Diseases Commons^™

Circulating Plasma Exosomal Proteins Of Either Shiv-Infected Rhesus Macaque Or Hiv-Infected Patient Indicates A Link To Neuropathogenesis, Partha K. Chandra, Stephen E. Braun, Sudipa Maity, Jorge A. Castorena-Gonzalez, Hogyoung Kim, Jeffrey G. Shaffer, Sinisa Cikic, Ibolya Rutkai, Jia Fan, Jessie J. Guidry, David K. Worthylake, Chenzhong Li, Asim B. Abdel-Mageed, David W. Busija

School of Medicine Faculty Publications

Despite the suppression of human immunodeficiency virus (HIV) replication by combined antiretroviral therapy (cART), 50–60% of HIV-infected patients suffer from HIV-associated neurocognitive disorders (HAND). Studies are uncovering the role of extracellular vesicles (EVs), especially exosomes, in the central nervous system (CNS) due to HIV infection. We investigated links among circulating plasma exosomal (crExo) proteins and neuropathogenesis in simian/human immunodeficiency virus (SHIV)-infected rhesus macaques (RM) and HIV-infected and cART treated patients (Patient-Exo). Isolated EVs from SHIV-infected (SHIV-Exo) and uninfected (CTL-Exo) RM were predominantly exosomes (particle size < 150 nm). Proteomic analysis quantified 5654 proteins, of which 236 proteins (~4%) were significantly, differentially expressed (DE) between SHIV-/CTL-Exo. Interestingly, different CNS cell specific markers were abundantly expressed in crExo. Proteins involved in latent viral reactivation, neuroinflammation, neuropathology-associated interactive as well as signaling molecules were expressed at significantly higher levels in SHIV-Exo than CTL-Exo. However, proteins involved in mitochondrial biogenesis, ATP production, autophagy, endocytosis, exocytosis, and cytoskeleton organization were significantly less expressed in SHIV-Exo than CTL-Exo. Interestingly, proteins involved in oxidative stress, mitochondrial biogenesis, ATP production, and autophagy were significantly downregulated in primary human brain microvascular endothelial cells exposed with HIV+/cART+ Patient-Exo. We showed that Patient-Exo significantly increased blood–brain barrier permeability, possibly due to loss of platelet endothelial cell adhesion molecule-1 protein and actin cytoskeleton structure. Our novel findings suggest that circulating exosomal proteins expressed CNS cell markers—possibly associated with viral reactivation and neuropathogenesis—that may elucidate the etiology of HAND.

Hiv-1 Genetic Diversity A Challenge For Aids Vaccine Development: A Retrospective Bibliometric Analysis, Abdur Rashid, Kang Li, Yi Feng, Tauseef Ahmad, Yimam Getaneh, Yueyang Yu, Xiaoyan Hu, Syed Hani Abidi, Yiming Shao

Department of Biological & Biomedical Sciences

Background: Despite recent advances in human immunodeficiency virus-1 (HIV-1) prevention, a fast, safe, and effective vaccine will probably be necessary to end the HIV/AIDS pandemic. This study was conducted to evaluate global research trends and map the key bibliometric indices in HIV-1 genetic diversity from 1998 to 2021.
Methods: A comprehensive online search was conducted in the Web of Science Core Collection database to retrieve published literature on HIV-1 genetic diversity. Key bibliometric indicators were calculated and evaluated using HistCiteTM, Bibliometrix: An R-tool, and VOSviewer software for windows.
Results: A total of 2,060 documents written by 9,201 authors and published …

The Role Of Actin Associated Sptbn1 Host Factor In Hiv-1 Infection In Microglial Cells, Hannah Matheney

