Medical Pathology Commons^™

Escherichia Coli Surface Display Of Single-Chain Antibody Vrc01 Against Hiv-1 Infection, Lin-Xu Wang, Michael Mellon, Dane Bowder, Meghan Quinn, Danielle Shea, Charles Wood, Shi-Hua Xiang

Nebraska Center for Virology: Faculty Publications

Human immunodeficiency virus type 1 (HIV-1) transmission and infection occur mainly via the mucosal surfaces. The commensal bacteria residing in these surfaces can potentially be employed as a vehicle for delivering inhibitors to prevent HIV-1 infection. In this study, we have employed a bacteria-based strategy to display a broadly neutralizing antibody VRC01, which could potentially be used to prevent HIV-1 infection. The VRC01 antibody mimics CD4-binding to gp120 and has broadly neutralization activities against HIV-1. We have designed a construct that can express the fusion peptide of the scFv-VRC01 antibody together with the autotransporter β-barrel domain of IgAP gene from …

Evidence For Placental Hpv Infection In Both Hiv Positive And Negative Women, Chrispin Chisanga, Dawn Eggert, Charles D. Mitchell, Charles Wood, Peter C. Angeletti

Nebraska Center for Virology: Faculty Publications

Human papillomaviruses (HPVs) have previously been reported to infect epithelial trophoblast cells of the placenta. To investigate this possibility, 200 placental samples from Zambian women were separated into HIV+ and HIV− groups and tested for HPV by redundant primer PCR, using GP5+/GP6+ and CPI/CPII primer sets. Three HPV genotypes (HPV6, 16 and 90) were detected in placental samples. Whereas, 20 different HPV genotypes were detected in vaginal sampling of the same patients, suggesting that compartment specific sub-populations of HPV may exist. The incidence of HPV16 in placental samples was almost 2-fold greater in HIV+ women compared to HIV− (p = …

The Hippo/Yap Pathway Interacts With Egfr Signaling And Hpv Oncoproteins To Regulate Cervical Cancer Progression, Chunbo He, Dagan Mao, Guohua Hua, Xiangmin Lv, Xingcheng Chen, Peter C. Angeletti, Jixin Dong, Steven W. Remmenga, Kerry J. Rodabaugh, Jin Zhou, Paul F. Lambert, Peixin Yang, John S. Davis, Cheng Wang

Nebraska Center for Virology: Faculty Publications

The Hippo signaling pathway controls organ size and tumorigenesis

through a kinase cascade that inactivates Yes-associated

protein (YAP). Here, we show that YAP plays a central role in

controlling the progression of cervical cancer. Our results suggest

that YAP expression is associated with a poor prognosis for cervical

cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo

signaling pathway and activate YAP to induce cervical cancer cell

proliferation and migration. Activated YAP allows for up-regulation

of TGF-α, AREG, and EGFR, forming a positive signaling loop to

drive cervical cancer cell proliferation. HPV E6 protein, a major

etiological molecule of …

Kaposi’S Sarcoma At The University Teaching Hospital, Lusaka, Zambia In The Antiretroviral Therapy Era, Owen Ngalamika, Veenu Minhas, Charles Wood

Nebraska Center for Virology: Faculty Publications

With great interest, we read the recent publication “Kaposi’s sarcoma in HIV-infected patients in South Africa: Multicohort study in the antiretroviral therapy era” by Bohlius et al. We congratulate the authors for their contribution to this field. In this study the authors observed a decrease in incidence of Kaposi’s sarcoma (KS) in patients treated with anti-retroviral therapy (ART) when compared to patients who are not on ART. These results are encouraging because of the ongoing HIV epidemic in sub-Saharan Africa where KS is still one of the most prevalent cancers. Also, it is a relevant topic to study in …

Activation And Degradation Of Open Reading Frame 45 By The Replication And Transcription Activator Of Kaposi's Sarcoma-Associated Herpesvirus, Ying Wang, Kai Yu, Xiuzhi Pei, Tiancheng Zhang, Yuying Guo, Charles Wood, Jinzhong Wang

Nebraska Center for Virology: Faculty Publications

The open reading frame 45 (ORF45) of the Kaposi's sarcoma-associated herpesvirus (KSHV) is an immediate-early phosphorylated tegument protein critical for viral escape from host immune surveillance. Its expression is upregulated by the viral replication and transcription activator (RTA), a key protein that controls the switch from latency to lytic replication. We report here that ORF45 expression was not only upregulated by RTA, but ORF45 could also be degraded by RTA in a proteasome-dependent manner. The ORF45 was activated by RTA via activation of the ORF45 promoter, and the promoter region from nt 69 271 to nt 69 026 was involved. …

