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Full-Text Articles in Life Sciences

Kinetics Of Hiv-1 Uncoating In C20 Microglial Cells, Melanie Anne Taylor May 2019

Kinetics Of Hiv-1 Uncoating In C20 Microglial Cells, Melanie Anne Taylor

MSU Graduate Theses

Uncoating is a poorly understood yet required step of HIV-1 replication that is defined as the disassembly of the viral capsid structure. The goal of this project is to characterize uncoating in C20 microglial cells. These cells are a natural target of HIV-1 that are infected to establish latent viral reservoirs and HIV-associated neurological disorders. A stable C20 cell line that expresses TRIM-CypA was established to study the kinetics of uncoating with the CsA washout assay. The expression of TRIM-CypA was confirmed by western blot and the functionality of the protein was confirmed by a viral infectivity assay. Using this ...


Anti-Drug Antibody Responses Impair Prophylaxis Mediated By Aav-Delivered Hiv-1 Broadly Neutralizing Antibodies, Matthew R. Gardner, Ina Fetzer, Lisa M. Kattenhorn, Meredith E. Davis-Gardner, Amber S. Zhou, Barnett Alfant, Jesse A. Weber, Hema R. Kondur, Jose M. Martinez-Navio, Sebastian P. Fuchs, Ronald C. Desrosiers, Guangping Gao, Jeffrey D. Lifson, Michael Farzan Mar 2019

Anti-Drug Antibody Responses Impair Prophylaxis Mediated By Aav-Delivered Hiv-1 Broadly Neutralizing Antibodies, Matthew R. Gardner, Ina Fetzer, Lisa M. Kattenhorn, Meredith E. Davis-Gardner, Amber S. Zhou, Barnett Alfant, Jesse A. Weber, Hema R. Kondur, Jose M. Martinez-Navio, Sebastian P. Fuchs, Ronald C. Desrosiers, Guangping Gao, Jeffrey D. Lifson, Michael Farzan

Open Access Articles

Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention of HIV-1 infection. The immunoglobulin G (IgG)1 subtype is usually selected for this application, because it efficiently mediates antibody effector functions and has a somewhat longer half-life. However, the use of IgG1-Fc has been associated with the generation of anti-drug antibodies (ADAs) that correlate with loss of antibody expression. In contrast, we have shown that expression of the antibody-like molecule eCD4-Ig bearing a rhesus IgG2-Fc domain showed reduced immunogenicity and completely protected rhesus macaques from simian-HIV (SHIV)-AD8 challenges. To directly ...


Serinc5: Its Sensitivity To Nef And Restriction Of Hiv-1, Weiwei Dai Aug 2018

Serinc5: Its Sensitivity To Nef And Restriction Of Hiv-1, Weiwei Dai

GSBS Dissertations and Theses

The accessory protein Nef of human immunodeficiency virus type 1 (HIV-1) has long been known to enhance the infectivity of HIV-1 progeny virions. The multipass transmembrane proteins serine incorporator 3 (SERINC3) and SERINC5 were recently identified as novel antiviral proteins that restrict HIV-1 infectivity. Nef enhances HIV-1 infectivity by removing SERINCs from the plasma membrane, which prevents their incorporation into progeny HIV-1 virions. To exploit this potent intrinsic antiretroviral factor for potential therapy development, it is critical to explore the determinants in SERINC5 that govern its downregulation by Nef and its restriction on HIV-1 infectivity. Here I report that the ...


Innate Detection Of Hiv-1 In Myeloid Dendritic Cells, Sean Matthew Mccauley Jul 2018

Innate Detection Of Hiv-1 In Myeloid Dendritic Cells, Sean Matthew Mccauley

GSBS Dissertations and Theses

Protective antiviral immune responses require priming of naïve T cells by dendritic cells (DCs) that have matured sufficiently to produce co-stimulatory cell surface molecules and cytokines. Although only low levels of productive HIV-1 infection are detected in ex vivo DCs following HIV-1 challenge, those few cells exhibit innate activation. Experimentally bypassing blocks to entry and replication leads to more efficient transduction of DCs and maturation as indicated by production of interferons and interferon stimulated genes. Furthermore, similar innate activation occurs upon transduction of macrophages or CD4+ T cells. However, the mechanism by which HIV-1 is detected to activate innate immune ...


