Author
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Basel T. Assaf, Adam D. Aulbach, Virunya Bhat, Brad Bolon, William M. Bracken, Alys E. Bradley, Glenn H. Cantor, Kevin B. Donnelly, Elodie Drevon-Gaillot, Stephen K. Durham, Jeffery A. Engelhardt, Daniela Ennulat, James Fikes, John Reginald Foster, Kathleen Funk, Sibylle Gröters, Magali R. Guffroy, Silvia Guionaud, Katherine Hammerman, Carole Harbison, Claudia Harper, Christopher Hurst, Evan B. Janovitz, Kevin Keane, Stephanie Klein, Rebecca Kohnken, Michael W. Leach, Xiantang Li, René Meisner, Keith Nelson, Thomas Nolte, Arun R. Pandiri, Jonathan A. Phillips, Colin G. Rousseaux, Daniel G. Rudmann, Keegan C. Rudmann, Aaron M. Sargeant, JoAnn C.L. Schuh, A. Eric Schultze, Rani S. Sellers, James A. Swenberg, Eric Tien, John L. Vahle, Lyn M. Wancket, and Charles E. Wood
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- 2023
3. 1153 Preclinical activity of C-C chemokine receptor 2 (CCR2)-targeted immune stimulating antibody conjugate (ISAC), motivating clinical testing of TAK-500
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Vicky Appleman, Atsushi Matsuda, Michelle Ganno, Angel Maldonado Lopez, Emily Rosentrater, Camilla Christensen, Samantha Merrigan, Hong Myung Lee, Min Young Lee, Linlin Dong, Jian Huang, Natasha Iartchouk, Dong Mei Zhang, Jianing Wang, He Xu, Tomoki Yoneyama, Konstantin Piatkov, Carole Harbison, and Adnan Abu-Yousif
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- 2022
4. Phase 1a/1b study design of the novel STING agonist, immune-stimulating antibody-conjugate (ISAC) TAK-500, with or without pembrolizumab in patients with advanced solid tumors
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Jennifer Robinson Diamond, Jason Timothy Henry, Gerald Steven Falchook, Anthony J. Olszanski, Harshabad Singh, E. Jane Leonard, Richard C. Gregory, Vicky A. Appleman, John Gibbs, Carole Harbison, Cong Li, Jessica M. Sapiro, Tomoki Yoneyama, Alexander A Parent, and Vincent Chung
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Cancer Research ,Oncology - Abstract
TPS2690 Background: Tumor resistance to immune checkpoint inhibitors (CPIs), including pembrolizumab, is common. Suggested mechanisms of resistance include reduced interferon (IFN) signaling, immune escape, and immunosuppressive tumor phenotypes. Innate immune cell stimulation in the tumor microenvironment may be a potential pathway to overcome this resistance. Stimulator of interferon genes (STING) is a cytosolic protein critical for initiation of type-1 IFN-dependent innate immunity. TAK-500 is a novel ISAC comprising a STING agonist (based on TAK-676, which is currently in phase 1 clinical trials [NCT04420884, NCT04879849]), an IgG1 anti-cysteine-cysteine chemokine receptor 2 (CCR2) antibody, and a self-immolating maleimide-containing protease-cleavable peptide linker. CCR2-expressing myeloid cells, including tumor associated macrophages (TAMs), promote immune evasion in part by reducing infiltration of CD8+ T cells into the tumor microenvironment. As such, TAK-500 has the potential to mitigate CPI resistance in solid tumors via targeted STING activation of tumor-infiltrating CCR2-expressing myeloid cells, thus leading to stimulation of innate and adaptive immunity within the tumor microenvironment through three potential mechanisms of action: activation of IFN signaling, reprogramming of CCR2-expressing myeloid cells to an inflammatory phenotype, and blockade of suppressive TAM recruitment. Methods: Adult patients with a diagnosis of locally advanced or metastatic gastroesophageal adenocarcinoma, pancreatic adenocarcinoma, hepatocellular carcinoma, non-squamous non-small cell lung cancer, squamous cell carcinoma of the head and neck, mesothelioma or triple-negative breast cancer are eligible. All patients must have progressive disease while on, or be intolerant to, all current standard therapies. Approximately 106 patients in total will be enrolled to the dose escalation and expansion cohorts. In the dose escalation phase, intravenous (IV) TAK-500 will be administered over the range 8–480 µg/kg on day 1 of every 21-day cycle (Q3W) to establish the pharmacologically active dose (PAD) range. An additional escalation cohort of patients will receive TAK-500 + IV pembrolizumab 200 mg Q3W, starting at a dose of TAK-500 that is 1–2 dose levels below the lowest PAD range established in the single agent cohort. Dose escalation in both cohorts will be guided by Bayesian Optimal Interval design. In the dose expansion phase, only the combination of TAK-500 + pembrolizumab will be evaluated. Primary objectives of this study are safety and tolerability; secondary objectives include determination of the PAD range, the recommended phase 2 dose, pharmacokinetics, pharmacodynamics, and antitumor activity of TAK-500 as a single agent and in combination with pembrolizumab. Clinical trial information: NCT05070247.