Single-Dose Cpg Immunization Protects Against A Heterosubtypic Challenge And Generates Antigen-Specific Memory T Cells, Alexander J. Vogel, Deborah M. Brown

Nebraska Center for Virology: Faculty Publications

Despite extensive research, influenza A virus (IAV) remains a major cause of morbidity, mortality, and healthcare expenditure. Emerging pandemics from highly pathogenic IAV strains, such as H5N1 and pandemic H1N1, highlight the need for universal, crossprotective vaccines. Current vaccine formulations generate strain-specific neutralizing antibodies primarily against the outer coat proteins, hemagglutinin and neuraminidase. In contrast to these highly mutable proteins, internal proteins of IAV are more conserved and are a favorable target for developing vaccines that induce strong T cell responses in addition to humoral immunity. Here, we found that intranasal administration with a single dose of CpG and inactivated …

Long-Acting Parenteral Combination Antiretroviral Loaded Nano-Drug Delivery System To Treat Chronic Hiv-1 Infection: A Humanized Mouse Model Study, Subhra Mandal, Guobin Kang, Pavan Kumar Prathipati, Wenjin Fan, Qingsheng Li, Christopher J. Destache

Nebraska Center for Virology: Faculty Publications

Human immunodeficiency virus (HIV) patients are often diagnosed in the chronic stage of HIV/AIDS. Combination antiretroviral therapy (cART) has improved quality of life for HIV-infected patients. Present study describes a novel long-acting parenteral formulation of combination antiretroviral (cARV) loaded nano-drugs for treating chronic HIV-1 (cHIV) in a humanized-BLT (hu-BLT) mice model. The cARV (elvitegravir + tenofovir alafenamide + emtricitabine; EVG + TAF + FTC) drugs (mimicking marketed Genvoy® one-pill for HIV-treatment) were encapsulated in poly (lactic-co-glycolic acid) nanoparticles (NPs). To establish cHIV, hu-BLT mice were intravaginally challenged with HIV-1 and maintained for 15 weeks. Plasma viral load (pVL) was monitored …

Imaging Luciferase-Expressing Viruses, Michael A. Barry, Shannon May, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

Optical imaging of luciferage gene expression has become a powerful tool to track cells and viruses in vivo in small animal models. Luciferase imaging has been used to study the location of infection by replication-defective and replication-competent viruses and to track changes in the distribution of viruses in mouse models. This approach has also been used in oncolytic studies as a non-invasive means to monitor the growth and killing of tumor cells modified with luciferase genes. In this chapter, we describe the techniques used for luciferase imaging as have been applied to track replication-defective and replication-competent adenoviruses in mouse and …

The Mucosal Expression Pattern Of Interferon-Ε In Rhesus Macaques, Andrew Demers, Guobin Kang, Fangrui Ma, Wuxun Lu, Zhe Yuan, Yue Li, Mark Lewis, Edmundo N. Kraiselburd, Luis Montaner, Qingsheng Li

Qingsheng Li Publications

Type I IFNs play an important role in innate and adaptive immunity against viral infections. A novel type I IFN, namely IFN-ε, which can protect against vaginal transmission of HSV2 and Chlamydia muridarum bacterial infection, has been described in mice and humans. Nevertheless, the principle cell type and the expression pattern of IFN-ε in tissues remain uncertain. In addition, the expression of IFN-ε in Indian rhesus macaques (Macaca mulatta) has not been reported. Here, we analyzed IFN-ε expression in multiple mucosal sites of uninfected or SIV-infected Indian rhesus macaques using IHCS. We report for the first time the …

Cd46-Mediated Transduction Of A Species D Adenovirus Vaccine Improves Mucosal Vaccine Efficacy, Zenaido T. Camacho, Michael A. Barry, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

The high levels of preexisting immunity against Adenovirus type 5 (Ad5) have deemed Ad5 unusable for translation as a human vaccine vector. Low seroprevalent alternative viral vectors may be less impacted by preexisting immunity, but they may also have significantly different phenotypes from that of Ad5. In this study we compare species D Ads (26, 28, and 48) to the species C Ad5. In vitro transduction studies show striking differences between the species C and D viruses. Most notably, Ad26 transduced human dendritic cells much more effectively than Ad5. In vivo imaging studies showed strikingly different transgene expression profiles. The …