Intron-Containing Rna From The Hiv-1 Provirus Activates Type I Interferon And Inflammatory Cytokines, Sean M. Mccauley, Kyusik Kim, Anetta Nowosielska, Ann Dauphin, Leonid Yurkovetskiy, William E. Diehl, Jeremy Luban Apr 2018

Intron-Containing Rna From The Hiv-1 Provirus Activates Type I Interferon And Inflammatory Cytokines, Sean M. Mccauley, Kyusik Kim, Anetta Nowosielska, Ann Dauphin, Leonid Yurkovetskiy, William E. Diehl, Jeremy Luban

Program in Molecular Medicine Publications and Presentations

HIV-1-infected people who take drugs that suppress viremia to undetectable levels are protected from developing AIDS. Nonetheless, these individuals have chronic inflammation associated with heightened risk of cardiovascular pathology. HIV-1 establishes proviruses in long-lived CD4+ memory T cells, and perhaps other cell types, that preclude elimination of the virus even after years of continuous antiviral therapy. Though the majority of proviruses that persist during antiviral therapy are defective for production of infectious virions, many are expressed, raising the possibility that the HIV-1 provirus or its transcripts contribute to ongoing inflammation. Here we found that the HIV-1 provirus activated innate immune ...


Primate Immunodeficiency Virus Vpx And Vpr Counteract Transcriptional Repression Of Proviruses By The Hush Complex, Leonid Yurkovetskiy, Mehmet Hakan Guney, Kyusik Kim, Shih Lin Goh, Sean M. Mccauley, Ann Dauphin, William E. Diehl, Jeremy Luban Apr 2018

Primate Immunodeficiency Virus Vpx And Vpr Counteract Transcriptional Repression Of Proviruses By The Hush Complex, Leonid Yurkovetskiy, Mehmet Hakan Guney, Kyusik Kim, Shih Lin Goh, Sean M. Mccauley, Ann Dauphin, William E. Diehl, Jeremy Luban

University of Massachusetts Medical School Faculty Publications

Drugs that inhibit HIV-1 replication and prevent progression to AIDS do not eliminate HIV-1 proviruses from the chromosomes of long-lived CD4+ memory T cells. To escape eradication by these antiviral drugs, or by the host immune system, HIV-1 exploits poorly defined host factors that silence provirus transcription. These same factors, though, must be overcome by all retroviruses, including HIV-1 and other primate immunodeficiency viruses, in order to activate provirus transcription and produce new virus. Here we show that Vpx and Vpr, proteins from a wide range of primate immunodeficiency viruses, activate provirus transcription in human CD4+ T cells. Provirus activation ...


The Three-Fold Axis Of The Hiv-1 Capsid Lattice Is The Species-Specific Binding Interface For Trim5alpha, Damien Morger, Franziska Zosel, Martin Buhlmann, Sara Zuger, Maximilian Mittelviefhaus, Benjamin Schuler, Jeremy Luban, Markus G. Grutter Feb 2018

The Three-Fold Axis Of The Hiv-1 Capsid Lattice Is The Species-Specific Binding Interface For Trim5alpha, Damien Morger, Franziska Zosel, Martin Buhlmann, Sara Zuger, Maximilian Mittelviefhaus, Benjamin Schuler, Jeremy Luban, Markus G. Grutter

Open Access Articles

Rhesus TRIM5alpha (rhTRIM5alpha) potently restricts replication of human immunodeficiency virus type 1 (HIV-1). Restriction is mediated through direct binding of the C-terminal B30.2 domain of TRIM5alpha to the assembled HIV-1 capsid core. This host-pathogen interaction involves multiple capsid molecules within the hexagonal HIV-1 capsid lattice. However, the molecular details of this interaction and the precise site at which the B30.2 domain binds remain largely unknown. The human orthologue of TRIM5alpha (hsTRIM5alpha) fails to block infection by HIV-1 both in vivo and in vitro This is thought to be due to differences in binding to the capsid lattice. To ...