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- 2022
5. Strain- and Diet-Related Lesion Variability in Aging DBA/2, C57BL/6, and DBA/2xC57BL/6 F1 Mice
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Roderick T. Bronson, Carole Harbison, and Ruth D. Lipman
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Male ,0301 basic medicine ,C57BL/6 ,Aging ,medicine.medical_specialty ,Genotype ,Physiology ,Biology ,Lesion ,Mice ,03 medical and health sciences ,Species Specificity ,Neoplasms ,medicine ,Animals ,Gene–environment interaction ,Caloric Restriction ,Periodontitis ,General Veterinary ,Glomerulonephritis ,medicine.disease ,biology.organism_classification ,Phenotype ,Diet ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Mice, Inbred DBA ,Immunology ,Female ,Gene-Environment Interaction ,Histopathology ,medicine.symptom - Abstract
Genetic and environmental factors both play a role in the occurrence of age-related disease. To examine the genetic contribution to the development of spontaneous lesions in aging animals, a complete range of tissues was comprehensively analyzed by histopathology from 180 individually housed ad libitum–fed or 40% calorically restricted 24-month-old male and female mice of 2 parental strains—DBA/2NNia (D2) and C57BL/6NNia (B6)—and the F1 cross B6D2F1/NNia. Several strain- and diet-dependent patterns of lesions were identified. Many lesions were genotype dependent and exhibited recessive phenotypic expression, defined as being common in 1 parental strain but infrequently observed in the F1 cross (eg, glomerulonephritis in B6 mice), while others were maintained from 1 parental strain to the F1 with similar frequencies (eg, reproductive tract leiomyoma in D2 mice). Other lesions were common regardless of genotype (osteoarthritis, periodontitis). Only rare lesions were more common in the F1 but underrepresented in the 2 parental strains. Furthermore, F1 mice had a lower number of overall total lesions and a lower number of tumors than either parental strain. Caloric restriction reduced the total number of lesions and neoplasms regardless of genotype but differentially affected genotype-dependent lesions in B6 and D2 mice, with B6 mice more sensitive to the effects of caloric restriction than D2 mice. In summary, genetics and environmental factors (eg, dietary restriction) both substantially contribute to the pattern of lesions that develop as animals age.
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- 2015
6. Identification of Emerging Macrophage-Tropic HIV-1 R5 Variants in Brain Tissue of AIDS Patients without Severe Neurological Complications
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Nilsa Silva, Paul R. Clapham, Saravanan Kaliyaperumal, Paul J. Peters, Carole Harbison, Sheila Cummings Sm Macri, Olivia O'Connell, Maria Paz Gonzalez-Perez, and Katherine Luzuriaga
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0301 basic medicine ,medicine.medical_specialty ,Neurology ,viruses ,Immunology ,Population ,Spleen ,Disease ,Biology ,Virus Replication ,Genes, env ,Microbiology ,Virus ,03 medical and health sciences ,Immune system ,Virology ,medicine ,Humans ,education ,Tropism ,Acquired Immunodeficiency Syndrome ,education.field_of_study ,Macrophages ,Virion ,Brain ,virus diseases ,Virus-Cell Interactions ,Viral Tropism ,030104 developmental biology ,medicine.anatomical_structure ,Viral replication ,Blood-Brain Barrier ,Insect Science ,HIV-1 - Abstract
Untreated HIV-positive (HIV-1 + ) individuals frequently suffer from HIV-associated neurocognitive disorders (HAND), with about 30% of AIDS patients suffering severe HIV-associated dementias (HADs). Antiretroviral therapy has greatly reduced the incidence of HAND and HAD. However, there is a continuing problem of milder neurocognitive impairments in treated HIV + patients that may be increasing with long-term therapy. In the present study, we investigated whether envelope ( env ) genes could be amplified from proviral DNA or RNA derived from brain tissue of 12 individuals with normal neurology or minor neurological conditions (N/MC individuals). The tropism and characteristics of the brain-derived Envs were then investigated and compared to those of Envs derived from immune tissue. We showed that (i) macrophage-tropic R5 Envs could be detected in the brain tissue of 4/12 N/MC individuals, (ii) macrophage-tropic Envs in brain tissue formed compartmentalized clusters distinct from non-macrophage-tropic (non-mac-tropic) Envs recovered from the spleen or brain, (iii) the evidence was consistent with active viral expression by macrophage-tropic variants in the brain tissue of some individuals, and (iv) Envs from immune tissue of the N/MC individuals were nearly all tightly non-mac-tropic, contrasting with previous data for neuro-AIDS patients where immune tissue Envs mediated a range of macrophage infectivities, from background levels to modest infection, with a small number of Envs from some patients mediating high macrophage infection levels. In summary, the data presented here show that compartmentalized and active macrophage-tropic HIV-1 variants are present in the brain tissue of individuals before neurological disease becomes overt or serious. IMPORTANCE The detection of highly compartmentalized macrophage-tropic R5 Envs in the brain tissue of HIV patients without serious neurological disease is consistent with their emergence from a viral population already established there, perhaps from early disease. The detection of active macrophage-tropic virus expression, and probably replication, indicates that antiretroviral drugs with optimal penetration through the blood-brain barrier should be considered even for patients without neurological disease (neuro-disease). Finally, our data are consistent with the brain forming a sanctuary site for latent virus and low-level viral replication in the absence of neuro-disease.
