Eigenvalues and Sensitivity Analysis for a Model of HIV-1 Pathogenesis With an Intracellular Delay

2008 ◽  
Author(s):  
Sun Yi ◽  
Patrick W. Nelson ◽  
A. Galip Ulsoy
Keyword(s):  
Time Delay ◽  
Significant Contribution ◽  
Critical Role ◽  
Delay Systems ◽  
Lambert W Function ◽  
The Past ◽  
Immunodeficiency Virus ◽  
Significant Research ◽  
Hiv 1

During the past decade significant research has been aimed at better understanding for human immunodeficiency virus type 1 (HIV-1), and the use of mathematical modeling to interpret experimental results has made a significant contribution. However, time-delays, which play a critical role in various biological models, are still not amenable to many traditional analysis methods. In this paper, we apply a recently developed approach using the Lambert W function to handle the time delay in a HIV-1 pathogenesis dynamic model. Dominant eigenvalues in the infinite eigenspectrum of these time-delay systems are obtained and used to understand the effects of the parameters of the model on the immune system. Also, the result is extended to analyze the sensitivity of the eigenvalues with respect to the parameters in the HIV-1 model. The research makes it possible to know which parameters are more influential than others, and the obtained information is used to investigate the HIV-1 dynamic system analytically.

scholarly journals Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 76 ◽  
Author(s):  
Mitch Brinkkemper ◽  
Kwinten Sliepen
Keyword(s):  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Broadly Neutralizing Antibodies ◽  
Viral Membrane ◽  
Immunodeficiency Virus ◽  
Hiv 1

The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing antibodies (bNAbs) that are capable of neutralizing the majority of circulating HIV-1 strains. The envelope glycoprotein (Env) trimer on the viral membrane is the sole target of bNAbs and the key component of vaccination approaches aimed at eliciting bNAbs. Multimeric presentation of Env on nanoparticles often plays a critical role in these strategies. Here, we will discuss the different aspects of nanoparticles in Env vaccination, including recent insights in immunological processes underlying their perceived advantages, the different nanoparticle platforms and the various immunogenicity studies that employed nanoparticles to improve (neutralizing) antibody responses against Env.

scholarly journals HIV-1/Mycobacterium tuberculosisCoinfection Immunology: How Does HIV-1 Exacerbate Tuberculosis?

2011 ◽  
Vol 79 (4) ◽  
pp. 1407-1417 ◽  
Author(s):  
Collin R. Diedrich ◽  
JoAnne L. Flynn
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Cells ◽  
Clinical Studies ◽  
Treatment Options ◽  
The Past ◽  
Multiple Hypotheses ◽  
Immunodeficiency Virus ◽  
Basic Understanding ◽  
Hiv 1

ABSTRACTHuman immunodeficiency virus type 1 (HIV) andMycobacterium tuberculosishave become intertwined over the past few decades in a “syndemic” that exacerbates the morbidity and mortality associated with each pathogen alone. The severity of the coinfection has been extensively examined in clinical studies. The extrapolation of peripheral evidence from clinical studies has increased our basic understanding of how HIV increases susceptibility to TB. These studies have resulted in multiple hypotheses of how HIV exacerbates TB pathology through the manipulation of granulomas. Granulomas can be located in many tissues, most prominently the lungs and associated lymph nodes, and are made up of multiple immune cells that can actively containM. tuberculosis. Granuloma-based research involving both animal models and clinical studies is needed to confirm these hypotheses, which will further our understanding of this coinfection and may lead to better treatment options. This review examines the data that support each hypothesis of how HIV manipulates TB pathology while emphasizing a need for more tissue-based experiments.

scholarly journals The Requirement for Cellular Transportin 3 (TNPO3 or TRN-SR2) during Infection Maps to Human Immunodeficiency Virus Type 1 Capsid and Not Integrase