A Long Cytoplasmic Loop Governs The Sensitivity Of The Anti-Viral Host Protein Serinc5 To Hiv-1 Nef, Weiwei Dai, Yoshiko Usami, Yuanfei Wu, Heinrich G. Gottlinger Jan 2018

A Long Cytoplasmic Loop Governs The Sensitivity Of The Anti-Viral Host Protein Serinc5 To Hiv-1 Nef, Weiwei Dai, Yoshiko Usami, Yuanfei Wu, Heinrich G. Gottlinger

Open Access Articles

We recently identified the multipass transmembrane protein SERINC5 as an antiviral protein that can potently inhibit HIV-1 infectivity and is counteracted by HIV-1 Nef. We now report that the anti-HIV-1 activity, but not the sensitivity to Nef, is conserved among vertebrate SERINC5 proteins. However, a Nef-resistant SERINC5 became Nef sensitive when its intracellular loop 4 (ICL4) was replaced by that of Nef-sensitive human SERINC5. Conversely, human SERINC5 became resistant to Nef when its ICL4 was replaced by that of a Nef-resistant SERINC5. In general, ICL4 regions from SERINCs that exhibited resistance to a given Nef conferred resistance to the same ...


Hiv-1 Unmasks The Plasticity Of Innate Lymphoid Cells, Yetao Wang, Kyle Gellatly, Alan G. Derr, Smita Jaiswal, Alper Kucukural, Patrick Mcdonel, Thomas C. Greenough, Jeanmarie Houghton, Manuel Garber, Jeremy Luban Jan 2018

Hiv-1 Unmasks The Plasticity Of Innate Lymphoid Cells, Yetao Wang, Kyle Gellatly, Alan G. Derr, Smita Jaiswal, Alper Kucukural, Patrick Mcdonel, Thomas C. Greenough, Jeanmarie Houghton, Manuel Garber, Jeremy Luban

University of Massachusetts Medical School Faculty Publications

Pharmaceuticals that suppress HIV-1 viremia preserve CD4+ T cells and prevent AIDS. Nonetheless, HIV-1 infected people taking these drugs have chronic inflammation attributable to persistent disruption of intestinal barrier function with increased rates of cardiovascular mortality. To better understand the etiology of this inflammation we examined the effect of HIV-1 infection on innate lymphoid cells (ILCs). These innate immune counterparts of T cells lack clonotypic antigen receptors, classify according to signature transcription factors and cytokines, and maintain homeostasis in inflamed tissues. ILCs have been defined, in part, by the IL-7Rα, CD127. Here we report that the vast majority of type ...


Characterizing Immune Response To Hiv-1 Infection In Bicd2-Knockout Cells, Omar Abdel-Rahim Jan 2018

Characterizing Immune Response To Hiv-1 Infection In Bicd2-Knockout Cells, Omar Abdel-Rahim

Master's Theses

An important part of the HIV-1 infection cycle is the attachment of the intracellular viral core to the host microtubule network, facilitated by attachment of the viral capsid to cargo adaptor proteins. One such cargo adaptor is Bicaudal D Homolog Protein 2 (BICD2). BICD2 can attach to both the HIV-1 capsid and the dynein/dynactin complex and facilitate the trafficking of the viral core towards the host nucleus. Removal of BICD2 can disrupt this viral translocation, resulting in an elevated immune response that impairs productive HIV-1 infection. In my research, we investigated what viral particles are detected in the absence ...