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- 2017
7. Emergence of CD4 Independence Envelopes and Astrocyte Infection in R5 Simian-Human Immunodeficiency Virus Model of Encephalitis
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James Blanchard, Agegnehu Gettie, Heather Knight, Susan V. Westmoreland, Ke Zhuang, Cecilia Cheng-Mayer, Lily Tsai, Ana Rachel Leda, and Carole Harbison
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CD4-Positive T-Lymphocytes ,Receptors, CXCR5 ,viruses ,Immunology ,Population ,Simian Acquired Immunodeficiency Syndrome ,Biology ,medicine.disease_cause ,Microbiology ,Receptors, HIV ,Viral envelope ,Virology ,medicine ,Animals ,Humans ,Encephalitis, Viral ,education ,education.field_of_study ,Microglia ,Macrophages ,Brain ,Gene Products, env ,Simian immunodeficiency virus ,medicine.disease ,Virus-Cell Interactions ,Disease Models, Animal ,Viral Tropism ,medicine.anatomical_structure ,Viral replication ,Astrocytes ,Insect Science ,HIV-1 ,Tissue tropism ,Macaca ,Simian Immunodeficiency Virus ,Viral load ,Encephalitis - Abstract
Human immunodeficiency virus type 1 (HIV-1) infection in the central nervous system (CNS) is characterized by replication in macrophages or brain microglia that express low levels of the CD4 receptor and is the cause of HIV-associated dementia and related cognitive and motor disorders that affect 20 to 30% of treatment-naive patients with AIDS. Independent viral envelope evolution in the brain has been reported, with the need for robust replication in resident CD4 low cells, as well as CD4-negative cells, such as astrocytes, proposed as a major selective pressure. We previously reported giant-cell encephalitis in subtype B and C R5 simian-human immunodeficiency virus (SHIV)-infected macaques (SHIV-induced encephalitis [SHIVE]) that experienced very high chronic viral loads and progressed rapidly to AIDS, with varying degrees of macrophage or microglia infection and activation of these immune cells, as well as astrocytes, in the CNS. In this study, we characterized envelopes (Env) amplified from the brains of subtype B and C R5 SHIVE macaques. We obtained data in support of an association between severe neuropathological changes, robust macrophage and microglia infection, and evolution to CD4 independence. Moreover, the degree of Env CD4 independence appeared to correlate with the extent of astrocyte infection in vivo . These findings further our knowledge of the CNS viral population phenotypes that are associated with the severity of HIV/SHIV-induced neurological injury and improve our understanding of the mechanism of HIV-1 cellular tropism and persistence in the brain. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection of astrocytes in the brain has been suggested to be important in HIV persistence and neuropathogenesis but has not been definitively demonstrated in an animal model of HIV-induced encephalitis (HIVE). Here, we describe a new nonhuman primate (NHP) model of R5 simian-human immunodeficiency virus (SHIV)-induced encephalitis (SHIVE) with several classical HIVE features that include astrocyte infection. We further show an association between severe neuropathological changes, robust resident microglia infection, and evolution to CD4 independence of viruses in the central nervous system (CNS), with expansion to infection of truly CD4-negative cells in vivo . These findings support the use of the R5 SHIVE models to study the contribution of the HIV envelope and viral clades to neurovirulence and residual virus replication in the CNS, providing information that should guide efforts to eradicate HIV from the body.
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- 2014
8. Meeting Report
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D. L. Hutto, Prachi Sharma, Heather A. Simmons, Richard J. Montali, S. Cummings Macri, M. Owston, A. Bradley, Shiva Kumar Shanmukhappa, Saravanan Kaliyaperumal, Keith Mansfield, Lisa M. Kattenhorn, E. Gruber-Dujardin, Linda J. Lowenstine, D. Liu, Basel T. Assaf, Andrew D. Miller, Martha A. Delaney, Kerstin Mätz-Rensing, C. Tremblay, L. D. Schmidt, J. F. Reindel, Audrey Baldessari, Karen A. Terio, J. E. Markovits, Joseph L. Mankowski, J. M. Cline, Vito G. Sasseville, Cynthia L. Courtney, and Carole Harbison
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Animal Experimentation ,Male ,Primates ,medicine.medical_specialty ,Biomedical Research ,Population ,Drug Evaluation, Preclinical ,Animals, Wild ,Gorilla ,medicine.disease_cause ,Macaque ,Article ,biology.animal ,medicine ,Animals ,Primate ,Animal testing ,education ,education.field_of_study ,General Veterinary ,biology ,Bonobo ,Primate Diseases ,Cytomegalovirus ,biology.organism_classification ,Macaca mulatta ,Macaca fascicularis ,Family medicine ,Models, Animal ,Immunology ,Animals, Zoo ,Female - Abstract
The combination of loss of habitat, human population encroachment, and increased demand of select nonhuman primates for biomedical research has significantly affected populations. There remains a need for knowledge and expertise in understanding background findings as related to the age, source, strain, and disease status of nonhuman primates. In particular, for safety/biomedical studies, a broader understanding and documentation of lesions would help clarify background from drug-related findings. A workshop and a minisymposium on spontaneous lesions and diseases in nonhuman primates were sponsored by the concurrent Annual Meetings of the American College of Veterinary Pathologists and the American Society for Veterinary Clinical Pathology held December 3–4, 2011, in Nashville, Tennessee. The first session had presentations from Drs Lowenstine and Montali, pathologists with extensive experience in wild and zoo populations of nonhuman primates, which was followed by presentations of 20 unique case reports of rare or newly observed spontaneous lesions in nonhuman primates (see online files for access to digital whole-slide images corresponding to each case report at http://www.scanscope.com/ACVP%20Slide%20Seminars/2011/Primate%20Pathology/view.apml). The minisymposium was composed of 5 nonhuman-primate researchers (Drs Bradley, Cline, Sasseville, Miller, Hutto) who concentrated on background and spontaneous lesions in nonhuman primates used in drug safety studies. Cynomolgus and rhesus macaques were emphasized, with some material presented on common marmosets. Congenital, acquired, inflammatory, and neoplastic changes were highlighed with a focus on clinical, macroscopic, and histopathologic findings that could confound the interpretation of drug safety studies.