2009 ◽  
Vol 84 (1) ◽  
pp. 397-406 ◽  
Author(s):  
Lavanya Krishnan ◽  
Kenneth A. Matreyek ◽  
Ilker Oztop ◽  
Kyeongeun Lee ◽  
Christopher H. Tipper ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nuclear Import ◽  
Critical Role ◽  
Bovine Immunodeficiency Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Recent genome-wide screens have highlighted an important role for transportin 3 in human immunodeficiency virus type 1 (HIV-1) infection and preintegration complex (PIC) nuclear import. Moreover, HIV-1 integrase interacted with recombinant transportin 3 protein under conditions whereby Moloney murine leukemia virus (MLV) integrase failed to do so, suggesting that integrase-transportin 3 interactions might underscore active retroviral PIC nuclear import. Here we correlate infectivity defects in transportin 3 knockdown cells with in vitro protein binding affinities for an expanded set of retroviruses that include simian immunodeficiency virus (SIV), bovine immunodeficiency virus (BIV), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), and Rous sarcoma virus (RSV) to critically address the role of integrase-transportin 3 interactions in viral infection. Lentiviruses, with the exception of FIV, display a requirement for transportin 3 in comparison to MLV and RSV, yielding an infection-based dependency ranking of SIV > HIV-1 > BIV and EIAV > MLV, RSV, and FIV. In vitro pulldown and surface plasmon resonance assays, in contrast, define a notably different integrase-transportin 3 binding hierarchy: FIV, HIV-1, and BIV > SIV and MLV > EIAV. Our results therefore fail to support a critical role for integrase binding in dictating transportin 3 dependency during retrovirus infection. In addition to integrase, capsid has been highlighted as a retroviral nuclear import determinant. Accordingly, MLV/HIV-1 chimera viruses pinpoint the genetic determinant of sensitization to transportin 3 knockdown to the HIV-1 capsid protein. We therefore conclude that capsid, not integrase, is the dominant viral factor that dictates transportin 3 dependency during HIV-1 infection.

scholarly journals Persistent Antibody Responses but Declining Cytotoxic T-Lymphocyte Responses to Multiple Human Immunodeficiency Virus Type 1 Antigens in a Long-Term Nonprogressing Individual with a Defective p17 Proviral Sequence and No Detectable Viral RNA Expression

1998 ◽  
Vol 72 (4) ◽  
pp. 3472-3474 ◽  
Author(s):  
James M. Binley ◽  
Xia Jin ◽  
Yaoxing Huang ◽  
Linqi Zhang ◽  
Yunzhen Cao ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Antibody Responses ◽  
The Past ◽  
Immunodeficiency Virus ◽  
Lymphocyte Responses ◽  
Hiv 1

ABSTRACT Long-term nonprogressor AD-18 has been infected with human immunodeficiency virus type 1 (HIV-1) for at least 16 years. During the past 5 years, he has had undetectable levels of plasma viremia, and HIV-1 cannot be isolated from him. Sequencing of proviral DNA indicates that the only HIV-1 sequences that can be identified in AD-18 have gross defects in the p17-encoding regions of the gag gene (Y. Huang, L. Zhang, and D. D. Ho, Virology 240:36–49, 1998). However, AD-18 has strong, sustained antibody responses to several HIV-1 antigens, including p17. Cytotoxic T-lymphocyte responses to Env and Gag antigens have gradually diminished over the past 4 years, at a time when the titers of antibodies to the same proteins have remained stable. We discuss what these observations might mean for the generation and maintenance of immunological memory.

Anatomy and pathology of HIV-1 peptidase

2002 ◽  
Vol 38 ◽  
pp. 113-127 ◽  
Author(s):  
Ben M Dunn
Keyword(s):  
Feline Immunodeficiency Virus ◽  
Drug Target ◽  
Concerted Effort ◽  
Drug Pressure ◽  
The Past ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1

The peptidase of the HIV type 1 (HIV PR) is required for the replication of and further infection by the virus. A concerted effort has taken place in the past 15 years to understand the properties of this enzyme, as it serves as an excellent drug target for control of the virus. Owing to drug pressure, many mutations arise during turnover of the virus and some of these lead to resistance to the effects of the inhibitors. Recent advances in the understanding of the changes these mutations cause to the enzyme and its interaction with substrates and inhibitors have been described. In addition, studies of closely related retroviral enzymes from simian immunodeficiency virus, feline immunodeficiency virus and HIV-2 have expanded the structure-function paradigm. The role of the flexibility of ligands and of the enzyme in active-site interactions is discussed.