Superresolved Three-Dimensional Analysis Of The Spatial Arrangement Of The Human Immunodeficiency Virus Type-1 (Hiv-1) Envelope Glycoprotein At Sites Of Viral Assembly, Carmen Anne Buttler Jan 2018

Superresolved Three-Dimensional Analysis Of The Spatial Arrangement Of The Human Immunodeficiency Virus Type-1 (Hiv-1) Envelope Glycoprotein At Sites Of Viral Assembly, Carmen Anne Buttler

Electronic Theses and Dissertations

Human Immunodeficiency Virus type 1 (HIV-1) replicates by forcing infected host cells to produce new virus particles, which assemble form protein components on the inner leaflet of the host cell's plasma membrane. This involves incorporation of the essential viral envelope glycoprotein (Env) into a structural lattice of viral Gag proteins. The mechanism of Env recruitment and incorporation is not well understood. To better define this process, we seek to describe the timing of Env-Gag encounters during particle assembly by measuring angular positions of Env proteins about the surfaces of budding particles. Using three-dimensional superresolution microscopy, we show that Env ...


Contribution Of The Gp120 V3 Loop To Envelope Glycoprotein Trimer Stability In Primate Immunodeficiency Viruses, Dane Bowder, Haley Hollingsead, Kate Durst, Duoyi Hu, Wenzhong Wei, Joshua Wiggins, Halima Medjahed, Andrés Finzi, Joseph Sodroski, Shi-Hua Xiang Jan 2018

Contribution Of The Gp120 V3 Loop To Envelope Glycoprotein Trimer Stability In Primate Immunodeficiency Viruses, Dane Bowder, Haley Hollingsead, Kate Durst, Duoyi Hu, Wenzhong Wei, Joshua Wiggins, Halima Medjahed, Andrés Finzi, Joseph Sodroski, Shi-Hua Xiang

Virology Papers

The V3 loop of the human immunodeficiency virus type 1 (HIV-1) gp120 exterior envelope glycoprotein (Env) becomes exposed after CD4 binding and contacts the coreceptor to mediate viral entry. Prior to CD4 engagement, a hydrophobic patch located at the tip of the V3 loop stabilizes the non-covalent association of gp120 with the Env trimer of HIV-1 subtype B strains. Here, we show that this conserved hydrophobic patch (amino acid residues 307, 309 and 317) contributes to gp120-trimer association in HIV-1 subtype C, HIV-2 and SIV. Changes that reduced the hydrophobicity of these V3 residues resulted in increased gp120 shedding and ...


Determinants Of Hiv-1 Transmission Fitness, Shilpa Iyer Jan 2017

Determinants Of Hiv-1 Transmission Fitness, Shilpa Iyer

Publicly Accessible Penn Dissertations

DETERMINANTS OF HIV-1 TRANSMISSION FITNESS

Shilpa S. Iyer

Beatrice H. Hahn

HIV-1 is predominantly transmitted by mucosal routes and almost 80 percent of new infections are initiated by a single variant. The elucidation of the biological properties of transmitted viruses which distinguish them from non-transmitted variants are critical for the development of therapeutic interventions. To identify such properties, we characterized the biology of 300 limiting dilution-derived virus isolates from the plasma and genital secretions of eight HIV-1 donor and recipient transmission pairs representing the most prevalent subtypes (B and C). Recipient viruses were more infectious per viral particle as determined ...


Engineering Chimeric Antigen Receptors For Durable Control Over Hiv-1 Replication, Rachel Leibman Jan 2017

Engineering Chimeric Antigen Receptors For Durable Control Over Hiv-1 Replication, Rachel Leibman

Publicly Accessible Penn Dissertations

This thesis project aimed to develop chimeric antigen receptors (CARs) capable of durably suppressing the Human Immunodeficiency Virus Type 1 (HIV) replication, by building upon a previous CD4-based CAR that was employed in several clinical trials. We applied lessons learned from cancer-targeting CARs to optimize the CAR vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains, in an effort to determine which components augmented the ability of CD8 T cells to control HIV replication. CD8 T cells expressing the optimized CARs were at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR ...


Fc Receptor-Mediated Activities Of Env-Specific Monoclonal Antibodies Generated From Human Volunteers Receiving A Dna Prime-Protein Boost Hiv Vaccine: A Dissertation, Matthew R. Costa Oct 2016

Fc Receptor-Mediated Activities Of Env-Specific Monoclonal Antibodies Generated From Human Volunteers Receiving A Dna Prime-Protein Boost Hiv Vaccine: A Dissertation, Matthew R. Costa

GSBS Dissertations and Theses

Human immunodeficiency type 1 (HIV-1) is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years’ infection and as a result, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that a moderate protection is possible, which may correlate with antibody dependent cellular cytotoxicity (ADCC) activity. Previous studies in the Lu lab demonstrated that in an HIV-1 vaccine phase I trial, DP6-001, a polyvalent Env DNA prime-protein boost formulation, could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities along with multiple Fc ...