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- 2012
9. Examining the cross-reactivity and neutralization mechanisms of a panel of mAbs against adeno-associated virus serotypes 1 and 5
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John A. Chiorini, Carole Harbison, Colin R. Parrish, Mavis Agbandje-McKenna, Brittney L. Gurda, and Wendy S. Weichert
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Animal ,viruses ,Antibodies, Monoclonal ,Gene delivery ,Biology ,Cross Reactions ,Dependovirus ,medicine.disease_cause ,Antibodies, Viral ,Virology ,Cross-reactivity ,Antibodies, Neutralizing ,Neutralization ,Epitope ,Mice ,Antigen ,Immunization ,Neutralization Tests ,Immunoglobulin G ,medicine ,biology.protein ,Animals ,Antibody ,Adeno-associated virus - Abstract
Neutralizing antibodies play a central role in the prevention and clearance of viral infections, but can be detrimental to the use of viral capsids for gene delivery. Antibodies present a major hurdle for ongoing clinical trials using adeno-associated viruses (AAVs); however, relatively little is known about the antigenic epitopes of most AAV serotypes or the mechanism(s) of antibody-mediated neutralization. We developed panels of AAV mAbs by repeatedly immunizing mice with AAV serotype 1 (AAV1) capsids, or by sequentially immunizing with AAV1 followed by AAV5 capsids, in order to examine the efficiency and mechanisms of antibody-mediated neutralization. The antibodies were not cross-reactive between heterologous AAV serotypes except for a low level of recognition of AAV1 capsids by the AAV5 antibodies, probably due to the initial immunization with AAV1. The neutralization efficiency of different IgGs varied and Fab fragments derived from these antibodies were generally poorly neutralizing. The antibodies appeared to display various alternative mechanisms of neutralization, which included inhibition of receptor-binding and interference with a post-attachment step.
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- 2012
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10. Role of Multiple Hosts in the Cross-Species Transmission and Emergence of a Pandemic Parvovirus
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Edward J. Dubovi, Jason T. Kaelber, Karla M. Stucker, Carole Harbison, Andrew B. Allison, Colin R. Parrish, Justin C. Brown, Michael K Keel, Israel Pagán, Edward C. Holmes, and Mark G. Ruder
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Antigenicity ,animal diseases ,viruses ,Molecular Sequence Data ,Immunology ,Cross-species transmission ,Transferrin receptor ,Biology ,Microbiology ,Host Specificity ,Virus ,Cell Line ,Parvoviridae Infections ,Parvovirus ,Dogs ,Antigen ,Virology ,Disease Transmission, Infectious ,Animals ,Pandemics ,Phylogeny ,Canine parvovirus ,biology.organism_classification ,Biological Evolution ,United States ,Genetic Diversity and Evolution ,Capsid ,Insect Science ,Cats ,Capsid Proteins ,Raccoons - Abstract
Understanding the mechanisms of cross-species virus transmission is critical to anticipating emerging infectious diseases. Canine parvovirus type 2 (CPV-2) emerged as a variant of a feline parvovirus when it acquired mutations that allowed binding to the canine transferrin receptor type 1 (TfR). However, CPV-2 was soon replaced by a variant virus (CPV-2a) that differed in antigenicity and receptor binding. Here we show that the emergence of CPV involved an additional host range variant virus that has circulated undetected in raccoons for at least 24 years, with transfers to and from dogs. Raccoon virus capsids showed little binding to the canine TfR, showed little infection of canine cells, and had altered antigenic structures. Remarkably, in capsid protein (VP2) phylogenies, most raccoon viruses fell as evolutionary intermediates between the CPV-2 and CPV-2a strains, suggesting that passage through raccoons assisted in the evolution of CPV-2a. This highlights the potential role of alternative hosts in viral emergence.
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- 2012
11. Immunohistochemical Characterization of Large Intestinal Adenocarcinoma in the Rhesus Macaque (Macaca mulatta)
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Andrew D. Miller, Carole Harbison, F. Taheri, and Heather Knight
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Male ,Pathology ,medicine.medical_specialty ,Macaque ,Cecum ,Ileocecal junction ,biology.animal ,Intestinal Neoplasms ,medicine ,Biomarkers, Tumor ,Animals ,Intestinal Mucosa ,beta Catenin ,Retrospective Studies ,General Veterinary ,biology ,Sirtuin 1 ,Monkey Diseases ,Mucins ,Large intestinal ,medicine.disease ,biology.organism_classification ,Prognosis ,Adenocarcinoma, Mucinous ,Immunohistochemistry ,Macaca mulatta ,Intestines ,Rhesus macaque ,medicine.anatomical_structure ,biology.protein ,Adenocarcinoma ,Female - Abstract
In rhesus macaques, adenocarcinomas of either the ileocecal junction or colon are common spontaneous tumors in aging populations. The macaque tumors have similar gross and histologic characteristics compared with their human counterpart, but little is known regarding the immunohistochemical expression of proteins that are commonly implicated in the pathogenesis of these tumors in humans. We performed a retrospective review of 22 cases of large intestinal carcinoma in the rhesus macaque and evaluated the expression pattern of a panel of potentially prognostically significant proteins identified from human studies. Histologic characteristics of the tumors included abundant mucin deposition, transmural spread, and lymphatic invasion. All rhesus adenocarcinomas displayed altered expression of 1 or more of CD10, β-catenin, sirtuin 1, cytokeratin 17, and p53 compared with age-matched controls. Zymographic analysis of active matrix metalloproteinases 2 and 9 in the serum from 5 animals failed to reveal statistically significant differences between adenocarcinoma cases and controls. Based on the data presented herein, large intestinal carcinomas in the macaque share many histomorphologic and immunohistochemical similarities to large intestinal tumors in humans. Further validation of this animal model is considered important for the development of novel therapeutics and a better understanding of the pathogenesis.