MSU Graduate Theses

Human immunodeficiency virus (HIV) is a chronic illness affecting more than 32.7 million individuals worldwide. The virus infects immune cells, weakening the immune system overtime eventually leading to acquired immunodeficiency syndrome (AIDS) if left untreated. Infection starts with a fusion step, followed by uncoating of the HIV capsid once in the cytoplasm of the cell. HIV uses host cell proteins to complete the infection process, like the actin associated factor, SPTBN1. The Hulme lab has previously shown that SPTBN1 knockdown by siRNA in microglial cells decreased HIV infection and delayed uncoating of HIV. Because fusion is prior to uncoating, it …

The Role Of The Host Factor Sptbn1 In Hiv-1 Infection Of Microglial Cells, Marc Gordon Havlicek

MSU Graduate Theses

HIV-1 is the etiological agent that cause AIDS. Since the 1980’s when HIV-1 was discovered, much has been discovered, however a cure for HIV-1 has eluded researchers. Effective therapeutics do exist but can have adverse side effects including HAND/HAD which leads to neurodegeneration in patients regardless of viral suppression. One area of research that holds the possibility of discovering new viral targets and therapeutics is host factor interaction within the replication process. One host factor that can cause a decrease in HIV-1 infectivity is SPTBN1. SPTBN1 is a cytoskeletal protein that was shown to bind to the capsid and nucleocapsid …

Role Of Cyclophilin A And Trim5Α In Hiv-1 Infection And Capsid Uncoating, Emma Lk Wise

MSU Graduate Theses

Microglial cells are immune cells that protect the central nervous system and are subject to HIV- 1 infection. HIV-1 infection of these cells can lead to HIV Associated Neurocognitive Disorders (HAND). Since HIV-1 only codes for 15 different proteins, the virus also uses cellular factors, like Cyclophilin A (CypA), to assist in viral replication. The cell also has antiretroviral restriction factors, like tripartite motif-containing protein 5 (TRIM5α), to protect against infection. The goal of this project is to investigate the role of CypA in the early steps of HIV-1 replication and TRIM5α restriction in microglial cells. I hypothesize that CypA …

Attenuated Negative Feedback In Monocyte-Derived Macrophages From Persons Living With Hiv: A Role For Ikaros, Celeste Faia, Karlie Plaisance-Bonstaff, Cecilia Vittori, Dorota Wyczechowska, Adam Lassak, Mary Meyaski-Schluter, Krzysztof Reiss, Francesca Peruzzi

School of Medicine Faculty Publications

Persons living with HIV (PLWH) are at higher risk of developing secondary illnesses than their uninfected counterparts, suggestive of a dysfunctional immune system in these individuals. Upon exposure to pathogens, monocytes undergo epigenetic remodeling that results in either a trained or a tolerant phenotype, characterized by hyper-responsiveness or hypo-responsiveness to secondary stimuli, respectively. We utilized CD14+ monocytes from virally suppressed PLWH and healthy controls for in vitro analysis following polarization of these cells toward a pro-inflammatory monocyte-derived macrophage (MDM) phenotype. We found that in PLWH-derived MDMs, pro-inflammatory signals (TNFA, IL6, IL1B, miR-155-5p, and IDO1) dominate over negative feedback signals (NCOR2, …

Using A Single Tablet Regimen Of Darunavir, Cobicistat, Emcitrabine, And Tenofovir Alafenamide In Virally Suppressed Hiv-1 Patients Is An Adequate Treatment Option For Controlling Hiv, Priya Kathuria

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Orkin C, Molina JM, Negredo E, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2018;5(1):e23-e34. https://doi.org/10.1016/S2352-3018(17)30179-0

for a patient with viriologically suppressed HIV-1.