Tissue Compartmentalization And Tropism Of Hiv-1: A Dissertation, Robin L. Brese Aug 2016

Tissue Compartmentalization And Tropism Of Hiv-1: A Dissertation, Robin L. Brese

GSBS Dissertations and Theses

Despite the development of effective antiretroviral treatments, there is still no cure for HIV-1. Major barriers to HIV-1 eradication include the diversity of intrapatient viral quasispecies and the establishment of reservoirs in tissue sanctuary sites. A better understanding of these populations is required for targeted treatments. While previous studies have examined the relationship between brain and blood or immune tissues, few have looked at and compared the properties of viruses from other tissue compartments. In this study, 75 full length HIV-1 envelopes were isolated from the frontal lobe, occipital lobe, parietal lobe, colon, lung, and lymph node of an HIV-1 ...


Hiv Vaccines: Progress, Limitations And A Crispr/Cas9 Vaccine, Omar A. Garcia Martinez May 2016

Hiv Vaccines: Progress, Limitations And A Crispr/Cas9 Vaccine, Omar A. Garcia Martinez

Biology: Student Scholarship & Creative Works

ABSTRACT: The HIV-1 pandemic continues to thrive due to ineffective HIV-1 vaccines. Historically, the world’s most infectious diseases, such as polio and smallpox, have been eradicated or have come close to eradication due to the advent of effective vaccines. Highly active antiretroviral therapy is able to delay the onset of AIDS but can neither rid the body of HIV-1 proviral DNA nor prevent further transmission. A prophylactic vaccine that prevents the various mechanisms HIV-1 has to evade and attack our immune system is needed to end the HIV-1 pandemic. Recent advances in engineered nuclease systems, like the CRISPR/Cas9 ...


Hiv-1 Capsid Is Involved In Post-Nuclear Entry Steps, Nan-Yu Chen, Lihong Zhou, Paul J. Gane, Silvana Opp, Neil J. Ball, Giuseppe Nicastro, Madeleine Zufferey, Cindy Buffone, Jeremy Luban, David Selwood, Felipe Diaz-Griffero, Ian Taylor, Ariberto Fassati Apr 2016

Hiv-1 Capsid Is Involved In Post-Nuclear Entry Steps, Nan-Yu Chen, Lihong Zhou, Paul J. Gane, Silvana Opp, Neil J. Ball, Giuseppe Nicastro, Madeleine Zufferey, Cindy Buffone, Jeremy Luban, David Selwood, Felipe Diaz-Griffero, Ian Taylor, Ariberto Fassati

Open Access Articles

BACKGROUND: HIV-1 capsid influences viral uncoating and nuclear import. Some capsid is detected in the nucleus but it is unclear if it has any function. We reported that the antibiotic Coumermycin-A1 (C-A1) inhibits HIV-1 integration and that a capsid mutation confers resistance to C-A1, suggesting that capsid might affect post-nuclear entry steps.

RESULTS: Here we report that C-A1 inhibits HIV-1 integration in a capsid-dependent way. Using molecular docking, we identify an extended binding pocket delimited by two adjacent capsid monomers where C-A1 is predicted to bind. Isothermal titration calorimetry confirmed that C-A1 binds to hexameric capsid. Cyclosporine washout assays in ...