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- 2014
12. Giant cell encephalitis and microglial infection with mucosally transmitted simian-human immunodeficiency virus SHIVSF162P3N in rhesus macaques
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Cecilia Cheng-Mayer, James Blanchard, Peter J. Didier, Susan V. Westmoreland, Agegnehu Gettie, Ke Zhuang, Carole Harbison, and Heather Knight
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AIDS Dementia Complex ,viruses ,Simian Acquired Immunodeficiency Syndrome ,Simian ,medicine.disease_cause ,Giant Cells ,Virus ,Article ,Pathogenesis ,Cellular and Molecular Neuroscience ,Virology ,medicine ,Animals ,Microglia ,biology ,virus diseases ,Simian immunodeficiency virus ,medicine.disease ,biology.organism_classification ,Macaca mulatta ,Rhesus macaque ,medicine.anatomical_structure ,Neurology ,Giant cell ,Immunology ,Simian Immunodeficiency Virus ,Neurology (clinical) ,Encephalitis - Abstract
Neurocognitive disorders such as dementia and cognitive/motor impairments are among the most significant complications associated with human immunodeficiency virus (HIV) infection, especially in aging populations, yet the pathogenesis remains poorly understood. Activated macrophages and microglia in white matter along with the hallmark multinucleated giant cells are prominent features of HIV encephalitis (HIVE) and of several simian immunodeficiency virus (SIV) models. While infected microglia have been demonstrated in HIVE, this feature is not routinely seen in experimental infections in rhesus macaques using SIV or chimeric simian/HIV (SHIV) strains, limiting utility in HIV-1 pathogenesis and treatment studies. Here, 50 rhesus macaques were inoculated with the CCR5 (R5)-tropic SHIVSF162P3N virus by one of three routes: intravenously (n = 9), intrarectally (n = 17), or intravaginally (n = 24). Forty-three monkeys became viremic, 26 developed AIDS, and 7 (7/26, 27 %) developed giant cell SIV encephalitis (SIVE). Rapid progressor phenotype was evident in five of seven (71 %) macaques with SIVE, and expansion to utilize the CXCR4 coreceptor (X4 coreceptor switch) was observed in four out of seven (57 %). SIVE lesions were present in gray and white matter in the cerebrum, cerebellum, thalamus, and brain stem of affected animals. Lesions were composed of virally infected CD68(+), CD163(+), and HLA-DR(+) macrophages accompanied by white matter damage, necrosis, and astroglial and microglial activation. Importantly, microglial infection was observed, which makes R5 SHIVSF162P3N infection of macaques an attractive animal model not only to study transmission and HIVE pathogenesis but also to conduct preclinical evaluation of therapeutic interventions aimed at eradicating HIV-1 from the central nervous system (CNS).
- Published
- 2014
13. Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer
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Quan Zhu, Jeffrey Pudney, Deborah J. Anderson, Wayne A. Marasco, Ussama M. Abdel-Motal, Thomas Han, Susan V. Westmoreland, and Carole Harbison
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viruses ,Genetic Vectors ,HIV Infections ,Biology ,HIV Antibodies ,HIV Envelope Protein gp120 ,Virus ,Article ,Cell Line ,AAV vectors ,Gene therapy ,Microbicide ,Genetics ,Animals ,Humans ,Vector (molecular biology) ,Molecular Biology ,Infectivity ,Epithelial Cells ,Genitalia, Female ,Dependovirus ,biology.organism_classification ,Virology ,Macaca mulatta ,In vitro ,3. Good health ,AIDS ,Rhesus macaque ,Cell culture ,Immunology ,HIV-1 ,Molecular Medicine ,Female ,Stem cell ,microbicide ,HeLa Cells ,epithelial stem cells ,rhesus macaque - Abstract
Topical microbicides are a leading strategy for prevention of HIV mucosal infection to women; however, numerous pharmacokinetic limitations associated with coitally related dosing strategy have contributed to their limited success. Here we test the hypothesis that adeno-associated virus (AAV) mediated delivery of the b12 human anti-HIV-1 gp120 minibody gene to the lower genital tract of female rhesus macaques (Rh) can provide prolonged expression of b12 minibodies in the cervical-vaginal secretions. Gene transfer studies demonstrated that, of various green fluorescent protein (GFP)-expressing AAV serotypes, AAV-6 most efficiently transduced freshly immortalized and primary genital epithelial cells (PGECs) of female Rh in vitro. In addition, AAV-6-b12 minibody transduction of Rh PGECs led to inhibition of SHIV162p4 transmigration and virus infectivity in vitro. AAV-6-GFP could also successfully transduce vaginal epithelial cells of Rh when applied intravaginally, including p63+ epithelial stem cells. Moreover, intravaginal application of AAV-6-b12 to female Rh resulted in prolonged minibody detection in their vaginal secretions throughout the 79-day study period. These data provide proof of principle that AAV-6-mediated delivery of anti-HIV broadly neutralizing antibody (BnAb) genes to the lower genital tract of female Rh results in persistent minibody detection for several months. This strategy offers promise that an anti-HIV-1 genetic microbicide strategy may be possible in which topical application of AAV vector, with periodic reapplication as needed, may provide sustained local BnAb expression and protection.
- Published
- 2013
14. Meeting report: Emerging respiratory viral infections and nonhuman primate case reports
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L. K. Crawford, E. J. Dick, Ingrid D. Pardo, D. Liu, Robert D. Murnane, M. G. Evans, Joseph L. Mankowski, S. Laing, L. D. Schmidt, Karen A. Terio, Vito G. Sasseville, S. M. Corner, Andrew D. Miller, J. Kaplan-Kees, Audrey Baldessari, J. H. Lane, Kerstin Mätz-Rensing, J. R. Reader, Carole Harbison, and Saravanan Kaliyaperumal
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Male ,medicine.medical_specialty ,General Veterinary ,Clinical pathology ,Pan troglodytes ,business.industry ,Primate Diseases ,Macaca mulatta ,Nonhuman primate ,Macaca fascicularis ,Virus Diseases ,Family medicine ,Immunology ,medicine ,Animals ,Macaca ,Female ,Respiratory system ,Macaca nemestrina ,business ,Respiratory Tract Infections ,Papio - Abstract
A workshop on Emerging Respiratory Viral Infections and Spontaneous Diseases in nonhuman primates was sponsored by the concurrent Annual Meetings of the American College of Veterinary Pathologists and the American Society for Veterinary Clinical Pathology, held December 1-5, 2012, in Seattle, Washington. The session had platform presentations from Drs Karen Terio, Thijs Kuiken, Guy Boivin, and Robert Palermo that focused on naturally occurring influenza, human respiratory syncytial virus, and metapneumovirus in wild and zoo-housed great apes; the molecular biology and pathology of these viral respiratory diseases in nonhuman primate (NHP) models; and the therapeutic and vaccine approaches to prevention and control of these emerging respiratory viral infections. These formal presentations were followed by presentations of 14 unique case studies of rare or newly observed spontaneous lesions in NHPs (see online files for access to digital whole-slide images corresponding to each case report at http://scanscope.com/ACVP%20Slide%20Seminars/2012/Primate%20Pathology/view.apml). The session was attended by meeting participants that included students, pathology trainees, and experienced pathologists from academia and industry with an interest in respiratory and spontaneous diseases of NHPs.