Hiv-1 Transcription Elongation By Tat-Mediated Recruitment Of P-Tefb, Elizabeth Griggs

Honors Theses

Over 38.0 million people live with the human immunodeficiency virus (HIV) as of 462019. HIV hijacks the host's cellular machinery to replicate its viral DNA and transcribe the corresponding RNA. HIV-1 transcription relies on both cellular and viral transcription factors for proper regulation. The viral transcriptional activator Tat is a primary regulator. Transcription activation and elongation is controlled through the interaction of Tat with Positive Transcription Elongation Factor b (P-TEFb), a cellular transcriptional activator. The focus of this paper is 1) an in-depth understanding of the interaction between P-TEFb and Tat in HIV transcription, and 2) a review of recent …

Hiv-1 Drug Resistance To Integrase Strand Transfer Inhibitors In Hiv-1 Non-B Subtypes, Emmanuel Ndashimye

Electronic Thesis and Dissertation Repository

Human immunodeficiency syndrome (HIV-1) has infected over 75 million people and over 35 million have succumbed to virus related illnesses. Despite access to a variety of antiretroviral therapy (ART) options, ART programs have been disproportionally spread in the world with low-and middle-income countries (LMICs) facing challenges to access the most potent ART options. With less potent ART remaining in use in LMICs, HIV-1 drug resistance (HIVDR) presents a growing challenge in LMICs. Since approval of the first-generation integrase strand transfer inhibitor (INSTIs), Raltegravir (RAL) in 2007, INSTIs remain the best choice as a backbone of ART. Access to second generation …

Investigating The Interactions Between Individual Calmodulin And Hiv-1 Protein Domains, Riley K. Kendall, Jerry Larue

Student Scholar Symposium Abstracts and Posters

The World Health Organization found that 37.9 million people were living with HIV by the end of 2018. HIV is a virus that weakens the immune system through viral replication and the destruction of CD4⁺ T-cells, which are white blood cells that detect infection and make antibodies. A cure for HIV has not yet been discovered. HIV-1 contains a Gag polyprotein which regulates the stages of viral replication. Previous studies suggest that the myristoyl group of a matrix protein peptide found on the Gag polyprotein, MA, forms a complex with a calcium-binding, multifunctional regulatory protein called Calmodulin (CaM). CaM …

Tobacco/Hiv-1-Induced Myeloid Cell-Derived Extracellular Vesicles In Hiv-1 Pathogenesis, Sanjana Haque

Theses and Dissertations (ETD)

Introduction. Smoking, which is highly prevalent in people living with HIV/AIDS, has been shown to exacerbate HIV-1 replication, in part via cytochrome P450 (CYP)-induced oxidative stress. CYP enzymes metabolize cigarette smoke condensate (CSC), causing oxidative stress and cytotoxicity. Our previous studies have demonstrated that CSC and specific CSC constituents, benzo(a)pyrene and nicotine, potentially induce CYPs, resulting in higher oxidative stress and subsequent exacerbation of HIV-1 replication in monocytes and macrophages. However, the exact mechanism behind tobacco-induced, oxidative stress-mediated enhancement of HIV-1 replication is still poorly understood. Extracellular vesicles (EVs) have recently gained attention for their unique nature as intercellular messengers …

Determining The Relative Transmission Fitness Of Hiv-1 Subtypes A, B, C, And D, Spencer Yeung

Electronic Thesis and Dissertation Repository

There is in vivo evidence that suggests the genetic diversity of HIV-1 subtypes influence heterosexual transmission efficiency. To recapitulate sexual transmission in vitro, blocks of genital tissue were exposed to mixtures of genetically different subtype viruses. Migrating immune cells were collected and co-cultured with a CD4+ T-cell line permissive to HIV infection (PM1) to measure dendritic cell virus transfer; HIV-exposed tissues were cultured separately. Next generation sequencing (NGS) of HIV-1 DNA was used to quantify relative infection rates of the various challenge viruses, and to assess fitness differences in infection of the tissue vs. migratory/T cell co-cultures. Our results …

Designing An Optimal Hiv-1 Env Immunogen For The Vesicular Stomatitis Virus Vaccine Platform And Elucidating The Role Of Hiv-1 Nef In Env Trafficking, Jason Knapp