Lineage-Specific Differences In The Gp120 Inner Domain Layer 3 Of Human And Simian Immunodeficiency Viruses, Shilei Ding, Halima Medjahed, Jérémie Prévost, Mathieu Coutu, Shi-Hua Xiang, Andrés Finzi Jan 2016

Lineage-Specific Differences In The Gp120 Inner Domain Layer 3 Of Human And Simian Immunodeficiency Viruses, Shilei Ding, Halima Medjahed, Jérémie Prévost, Mathieu Coutu, Shi-Hua Xiang, Andrés Finzi

Virology Papers

Binding of HIV-1 and SIV gp120 exterior envelope glycoprotein to CD4 triggers conformational changes in gp120 that promote its interaction with one of the chemokine receptors, usually CCR5, ultimately leading to gp41-mediated virus-cell membrane fusion and entry. We previously described that topological Layers (Layer 1, Layer 2 and Layer 3) in the gp120 inner domain contribute to gp120-trimer association in the unliganded state but also help secure CD4 binding. Relative to Layer 1 of HIV-1 gp120, the SIVmac239 gp120 Layer 1 plays a more prominent role in maintaining gp120-trimer association but is minimally involved in promoting CD4 binding, which could ...


The Role Of Bst-2/Tetherin In Host Protection And Disease Manifestation, Wadie D Mahauad-Fernandez, Chioma M Okeoma Dec 2015

The Role Of Bst-2/Tetherin In Host Protection And Disease Manifestation, Wadie D Mahauad-Fernandez, Chioma M Okeoma

Department of Microbiology and Immunology Publications

Host cells respond to viral infections by activating immune response genes that are not only involved in inflammation, but may also predispose cells to cancerous transformation. One such gene is BST-2, a type II transmembrane protein with a unique topology that endows it tethering and signaling potential. Through this ability to tether and signal, BST-2 regulates host response to viral infection either by inhibiting release of nascent viral particles or in some models inhibiting viral dissemination. However, despite its antiviral functions, BST-2 is involved in disease manifestation, a function linked to the ability of BST-2 to promote cell-to-cell interaction. Therefore ...


Recombination Elevates The Effective Evolutionary Rate And Facilitates The Establishment Of Hiv-1 Infection In Infants After Mother-To-Child Transmission, Keri B. Sanborn, Mohan Somasundaran, Katherine Ruiz De Luzuriaga, Thomas Leitner Nov 2015

Recombination Elevates The Effective Evolutionary Rate And Facilitates The Establishment Of Hiv-1 Infection In Infants After Mother-To-Child Transmission, Keri B. Sanborn, Mohan Somasundaran, Katherine Ruiz De Luzuriaga, Thomas Leitner

Open Access Articles

BACKGROUND: Previous studies have demonstrated that single HIV-1 genotypes are commonly transmitted from mother to child, but such analyses primarily used single samples from mother and child. It is possible that in a single sample, obtained early after infection, only the most replication competent virus is detected even when other forms may have been transmitted. Such forms may have advantages later in infection, and may thus be detected in follow-up samples. Because HIV-1 frequently recombines, phylogenetic analyses that ignore recombination may miss transmission of multiple forms if they recombine after transmission. Moreover, recombination may facilitate adaptation, thus providing an advantage ...


Exosomes: Implications In Hiv-1 Pathogenesis, Marisa N Madison, Chioma M Okeoma Jul 2015

Exosomes: Implications In Hiv-1 Pathogenesis, Marisa N Madison, Chioma M Okeoma

Department of Microbiology and Immunology Publications

Exosomes are membranous nanovesicles of endocytic origin that carry host and pathogen derived genomic, proteomic, and lipid cargos. Exosomes are secreted by most cell types into the extracellular milieu and are subsequently internalized by recipient cells. Upon internalization, exosomes condition recipient cells by donating their cargos and/or activating various signal transduction pathways, consequently regulating physiological and pathophysiological processes. The role of exosomes in viral pathogenesis, especially human immunodeficiency virus type 1 [HIV-1] is beginning to unravel. Recent research reports suggest that exosomes from various sources play important but different roles in the pathogenesis of HIV-1. From these reports, it ...