Deep Rna Sequencing Reveals Hidden Features And Dynamics Of Early Gene Transcription In Paramecium Bursaria Chlorella Virus 1, Guillaume Blanc, Michael Mozar, Irina V. Agarkova, James R. Gurnon, Giane Yanai-Balser, Janet M. Rowe, Yuannan Xia, Jean-Jack Riethoven, David D. Dunigan, James L. Van Etten

Nebraska Center for Virology: Faculty Publications

Paramecium bursaria chlorella virus 1 (PBCV-1) is the prototype of the genus Chlorovirus (family Phycodnaviridae) that infects the unicellular, eukaryotic green alga Chlorella variabilis NC64A. The 331-kb PBCV-1 genome contains 416 major open reading frames. A mRNA-seq approach was used to analyze PBCV-1 transcriptomes at 6 progressive times during the first hour of infection. The alignment of 17 million reads to the PBCV-1 genome allowed the construction of single-base transcriptome maps. Significant transcription was detected for a subset of 50 viral genes as soon as 7 min after infection. By 20 min post infection (p.i.), transcripts were detected for …

Vaccines Within Vaccines: The Use Of Adenovirus Types 4 And 7 As Influenza Vaccine Vectors, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

Adenovirus Types 4 and 7 (Ad4 and Ad7) are associated with acute respiratory distress (ARD). In order to prevent widespread Ad-associated ARD (Ad-ARD) the United States military immunizes new recruits using a safe and effective lyophilized wildtype Ad4 and Ad7 delivered orally in an enteric-coated capsule. We cloned Ad4 and Ad7 and modified them to express either a GFP-Luciferase (GFPLuc) fusion gene or a centralized influenza H1 hemagglutinin (HA1-con). BALB/c mice were injected with GFPLuc expressing viruses intramuscularly (i.m.) and intranasally (i.n.). Ad4 induced significantly higher luciferase expression levels as compared with Ad7 by both routes. Ad7 transduction was restored …

Systematic Analysis Of A Xenograft Mice Model For Kshv+ Primary Effusion Lymphoma (Pel), Lu Dai, Jimena Trillo-Tinoco, Lihua Bai, Baoli Kang, Zengguang Xu, Xiaofei Wen, Luis Del Valle, Zhiqiang Qin

School of Medicine Faculty Publications

Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), which arises preferentially in the setting of infection with human immunodeficiency virus (HIV). Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV(+) PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells …

Inflammation Enhances Il-2 Driven Differentiation Of Cytolytic Cd4 T Cells, Aspen M. Workman, Ashley K. Jacobs, Alexander J. Vogel, Shirley Condon, Deborah M. Brown

Nebraska Center for Virology: Faculty Publications

Cytolytic CD4 T cells (CD4 CTL) have been identified in vivo in response to viral infections; however, the factors necessary for driving the cytolytic phenotype have not been fully elucidated. Our previously published work suggests IL-2 may be the master regulator of perforin-mediated cytotoxicity in CD4 effectors. To further dissect the role of IL-2 in CD4 CTL generation, T cell receptor transgenic mice deficient in the ability to produce IL-2 or the high affinity IL-2 receptor (IL-2Rα, CD25) were used. Increasing concentrations of IL-2 were necessary to drive perforin (Prf) expression and maximal cytotoxicity. Granzyme B (GrB) expression and killing …

High Prevalence Of Early Childhood Infection By Kshv In A Minority Population In China, Yifei Cao, Veenu Minhas, Xiaohua Tan, Jin Huang, Baodong Wang, Meiyi Zhu, Yuan Gao, Tingting Zhao, Lei Yang, Charles Wood

Nebraska Center for Virology: Faculty Publications

In China, KSHV seroprevalence varies considerably among different regions and ethnicities. But in Xinjiang province, located in the northwestern China, there is a very high seroprevalence of KSHV in adults of Kazak and Ughur ethnicities. However, KSHV prevalence in children and the risk factors associated with the acquisition of infection are currently not known. The aim of this study was to investigate the prevalence of KSHV infection, identify associated socio-economic or behavioral risk factors and the humoral immune response among children in this population. This is a cross-sectional study (N=178) to screen children and their caregivers from Xinjiang for total …