Electronic Thesis and Dissertation Repository

Current vesicular stomatitis virus (VSV)-based HIV vaccines require an optimal HIV envelope immunogen to improve protection in vivo. Furthermore, the involvement of viral proteins, such as HIV Nef, in the trafficking of HIV Env to sites of viral assembly remains poorly understood and may provide additional insights for the design of a VSV-based HIV vaccine. We constructed new codon-optimized chimeric Env immunogens containing the signal sequence of honeybee melittin and the transmembrane and cytoplasmic tail domains of SIV, Zaire Ebola, or VSV glycoproteins. We showed that all chimeric Env immunogens had enhanced expression levels within producer cells. Utilizing bimolecular …

Crispr/Cas9 Driven Eradication Of Hiv-1 In Infected Human Genome, Sydney Loechler

Senior Seminars and Capstones

Once infected with HIV-1, the host immune system is incapable of ridding itself of the virus. HIV-1 uses latent viral reservoirs (LR) within CD4+ T cells to replicate. Within these reservoirs, HIV-1 is able to go into a latent state where it cannot be detected by the host's immune system or current HIV-1 treatments. By utilizing viewing assays and CRISPR-Cas9, there may be a possibility to identify, isolate, and then cut out HIV-1 from an infected cell. Two possible viewing assays have been proposed and studied in recent research. PCR assays are quicker and easier to administer while viral outgrowth …

Development Of A Long-Acting Nanoformulation Of Dolutegravir For Prevention And Treatment Of Hiv-1 Infection, Brady Sillman

Theses & Dissertations

Dolutegravir (DTG) is a potent human immunodeficiency virus type 1 (HIV-1) integrase strand-transfer inhibitor (INSTI) with a high barrier to viral drug resistance. However, opportunities to improve its profile abound. These include extending the drug’s apparent half-life, increasing penetrance to “putative” viral reservoirs, and reducing inherent toxicities. These highlight, in part, the need for long-acting, slow effective release antiretroviral therapy (LASER ART) delivery schemes. A long-acting (LA) DTG was made by synthesizing a hydrophobic and lipophilic prodrug encased with poloxamer (P407) surfactant. This modified DTG (MDTG) reduced systemic metabolism and polarity, increased lipophilicity and membrane permeability, improved encapsulation, and formed …

Hiv-1 Group M Subtype Fitness, Disease Progression, And Entry Efficiency, Colin M. Venner

Electronic Thesis and Dissertation Repository

Human immunodeficiency virus type 1 (HIV-1) emerged in the human population shortly after the turn of the 19th century. Distribution of HIV-1 across the globe over the past 30–35 years can be traced to founder events with primordial HIV strains from sub-Saharan Africa. Even considering the burden of HIV in Africa, our knowledge of HIV-1 disease is still largely limited to subtype B HIV-1, a strain responsible for 3 million infections in North America and Europe as compared to the 33 million that are infected with HIV-1 subtypes A, C, D, and circulating and unique recombinant forms.

This dissertation analyzes …

Consumption Of Sutherlandia Frutescens By Hiv-Seropositive South African Adults: An Adaptive Double-Blind Randomized Placebo Controlled Trial., Douglas Wilson, Kathy Goggin, Karen Williams, Mary M. Gerkovich, Nceba Gqaleni, James Syce, Patricia Bartman, Quinton Johnson, William R. Folk

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Sutherlandia frutescens (L.) R. Br. is widely used as an over the counter complementary medicine and in traditional medications by HIV seropositive adults living in South Africa; however the plant's safety has not been objectively studied. An adaptive two-stage randomized double-blind placebo controlled study was used to evaluate the safety of consuming dried S. frutescens by HIV seropositive adults with CD4 T-lymphocyte count of >350 cells/μL.