Lv4 Is A Capsid-Specific Antiviral Activity In Human Blood Cells That Restricts Viruses Of The Sivmac/Sivsm/Hiv-2 Lineage Prior To Integration, Massimo Pizzato, Sean Matthew Mccauley, Martha R. Neagu, Thomas Pertel, Claudia Firrito, Serena Ziglio, Ann Dauphin, Madeleine Zufferey, Lionel Berthoux, Jeremy Luban Jul 2015

Lv4 Is A Capsid-Specific Antiviral Activity In Human Blood Cells That Restricts Viruses Of The Sivmac/Sivsm/Hiv-2 Lineage Prior To Integration, Massimo Pizzato, Sean Matthew Mccauley, Martha R. Neagu, Thomas Pertel, Claudia Firrito, Serena Ziglio, Ann Dauphin, Madeleine Zufferey, Lionel Berthoux, Jeremy Luban

Open Access Articles

HIV-2 and SIVMAC are AIDS-causing, zoonotic lentiviruses that jumped to humans and rhesus macaques, respectively, from SIVSM-bearing sooty mangabey monkeys. Cross-species transmission events such as these sometimes necessitate virus adaptation to species-specific, host restriction factors such as TRIM5. Here, a new human restriction activity is described that blocks viruses of the SIVSM/SIVMAC/HIV-2 lineage. Human T, B, and myeloid cell lines, peripheral blood mononuclear cells and dendritic cells were 4 to > 100-fold less transducible by VSV G-pseudotyped SIVMAC, HIV-2, or SIVSM than by HIV-1. In contrast, transduction of six epithelial cell lines was equivalent to that by HIV-1. Substitution ...


Structural Analysis Of A Novel Rabbit Monoclonal Antibody R53 Targeting An Epitope In Hiv-1 Gp120 C4 Region Critical For Receptor And Co-Receptor Binding, Ruimin Pan, Yuxin Chen, Michael Vaine, Guangnan Hu, Shixia Wang, Shan Lu, Xiang-Peng Kong Jul 2015

Structural Analysis Of A Novel Rabbit Monoclonal Antibody R53 Targeting An Epitope In Hiv-1 Gp120 C4 Region Critical For Receptor And Co-Receptor Binding, Ruimin Pan, Yuxin Chen, Michael Vaine, Guangnan Hu, Shixia Wang, Shan Lu, Xiang-Peng Kong

Open Access Articles

The fourth conserved region (C4) in the HIV-1 envelope glycoprotein (Env) gp120 is a structural element that is important for its function, as it binds to both the receptor CD4 and the co-receptor CCR5/CXCR4. It has long been known that this region is highly immunogenic and that it harbors B-cell as well as T-cell epitopes. It is the target of a number of antibodies in animal studies, which are called CD4-blockers. However, the mechanism by which the virus shields itself from such antibody responses is not known. Here, we determined the crystal structure of R53 in complex with its ...


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 Apr 2015

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 ...


A Sensitive Assay Using A Native Protein Substrate For Screening Hiv-1 Maturation Inhibitors Targeting The Protease Cleavage Site Between The Matrix And Capsid, Sook-Kyung Lee, Nancy Cheng, Emily Hull-Ryde, Marc Potempa, Celia Schiffer, William Janzen, Ronald Swanstrom Jan 2015

A Sensitive Assay Using A Native Protein Substrate For Screening Hiv-1 Maturation Inhibitors Targeting The Protease Cleavage Site Between The Matrix And Capsid, Sook-Kyung Lee, Nancy Cheng, Emily Hull-Ryde, Marc Potempa, Celia Schiffer, William Janzen, Ronald Swanstrom

Celia A. Schiffer

The matrix/capsid processing site in the HIV-1 Gag precursor is likely the most sensitive target to inhibit HIV-1 replication. We have previously shown that modest incomplete processing at the site leads to a complete loss of virion infectivity. In the study presented here, a sensitive assay based on fluorescence polarization that can monitor cleavage at the MA/CA site in the context of the folded protein substrate is described. The substrate, an MA/CA fusion protein, was labeled with the fluorescein-based FlAsH (fluorescein arsenical hairpin) reagent that binds to a tetracysteine motif (CCGPCC) that was introduced within the N-terminal ...