- Published
- 2013
15. Effects of canine parvovirus strain variations on diagnostic test results and clinical management of enteritis in dogs
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Jessica E. Markovich, Karla M. Stucker, Janet M. Scarlett, Alaina H Carr, Carole Harbison, and Colin R. Parrish
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Male ,Genotype ,Parvovirus, Canine ,animal diseases ,viruses ,Enzyme-Linked Immunosorbent Assay ,Polymerase Chain Reaction ,Sensitivity and Specificity ,Severity of Illness Index ,Enteritis ,Diagnosis, Differential ,Parvoviridae Infections ,Feces ,Dogs ,Antigen ,medicine ,Animals ,Dog Diseases ,Prospective Studies ,General Veterinary ,Strain (chemistry) ,biology ,Parvovirus ,Canine parvovirus ,Diagnostic test ,biology.organism_classification ,medicine.disease ,Virology ,Female - Abstract
Objective—To estimate the prevalence of canine parvovirus (CPV) strains among dogs with enteritis admitted to a referral hospital in the southwestern United States during an 11-month period and to compare diagnostic test results, disease severity, and patient outcome among CPV strains. Design—Prospective observational study. Animals—72 dogs with histories and clinical signs of parvoviral enteritis. Procedures—For each dog, a fecal sample or rectal swab specimen was evaluated for CPV antigen via an ELISA. Subsequently, fecal samples (n = 42 dogs) and pharyngeal swab specimens (16) were obtained and tested for CPV antigen via an ELISA and CPV DNA via a PCR assay. For specimens with CPV-positive results via PCR assay, genetic sequencing was performed to identify the CPV strain. Results—56 dogs tested positive for CPV via ELISA or PCR assay. For 42 fecal samples tested via both ELISA and PCR assay, 27 had positive results via both assays, whereas 6 had positive PCR assay results only. Ten pharyngeal swab specimens yielded positive PCR assay results. Genetic sequencing was performed on 34 fecal or pharyngeal swab specimens that had CPV-positive PCR assay results; 25 (73.5%) were identified as containing CPV type-2c, and 9 (26.5%) were identified as containing CPV type-2b. No association was found between CPV strain and disease severity or clinical outcome. Conclusions and Clinical Relevance—CPV type-2b and CPV type-2c posed similar health risks for dogs; therefore, genetic sequencing of CPV does not appear necessary for clinical management of infected patients. The diagnostic tests used could detect CPV type-2c.
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- 2012
16. Limited transferrin receptor clustering allows rapid diffusion of canine parvovirus into clathrin endocytic structures
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Colin R. Parrish, David K. Cureton, Tomas Kirchhausen, Carole Harbison, and Emmanuele Cocucci
- Subjects
Parvovirus, Canine ,media_common.quotation_subject ,viruses ,Immunology ,Endocytic cycle ,Transferrin receptor ,Biology ,Endocytosis ,Microbiology ,Clathrin ,Cell Line ,Cell membrane ,Diffusion ,Capsid ,Dogs ,Virology ,Receptors, Transferrin ,medicine ,Animals ,Internalization ,media_common ,Parvovirus ,Virus Assembly ,Cell Membrane ,Canine parvovirus ,Coated Pits, Cell-Membrane ,Virus Internalization ,biology.organism_classification ,Cell biology ,Virus-Cell Interactions ,Kinetics ,medicine.anatomical_structure ,Insect Science ,biology.protein ,Cats ,Receptors, Virus ,Protein Binding - Abstract
Viral pathogens usurp cell surface receptors to access clathrin endocytic structures, yet the mechanisms of virus incorporation into these structures remain incompletely understood. Here we used fluorescence microscopy to directly visualize the association of single canine parvovirus (CPV) capsids with cellular transferrin receptors (TfR) on the surfaces of live feline cells and to monitor how these CPV-TfR complexes access endocytic structures. We found that most capsids associated with fewer than five TfRs and that ∼25% of TfR-bound capsids laterally diffused into assembling clathrin-coated pits less than 30 s after attachment. Capsids that did not encounter a coated pit dissociated from the cell surface with a half-life of ∼30 s. Together, our results show how CPV exploits the natural mechanism of TfR endocytosis to engage the clathrin endocytic pathway and reveal that the low affinity of capsids for feline TfRs limits the residence time of capsids on the cell surface and thus the efficiency of virus internalization.