METHODS: In Stage 1 56 participants were randomized to S. frutescens 400, 800 or 1,200 mg twice daily or matching placebo for 24 weeks. In Stage 2 77 additional participants were randomized to …

Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors, Bruno Ramos-Molina, Adam N. Lick, Amir Nasrolahi Shirazi, Donghoon Oh, Rakesh Tiwari, Naglaa Salem El-Sayed, Keykavous Parang, Iris Lindberg

Pharmacy Faculty Articles and Research

Cationic cell-penetrating peptides have been widely used to enhance the intracellular delivery of various types of cargoes, such as drugs and proteins. These reagents are chemically similar to the multi-basic peptides that are known to be potent proprotein convertase inhibitors. Here, we report that both HIV-1 TAT47-57 peptide and the Chariot reagent are micromolar inhibitors of furin activity in vitro. In agreement, HIV-1 TAT47-57 reduced HT1080 cell migration, thought to be mediated by proprotein convertases, by 25%. In addition, cyclic polyarginine peptides containing hydrophobic moieties which have been previously used as transfection reagents also exhibited potent furin inhibition in vitro …

True Durability: Hiv Virologic Suppression In An Urban Clinic And Implications For Timing Of Intensive Adherence Efforts And Viral Load Monitoring., Debra A Benator, Angelo Elmi, Manuel D Rodriguez, Howard B Gale, Virginia L. Kan, Heather J. Hoffman, Susan Tramazzo, Karen Hall, Angela Mcknight, Leah Squires

Medicine Faculty Publications

Although the majority of HIV-infected patients who begin potent antiretroviral therapy should expect long-term virologic suppression, the realities in practice are less certain. Durability of viral suppression was examined to define the best timing of targeted adherence strategies and intensive viral load monitoring in an urban clinic population with multiple challenges to ART adherence. We examined the risk of viral rebound for patients who achieved two consecutive viral loads lower than the lower limit of quantification (LLOQ) within 390 days. For 791 patients with two viral loads below the LLOQ, viral rebound >LLOQ from the first viral load was 36.9 …

Cooperative Effects Of Drug-Resistance Mutations In The Flap Region Of Hiv-1 Protease, Jennifer Foulkes-Murzycki, Christina Rosi, Nese Yilmaz, Robert Shafer, Celia Schiffer

Celia A. Schiffer

Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors. As HIV-1 protease continues to adapt and evade inhibitors while still maintaining the ability to specifically recognize and efficiently cleave its substrates, the problem of drug resistance has become more complicated. Under the selective pressure of therapy, correlated mutations accumulate throughout the enzyme to compromise inhibitor binding, but characterizing their energetic interdependency is not straightforward. A particular drug resistant variant (L10I/G48V/I54V/V82A) displays extreme entropy-enthalpy compensation relative to wild-type enzyme but a similar variant (L10I/G48V/I54A/V82A) does not. Individual mutations of sites …

Structural And Thermodynamic Basis Of Amprenavir/Darunavir And Atazanavir Resistance In Hiv-1 Protease With Mutations At Residue 50, Seema Mittal, Rajintha Bandaranayake, Nancy King, Moses Prabu-Jeyabalan, Madhavi Nalam, Ellen Nalivaika, Nese Yilmaz, Celia Schiffer

Celia A. Schiffer

Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, …

Persistence Of Episomal Hiv-1 Infection Intermediates In Patients On Highly Active Anti-Retroviral Therapy, Mark Sharkey, Ian Teo, Thomas Greenough, Natalia Sharova, Katherine Luzuriaga, John Sullivan, R. Bucy, Leondios Kostrikis, Ashley Haase, Claire Veryard, Raul Davaro, Sarah Cheeseman, Jennifer Daly, Carol Bova, Richard Ellison, Brian Mady, Kwan Lai, Graeme Moyle, Mark Nelson, Brian Gazzard, Sunil Shaunak, Mario Stevenson