Global Analysis Of Chlorella Variabilis Nc64a Mrna Profiles During The Early Phase Of Paramecium Bursaria Chlorella Virus-1 Infection, Janet M. Rowe, Adrien Jeanniard, James R. Gurnon, Yuannan Xia, David D. Dunigan, James L. Van Etten, Guillaume Blanc

Nebraska Center for Virology: Faculty Publications

The PBCV-1/Chlorella variabilis NC64A system is a model for studies on interactions between viruses and algae. Here we present the first global analyses of algal host transcripts during the early stages of infection, prior to virus replication. During the course of the experiment stretching over 1 hour, about a third of the host genes displayed significant changes in normalized mRNA abundance that either increased or decreased compared to uninfected levels. The population of genes with significant transcriptional changes gradually increased until stabilizing at 40 minutes post infection. Functional categories including cytoplasmic ribosomal proteins, jasmonic acid biosynthesis and anaphase promoting …

Dynamic Attachment Of Chlorovirus Pbcv-1 To Chlorella Variabilis, Irina Agarkova, Brigitte Hertel, Xinzheng Zhang, Les Lane, Alexander Tchourbanov, David D. Dunigan, Gerhard Thiel, Michael G. Rossmann, James L. Van Etten

Nebraska Center for Virology: Faculty Publications

Chloroviruses infect their hosts by specifically binding to and degrading the cell wall of their algal hosts at the site of attachment, using an intrinsic digesting enzyme(s). Chlorovirus PBCV-1 stored as a lysate survived longer than virus alone, suggesting virus attachment to cellular debris may be reversible. Ghost cells (algal cells extracted with methanol) were used as a model to study reversibility of PBCV-1 attachment because ghost cells are as susceptible to attachment and wall digestion as are live cells. Reversibility of attachment to ghost cells was examined by releasing attached virions with a cell wall degrading enzyme extract. The …

Genetic Variation And Possible Mechanisms Driving The Evolution Of Worldwide Fig Mosaic Virus Isolates, Jeewan Jyot Walia, Anouk Willemsen, Eminur Elci, Kadriye Caglayan, Bryce W. Falk, Luis Rubio

Nebraska Center for Virology: Faculty Publications

Fig mosaic virus (FMV) is a multipartite negative-sense RNA virus infecting fig trees worldwide. FMV is transmitted by vegetative propagation and grafting of plant materials, and by the eriophyid mite Aceria ficus. In this work, the genetic variation and evolutionary mechanisms shaping FMV populations were characterized. Nucleotide sequences from four genomic regions (each within the genomic RNAs 1, 2, 3, and 4) from FMV isolates from different countries were determined and analyzed. FMV genetic variation was low, as is seen for many other plant viruses. Phylogenetic analysis showed some geographically distant FMV isolates which clustered together, suggesting long-distance migration. …

Risk Factors For Early Childhood Infection Of Human Herpesvirus-8 In Zambian Children: The Role Of Early Childhood Feeding Practices, Kay L. Crabtree, Janet M. Wojcicki, Veenu Minhas, David R. Smith, Chipepo Kankasa, Charles D. Mitchell, Charles Wood

Nebraska Center for Virology: Faculty Publications

Background—Human herpesvirus-8 (HHV-8) infection in early childhood is common throughout sub-Saharan Africa with prevalence increasing throughout childhood. Specific routes of transmission have not been clearly delineated, though HHV-8 is present in high concentrations in saliva.

Methods—To understand the horizontal transmission of HHV-8 within households to children we enrolled for cross-sectional analysis, 251 households including 254 children, age two and under, in Lusaka, Zambia. For all children, plasma was screened for HHV-8 and HIV-1 and health and behavioral questionnaires were completed. Multi-level logistic regression analysis was conducted to assess independent factors for HHV-8 infection in children.

Results—Risk factors for HHV-8 infection …

Turnip Crinkle Virus Coat Protein Inhibits The Basal Immune Response To Virus Invasion In Arabidopsis By Binding To The Nac Transcription Factor Tip, Teresa Donze, Feng Qu, Paul Twigg, T. Jack Morris

Nebraska Center for Virology: Faculty Publications

Turnip crinkle virus (TCV) has been shown to interact with a NAC transcription factor, TIP, of Arabidopsis thaliana, via its coat protein (CP). This interaction correlates with the resistance response manifested in TCV-resistant Arabidopsis ecotype Di-17. We report that failure of a mutated CP to interact with TIP triggered the corresponding TCV mutant (R6A) to cause more severe symptoms in the TCV-susceptible ecotype Col-0. We hypothesized that TCV regulates antiviral basal immunity through TIP-CP interaction. Consistent with this hypothesis, we found that the rate of accumulation of R6A was measurably slower than wild-type TCV over the course of an …