Substrate Envelope-Designed Potent Hiv-1 Protease Inhibitors To Avoid Drug Resistance, Madhavi Nalam, Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima Anjum, Michael Altman, Nese Yilmaz, Bruce Tidor, Tariq Rana, Celia Schiffer Jan 2015

Substrate Envelope-Designed Potent Hiv-1 Protease Inhibitors To Avoid Drug Resistance, Madhavi Nalam, Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima Anjum, Michael Altman, Nese Yilmaz, Bruce Tidor, Tariq Rana, Celia Schiffer

Celia A. Schiffer

The rapid evolution of HIV under selective drug pressure has led to multidrug resistant (MDR) strains that evade standard therapies. We designed highly potent HIV-1 protease inhibitors (PIs) using the substrate envelope model, which confines inhibitors within the consensus volume of natural substrates, providing inhibitors less susceptible to resistance because a mutation affecting such inhibitors will simultaneously affect viral substrate processing. The designed PIs share a common chemical scaffold but utilize various moieties that optimally fill the substrate envelope, as confirmed by crystal structures. The designed PIs retain robust binding to MDR protease variants and display exceptional antiviral potencies against ...


Characterization Of Envelope-Specific Antibody Response Elicited By Hiv-1 Vaccines: A Dissertation, Yuxin Chen Jan 2015

Characterization Of Envelope-Specific Antibody Response Elicited By Hiv-1 Vaccines: A Dissertation, Yuxin Chen

GSBS Dissertations and Theses

Despite 30 years of intensive research,an effective human immunodeficiency virus (HIV) vaccine still remains elusive. The desirable immune response capable of providing protection against HIV acquisition is still not clear. The accumulating evidence learned from a recent vaccine efficacy correlate study not only confirmed the importance of antibody responses, but also highlighted potential protective functions of antibodies with a broad repertoire of HIV-1 epitope specificities and a wide range of different antiviral mechanisms. This necessitates a deep understanding of the complexity and diversity of antibody responses elicited by HIV-1 vaccines. My dissertation characterizes antibody response profiles of HIV-1 Env ...


Hiv Integrase Mechanisms Of Resistance To Raltegravir, Elvitegravir, And Dolutegravir, Kyla Nicole Ross Jan 2015

Hiv Integrase Mechanisms Of Resistance To Raltegravir, Elvitegravir, And Dolutegravir, Kyla Nicole Ross

Wayne State University Theses

ABSTRACT

HIV INTEGRASE MECHANISMS OF RESISTANCE TO RALTEGRAVIR, ELVITEGRAVIR, AND DOLUTEGRAVIR

by

KYLA ROSS

December 2015

Advisor: Dr. Ladislau Kovari

Major: Biochemistry and Molecular Biology

Degree: Master of Science

HIV-1 integrase (HIV-1 IN or IN) is a multimeric enzyme that integrates the HIV-1 genome into the chromosomes of infected CD4+ T-cells. Currently there are three FDA approved HIV-1 IN strand transfer inhibitors (INSTIs) used in clinical practice: raltegravir (RAL), elvitegravir (ELV), and dolutegravir (DTG). The [Q148H], [Q148H, G140S], [Q148R], [Q148R, G140A] and [N155H, E92Q] mutations decrease IN susceptibility to RAL and ELV and may result in therapeutic failure. As an ...


Insights Into The Role Of Chemokines And Chemokine Receptors During Hiv-1 Pathogenesis, Zahra Folasade Parker Jan 2015

Insights Into The Role Of Chemokines And Chemokine Receptors During Hiv-1 Pathogenesis, Zahra Folasade Parker

Publicly Accessible Penn Dissertations

Sexual transmission of HIV-1 is often established by one genetic variant, the transmitted/founder (T/F) virus. T/F HIV-1 may have specific phenotypic properties that are selected for during transmission. To date, the most consistent phenotypic property associated with T/F viruses is use of the chemokine receptor CCR5 as a coreceptor for entry. Small molecule CCR5 antagonists, such as Maraviroc (MVC), inhibit HIV-1 entry by functioning as allosteric inhibitors. These molecules bind within the transmembrane helices of CCR5, inducing a conformational change that prevents the HIV-CCR5 interaction. As with most drugs, HIV-1 has developed strategies to overcome this ...