- Published
- 2012
17. Early steps in cell infection by parvoviruses: host-specific differences in cell receptor binding but similar endosomal trafficking
- Author
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Colin R. Parrish, Carole Harbison, Wendy S. Weichert, and Sangbom M. Lyi
- Subjects
Parvovirus, Canine ,viruses ,Cells ,Immunology ,Transferrin receptor ,Feline panleukopenia ,Endosomes ,Endocytosis ,Microbiology ,Virus ,Cell Line ,Dogs ,Species Specificity ,Virology ,Receptors, Transferrin ,Animals ,Pseudopodia ,biology ,Canine parvovirus ,biology.organism_classification ,Virus-Cell Interactions ,Cell culture ,rab GTP-Binding Proteins ,Insect Science ,Host-Pathogen Interactions ,Cats ,Receptors, Virus ,Capsid Proteins ,Rab ,Feline Panleukopenia Virus ,Intracellular - Abstract
Canine parvovirus (CPV) and feline panleukopenia virus (FPV) are closely related parvoviruses that differ in their host ranges for cats and dogs. Both viruses bind their host transferrin receptor (TfR), enter cells by clathrin-mediated endocytosis, and traffic with that receptor through endosomal pathways. Infection by these viruses appears to be inefficient and slow, with low numbers of virions infecting the cell after a number of hours. Species-specific binding to TfR controls viral host range, and in this study FPV and strains of CPV differed in the levels of cell attachment, uptake, and infection in canine and feline cells. During infection, CPV particles initially bound and trafficked passively on the filopodia of canine cells while they bound to the cell body of feline cells. That binding was associated with the TfR as it was disrupted by anti-TfR antibodies. Capsids were taken up from the cell surface with different kinetics in canine and feline cells but, unlike transferrin, most did not recycle. Capsids labeled with fluorescent markers were seen in Rab5-, Rab7-, or Rab11-positive endosomal compartments within minutes of uptake, but reached the nucleus. Constitutively active or dominant negative Rab mutants changed the intracellular distribution of capsids and affected the infectivity of virus in cells.
- Published
- 2009
18. The parvovirus capsid odyssey: from the cell surface to the nucleus
- Author
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John A. Chiorini, Carole Harbison, and Colin R. Parrish
- Subjects
Microbiology (medical) ,Cell type ,Cytoplasm ,Endosome ,viruses ,Cell ,Endosomes ,Biology ,Microbiology ,Parvovirus ,Capsid ,Virology ,medicine ,Animals ,Humans ,Receptor ,Cell Nucleus ,Cell Membrane ,biology.organism_classification ,Cell biology ,Infectious Diseases ,medicine.anatomical_structure ,Nucleus - Abstract
During cellular entry and infection, the parvovirus capsid follows a complex path from the cell surface to the nucleus, where the DNA is replicated. Various receptors have been characterized that bind to different parvoviruses and mediate their entry into cells. However, the subsequent trafficking pathways within the endosomal system, cytoplasm and into the nucleus are still not well defined. Studies of viruses entering various cell types under different conditions show particles located in many different endosomal compartments, within the cytoplasm and in the nucleus with significant variations in timing and distribution. Here, we define the previously unresolved issues that are now better understood for the infection pathways of these viruses, and outline some of the areas that remain to be clarified in future studies.
- Published
- 2007
19. Feline aminopeptidase N is not a functional receptor for avian infectious bronchitis virus
- Author
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Lisa J. McElroy, Jed M Aronson, Trisha J. Oura, Carole Harbison, Victor C. Chu, Beverley E. Bauman, and Gary R. Whittaker
- Subjects
animal structures ,Human coronavirus 229E ,viruses ,Infectious bronchitis virus ,Virus Attachment ,CD13 Antigens ,medicine.disease_cause ,lcsh:Infectious and parasitic diseases ,Cell Line ,03 medical and health sciences ,Cricetinae ,Virology ,Baby hamster kidney cell ,medicine ,Animals ,lcsh:RC109-216 ,Receptor ,030304 developmental biology ,Coronavirus ,0303 health sciences ,biology ,030306 microbiology ,Research ,Canine coronavirus ,biology.organism_classification ,3. Good health ,Infectious Diseases ,Cell culture ,embryonic structures ,Cats ,Receptors, Virus ,Avian infectious bronchitis virus ,Chickens - Abstract
Background Coronaviruses are an important cause of infectious diseases in humans, including severe acute respiratory syndrome (SARS), and have the continued potential for emergence from animal species. A major factor in the host range of a coronavirus is its receptor utilization on host cells. In many cases, coronavirus-receptor interactions are well understood. However, a notable exception is the receptor utilization by group 3 coronaviruses, including avian infectious bronchitis virus (IBV). Feline aminopeptidase N (fAPN) serves as a functional receptor for most group 1 coronaviruses including feline infectious peritonitis virus (FIPV), canine coronavirus, transmissible gastroenteritis virus (TGEV), and human coronavirus 229E (HCoV-229E). A recent report has also suggested a role for fAPN during IBV entry (Miguel B, Pharr GT, Wang C: The role of feline aminopeptidase N as a receptor for infectious bronchitis virus. Brief review. Arch Virol 2002, 147:2047–2056. Results Here we show that, whereas both transient transfection and constitutive expression of fAPN on BHK-21 cells can rescue FIPV and TGEV infection in non-permissive BHK cells, fAPN expression does not rescue infection by the prototype IBV strain Mass41. To account for the previous suggestion that fAPN could serve as an IBV receptor, we show that feline cells can be infected with the prototype strain of IBV (Mass 41), but with low susceptibility compared to primary chick kidney cells. We also show that BHK-21 cells are slightly susceptible to certain IBV strains, including Ark99, Ark_DPI, CA99, and Iowa97 ( Conclusion We conclude that fAPN is not a functional receptor for IBV, the identity of which is currently under investigation.