Cell- And Virus-Mediated Regulation Of The Barrier-To-Autointegration Factor’S Phosphorylation State Controls Its Dna Binding, Dimerization, Subcellular Localization, And Antipoxviral Activity, Augusta Jamin, April Wicklund, Matthew S. Wiebe

Nebraska Center for Virology: Faculty Publications

Barrier-to-autointegration factor (BAF) is a DNA binding protein with multiple cellular functions, including the ability to act as a potent defense against vaccinia virus infection. This antiviral function involves BAF’s ability to condense double-stranded DNA and subsequently prevent viral DNA replication. In recent years, it has become increasingly evident that dynamic phosphorylation involving the vaccinia virus B1 kinase and cellular enzymes is likely a key regulator of multiple BAF functions; however, the precise mechanisms are poorly understood. Here we analyzed how phosphorylation impacts BAF’s DNA binding, subcellular localization, dimerization, and antipoxviral activity through the characterization of BAF phosphomimetic and unphosphorylatable …

Characterization Of A Dual-Tropic Human Immunodeficiency Virus (Hiv-1) Strain Derived From The Prototypical X4 Isolate Hxbc2, Shi-Hua Xiang, Beatriz Pacheco, Dane Bowder, Wen Yuan, Joseph Sodroski

Nebraska Center for Virology: Faculty Publications

Human immunodeficiency virus type 1 (HIV-1) coreceptor usage and tropism can be modulated by the V3 loop sequence of the gp120 exterior envelope glycoprotein. For coreceptors, R5 viruses use CCR5, X4 viruses use CXCR4, and dual-tropic (R5X4) viruses use either CCR5 or CXCR4. To understand the requirements for dual tropism, we derived and analyzed a dual-tropic variant of an X4 virus. Changes in the V3 base, which allow gp120 to interact with the tyrosine-sulfated CCR5 N-terminus, and deletion of residues 310/311 in the V3 tip were necessary for efficient CCR5 binding and utilization. Thus, both sets of V3 changes allowed …

Live Siv Vaccine Correlate Of Protection: Immune Complex-Inhibitory Fc Receptor Interactions That Reduce Target Cell Availability, Anthony J. Smith, Stephen W. Wietgrefe, Liang Shang, Cavan S. Reilly, Peter J. Southern, Katherine E. Perkey, Lijie Duan, Heinz Kohler, Sybille Muller, James Robinson, John V. Carlis, Qingsheng Li, R. Paul Johnson, Ashley T. Haase

Nebraska Center for Virology: Faculty Publications

Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to

protect women in the pandemic’s epicentre in Africa. We have been seeking these principles by

identifying correlates of the robust protection associated with SIV_mac239Δnef vaccination in the

SIV-rhesus macaque animal model of HIV-1 transmission to women. We have identified one

correlate of SIV_mac239Δnef protection against vaginal challenge as a resident mucosal system for

SIV-gp41 trimer antibody production and neonatal Fc receptor (FcRn)-mediated concentration of

these antibodies on the path of virus entry to inhibit establishment of infected founder populations

at the …

Review Of Epidemiology And Transmission Of Kaposi’S Sarcoma-Associated Herpesvirus, Veenu Minhas, Charles Wood

Nebraska Center for Virology: Faculty Publications

This review summarizes the current knowledge pertaining to Kaposi sarcoma-associated herpesvirus (KSHV) epidemiology and transmission. Since the identification of KSHV twenty years ago, it is now known to be associated with Kaposi’s sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s disease. Many studies have been conducted to understand its epidemiology and pathogenesis and their results clearly show that the worldwide distribution of KSHV is uneven. Some geographical areas, such as sub-Saharan Africa, the Mediterranean region and the Xinjiang region of China, are endemic areas, but Western Europe and United States have a low prevalence in the general population. This makes …

Seroprevalence Of Human Herpesvirus 8 And Hepatitis C Virus Among Drug Users In Shanghai, China, Tiejun Zhang, Ying Liu, Yuyan Zhang, Jun Wang, Veenu Minhas, Charles Wood, Na He