Associate Professor Mark Nelson

Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication …

Combined Effects Of Hyperglycemic Conditions And Hiv-1 Nef: A Potential Model For Induced Hiv Neuropathogenesis., Edward A Acheampong, Cassandra Roschel, Muhammad Mukhtar, Alagarsamy Srinivasan, Mohammad Rafi, Roger J Pomerantz, Zahida Parveen

Department of Neurology Faculty Papers

Hyperglycemic conditions associated with diabetes mellitus (DM) or with the use of antiretroviral therapy may increase the risk of central nervous system (CNS) disorders in HIV-1 infected patients. In support of this hypothesis, we investigated the combined effects of hyperglycemic conditions and HIV-1 accessory protein Nef on the CNS using both in vitro and in vivo models. Astrocytes, the most abundant glial cell type required for normal synaptic transmission and other functions were selected for our in vitro study. The results show that in vitro hyperglycemic conditions enhance the expression of proinflammatory cytokines including caspase-3, complement factor 3 (C3), and …

A Comprehensive Analysis Of The Naturally Occurring Polymorphisms In Hiv-1 Vpr: Potential Impact On Ctl Epitopes., Alagarsamy Srinivasan, Velpandi Ayyavoo, Sundarasamy Mahalingam, Aarthi Kannan, Anne Boyd, Debduti Datta, Vaniambadi S Kalyanaraman, Anthony Cristillo, Ronald G Collman, Nelly Morellet, Bassel E Sawaya, Ramachandran Murali

Department of Microbiology and Immunology Faculty Papers

The enormous genetic variability reported in HIV-1 has posed problems in the treatment of infected individuals. This is evident in the form of HIV-1 resistant to antiviral agents, neutralizing antibodies and cytotoxic T lymphocytes (CTLs) involving multiple viral gene products. Based on this, it has been suggested that a comprehensive analysis of the polymorphisms in HIV proteins is of value for understanding the virus transmission and pathogenesis as well as for the efforts towards developing anti-viral therapeutics and vaccines. This study, for the first time, describes an in-depth analysis of genetic variation in Vpr using information from global HIV-1 isolates …

Hiv-1 Tat Protein Alter The Tight Junction Integrity And Function Of Retinal Pigment Epithelium: An In Vitro Study., Ling Bai, Zhenping Zhang, Hui Zhang, Xiumei Li, Qiurong Yu, Haotian Lin, Wenhui Yang

Department of Medicine Faculty Papers

BACKGROUND: How HIV-1 enter into the eyes remains obscure. We postulated that HIV-1 Tat protein can alter the expression of specific tight-junction proteins and disturb the blood retinal barrier, and contributes to HIV trafficking into the eyes. This study is to determine the effects of HIV-1 Tat proteins on the barrier function and tight-junction protein expression of retinal pigment epithelial cell (RPE). METHODS: A human RPE cell line (D407) cultured on microporous filter-supports was used. After treating with HIV-1 Tat protein, transepithelial electrical resistance (TER) of confluent RPE cells was measured by epithelial voltmeter. The permeability of the RPE cells …

Direct Inhibition Of Cdk9 Blocks Hiv-1 Replication Without Preventing T Cell Activation In Primary Human Peripheral Blood Lymphocytes, Dominic Salerno, Muneer G Hasham, Renée Marshall Demarest, Judit Garriga, Alexander Y Tsygankov, Xavier Graña

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

HIV-1 transcription is essential for the virus replication cycle. HIV-1 Tat is a viral transactivator that strongly stimulates the processivity of RNA polymerase II (RNAPII) via recruitment of the cyclin T1/CDK9 positive transcription elongation factor, which phosphorylates the C-terminal domain (CTD) of RNAPII. Consistently, HIV-1 replication in transformed cells is very sensitive to direct CDK9 inhibition. Thus, CDK9 could be a potential target for anti-HIV-1 therapy. A clearer understanding of the requirements for CDK9 activity in primary human T cells is needed to assess whether the CDK9-dependent step in HIV-1 transcription can be targeted clinically. We have investigated the effects …