- Published
- 2007
20. Evolutionary Reconstructions of the Transferrin Receptor of Caniforms Supports Canine Parvovirus Being a Re-emerged and Not a Novel Pathogen in Dogs
- Author
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Alicia N. Ortega, Jason T. Kaelber, Sara L. Sawyer, Carole Harbison, Andrew B. Allison, Laura B. Goodman, Colin R. Parrish, and Ann Demogines
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Glycosylation ,viruses ,medicine.disease_cause ,Emerging Viral Diseases ,Cricetinae ,Dog Diseases ,Biology (General) ,Phylogeny ,Genetics ,0303 health sciences ,Mutation ,Transferrin ,Canine parvovirus ,Biological Evolution ,Jackal ,Viral evolution ,Host-Pathogen Interactions ,Receptors, Virus ,Research Article ,Protein Binding ,Virus genetics ,Parvovirus, Canine ,QH301-705.5 ,Immunology ,Transferrin receptor ,CHO Cells ,Biology ,Viral Attachment ,Microbiology ,Viral Evolution ,Parvoviridae Infections ,03 medical and health sciences ,Capsid ,Dogs ,Species Specificity ,Virology ,biology.animal ,Receptors, Transferrin ,medicine ,Animals ,Amino Acid Sequence ,Selection, Genetic ,Molecular Biology ,Gene ,Canidae ,030304 developmental biology ,Base Sequence ,030306 microbiology ,Parvovirus ,Host Cells ,Sequence Analysis, DNA ,RC581-607 ,biology.organism_classification ,Capsid Proteins ,Parasitology ,Immunologic diseases. Allergy ,Viral Transmission and Infection - Abstract
Parvoviruses exploit transferrin receptor type-1 (TfR) for cellular entry in carnivores, and specific interactions are key to control of host range. We show that several key mutations acquired by TfR during the evolution of Caniforms (dogs and related species) modified the interactions with parvovirus capsids by reducing the level of binding. These data, along with signatures of positive selection in the TFRC gene, are consistent with an evolutionary arms race between the TfR of the Caniform clade and parvoviruses. As well as the modifications of amino acid sequence which modify binding, we found that a glycosylation site mutation in the TfR of dogs which provided resistance to the carnivore parvoviruses which were in circulation prior to about 1975 predates the speciation of coyotes and dogs. Because the closely-related black-backed jackal has a TfR similar to their common ancestor and lacks the glycosylation site, reconstructing this mutation into the jackal TfR shows the potency of that site in blocking binding and infection and explains the resistance of dogs until recent times. This alters our understanding of this well-known example of viral emergence by indicating that canine parvovirus emergence likely resulted from the re-adaptation of a parvovirus to the resistant receptor of a former host., Author Summary Parvoviruses in cats and dogs have been studied as a model system to understand how viruses gain the ability to infect new host species. By studying the evolution of the transferrin receptor, which the virus uses to enter a cell, we discovered that the ancestors of dogs were likely infected by a parvovirus millions of years ago until they evolved and became resistant; this was caused by their transferrin receptor changing so it no longer bound the virus. When a variant virus that infects dogs emerged in the 1970s, it had adapted to overcome this block. This story suggests that diseases which were once eliminated from a species can evolve and regain the infectivity for that host, therefore having high potential to be emerging diseases. We identified features of the receptor that were important to the evolution of this host-virus interaction and confirmed their role in regulating virus binding in cell culture.
- Published
- 2012
21. Mucosal transmissibility, disease induction and coreceptor switching of R5 SHIVSF162P3N molecular clones in rhesus macaques
- Author
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Carole Harbison, Ke Zhuang, Heather Knight, Alexandra Mumbauer, Susan V. Westmoreland, Cecilia Cheng-Mayer, James Blanchard, Agegnehu Gettie, and Wuze Ren
- Subjects
lcsh:Immunologic diseases. Allergy ,CD4-Positive T-Lymphocytes ,Receptors, CCR5 ,Coreceptor switch ,Simian Acquired Immunodeficiency Syndrome ,Disease ,HIV Antibodies ,HIV Envelope Protein gp120 ,medicine.disease_cause ,R5 SHIV molecular clone ,Immunodeficiency virus ,Neutralization ,Macrophage infection ,03 medical and health sciences ,Receptors, HIV ,Antiviral antibody response ,Virology ,medicine ,Animals ,030304 developmental biology ,Recombination, Genetic ,0303 health sciences ,Mucous Membrane ,biology ,030306 microbiology ,Research ,Rectum ,Simian immunodeficiency virus ,Virus Internalization ,Antibodies, Neutralizing ,Macaca mulatta ,Transmissibility (vibration) ,3. Good health ,Viral Tropism ,Infectious Diseases ,Amino Acid Substitution ,biology.protein ,Tissue tropism ,HIV-1 ,Simian Immunodeficiency Virus ,Antibody ,lcsh:RC581-607 - Abstract
Background Mucosally transmissible and pathogenic CCR5 (R5)-tropic simian-human immunodeficiency virus (SHIV) molecular clones are useful reagents to identity neutralization escape in HIV-1 vaccine experiments and to study the envelope evolutionary process and mechanistic basis for coreceptor switch during the course of natural infection. Results We observed progression to AIDS in rhesus macaques infected intrarectally with molecular clones of the pathogenic R5 SHIVSF162P3N isolate. Expansion to CXCR4 usage was documented in one diseased macaque that mounted a neutralizing antibody response and in another that failed to do so, with the latter displaying a rapid progressor phenotype. V3 loop envelop glycoprotein gp120 sequence changes that are predictive of a CXCR4 (X4)-using phenotype in HIV-1 subtype B primary isolates, specifically basic amino acid substations at positions 11 (S11R), 24 (G24R) and 25 (D25K) of the loop were detected in the two infected macaques. Functional assays showed that envelopes with V3 S11R or D25K mutation were dual-tropic, infecting CD4+ target cells that expressed either the CCR5 or CXCR4 coreceptor. And, consistent with findings of coreceptor switching in macaques infected with the pathogenic isolate, CXCR4-using variant was first detected in the lymph node of the chronically infected rhesus monkey several weeks prior to its presence in peripheral blood. Moreover, X4 emergence in this macaque coincided with persistent peripheral CD4+ T cell loss and a decline in neutralizing antibody titer that are suggestive of immune deterioration, with macrophages as the major virus-producing cells at the end-stage of disease. Conclusions The data showed that molecular clones derived from the R5 SHIVSF162P3N isolate are mucosally transmissible and induced disease in a manner similar to that observed in HIV-1 infected individuals, providing a relevant and useful animal infection model for in-depth analyses of host selection pressures and the env evolutionary changes that influence disease outcome, coreceptor switching and vaccine escape.
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