Nebraska Center for Virology: Faculty Publications

To elucidate and compare the seroprevalence of human herpesvirus 8 (HHV8) and hepatitis C virus (HCV) among Chinese drug users, a cross-sectional study of 441 participants, was conducted in Shanghai, China, from 2012 through 2013. Seventy-seven (17.5%) participants were found to be positive for HHV8 antibodies, while 271 (61.5%) participants were positive for HCV. No significant association between HHV8 seropositivity and drug use characteristics, sexual behaviors, HCV, or syphilis was observed. In contrast, a statistically significant association between HCV seropositivity and injected drug history (OR, 2.18, 95% CI 1.41–3.37) was detected, whereas no statistically significant association between HCV seropositivity and …

Vaccines Within Vaccines: The Use Of Adenovirus Types 4 And 7 As Influenza Vaccine Vectors, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

adenovirus Types 4 and 7 (ad4 and ad7) are associated with acute respiratory distress (aRD). In order to prevent wide- spread ad-associated aRD (ad-aRD) the United states military immunizes new recruits using a safe and effective lyophi- lized wildtype ad4 and ad7 delivered orally in an enteric-coated capsule. We cloned ad4 and ad7 and modified them to express either a GFP-Luciferase (GFPLuc) fusion gene or a centralized influenza H1 hemagglutinin (Ha1-con). BaLB/c mice were injected with GFPLuc expressing viruses intramuscularly (i.m.) and intranasally (i.n.). ad4 induced significantly higher luciferase expression levels as compared with ad7 by both routes. ad7 transduction …

The Role Of Indoleamine 2,3-Dioxygenase In Lp-Bpm5 Murine Retroviral Disease Progression, Megan A. O'Connor, William R. Green

Dartmouth Scholarship

Indoleamine 2,3-dioxygenase (IDO) is an immunomodulatory intracellular enzyme involved in tryptophan degradation. IDO is induced during cancer and microbial infections by cytokines, ligation of co-stimulatory molecules and/or activation of pattern recognition receptors, ultimately leading to modulation of the immune response. LP-BM5 murine retroviral infection induces murine AIDS (MAIDS), which is characterized by profound and broad immunosuppression of T- and B-cell responses. Our lab has previously described multiple mechanisms regulating the development of immunodeficiency of LP-BM5-induced disease, including Programmed Death 1 (PD-1), IL-10, and T-regulatory (Treg) cells. Immunosuppressive roles of IDO have been demonstrated in other retroviral models, suggesting a possible …

Stimulation Through Tlr4 Increases Fviii Inhibitor Formation In A Mouse Model Of Hemophilia A, Claire K. Holley

Dissertations and Theses (Open Access)

Hemophilia A is a clotting disorder caused by functional factor VIII (FVIII) deficiency. About 25% of patients treated with therapeutic recombinant FVIII develop antibodies (inhibitors) that render subsequent FVIII treatments ineffective. The immune mechanisms of inhibitor formation are not entirely understood, but circumstantial evidence indicates a role for increased inflammatory response, possibly via stimulation of Toll-like receptors (TLRs), at the time of FVIII immunization. I hypothesized that stimulation through TLR4 in conjunction with FVIII treatments would increase the formation of FVIII inhibitors. To test this hypothesis, FVIII K.O. mice were injected with recombinant human FVIII with or without concomitant doses …

Neuroinflammation And Psychiatric Illness, Souhel Najjar, Daniel M. Pearlman, Kenneth Alper, Amanda Najjar, Orrin Devinsky

Dartmouth Scholarship

Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence …

Molecular Architecture Of The Uncleaved Hiv-1 Envelope Glycoprotein Trimer, Youdong Mao, Luis Castillo-Menendez, Liping Wang, Christopher Gu, Alon Herschhorn, Anik Désormeaux, Andrés Finzi, Shi-Hua Xiang, Joseph Sodroski

Nebraska Center for Virology: Faculty Publications

The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer, a membrane-fusing machine, mediates virus entry into host cells and is the sole virusspecific target for neutralizing antibodies. Binding the receptors, CD4 and CCR5/CXCR4, triggers Env conformational changes from the metastable unliganded state to the fusion-active state. We used cryo-electron microscopy to obtain a 6-Å structure of the membranebound, heavily glycosylated HIV-1 Env trimer in its uncleaved and unliganded state. The spatial organization of secondary structure elements reveals that the unliganded conformations of both gp120 and gp41 subunits differ from those induced by receptor binding. The gp120 trimer association domains, which …