scholarly journals Effect of Amino Acid Substitution of the V3 and Bridging Sheet Residues in Human Immunodeficiency Virus Type 1 Subtype C gp120 on CCR5 Utilization

2003 ◽  
Vol 77 (6) ◽  
pp. 3832-3837 ◽  
Author(s):  
Pirada Suphaphiphat ◽  
Arunee Thitithanyanont ◽  
Saowakon Paca-Uccaralertkun ◽  
Max Essex ◽  
Tun-Hou Lee
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Fusion ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Critical Role ◽  
Subtype C ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The V3 loop and the bridging sheet domain of human immunodeficiency virus type 1 (HIV-1) subtype B envelope glycoprotein gp120 have been implicated in CCR5 coreceptor utilization. In this study, mutant envelope glycoproteins of a subtype C isolate containing substitutions in the V3 or C4 region were generated to determine which are required for efficient CCR5-dependent cell fusion and viral entry. We found that the V3 crown and C4 residues are relatively dispensable for cell-cell fusion, although some residues may be involved in the regulation of early postentry steps in viral replication. In contrast, seven highly conserved residues located in the V3 stem are critical for CCR5 utilization, which can explain the apparent paradox that the functional convergence in CCR5 usage by genetically divergent HIV-1 strains involves a variable region. The finding that C4 residues do not have a critical role may appear to contradict the current model that bridging sheet residues are involved in the gp120-CCR5 interaction. However, a plausible interpretation is that these C4 residues may have a distinct role in the binding and fusion steps of the gp120-CCR5 interaction.

scholarly journals Identification of a gp41 Core-Binding Molecule with Homologous Sequence of Human TNNI3K-Like Protein as a Novel Human Immunodeficiency Virus Type 1 Entry Inhibitor

2010 ◽  
Vol 84 (18) ◽  
pp. 9359-9368 ◽  
Author(s):  
Yun Zhu ◽  
Lu Lu ◽  
Liling Xu ◽  
Hengwen Yang ◽  
Shibo Jiang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Critical Role ◽  
Heptad Repeat ◽  
Helix Bundle ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) gp41 plays a critical role in the viral fusion process, and its N- and C-terminal heptad repeat domains serve as important targets for developing anti-HIV-1 drugs, like T-20 (generic name, enfuvirtide; brand name, Fuzeon). Here, we conducted a yeast two-hybrid screening on a human bone marrow cDNA library using the recombinant soluble gp41 ectodomain as the bait and identified a novel gp41 core-binding molecule, designated P20. P20 showed no homology with a current HIV fusion inhibitor, T-20, but had sequence homology to a human protein, troponin I type 3 interacting kinase (TNNI3K)-like protein. While it could bind to the six-helix bundle core structure formed by the N- and C-terminal heptad repeats, P20 did not interrupt the formation of the six-helix bundle. P20 was effective in blocking HIV-1 Env-mediated syncytium formation and inhibiting infection by a broad spectrum of HIV-1 strains with distinct subtypes and coreceptor tropism, while it was ineffective against other enveloped viruses, such as vesicular stomatitis virus and influenza A virus. P20 exhibited no significant cytotoxicity to the CD4+ cells that were used for testing antiviral activity. Among the 11 P20 mutants, four analogous peptides with a common motif (WGRLEGRRT) exhibited significantly reduced anti-HIV-1 activity, suggesting that this region is the critical active site of P20. Therefore, this peptide can be used as a lead for developing novel HIV fusion inhibitors and as a probe for studying the membrane-fusogenic mechanism of HIV.

scholarly journals Human Immunodeficiency Virus Type 1 Nef Binds to Tumor Suppressor p53 and Protects Cells against p53-Mediated Apoptosis

2002 ◽  
Vol 76 (6) ◽  
pp. 2692-2702 ◽  
Author(s):  
Alison L. Greenway ◽  
Dale A. McPhee ◽  
Kelly Allen ◽  
Ricky Johnstone ◽  
Gavan Holloway ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Tumor Suppressor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Transcriptional Activation ◽  
Cell Function ◽  
Critical Role ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The nef gene product of human immunodeficiency virus type 1 (HIV-1) is important for the induction of AIDS, and key to its function is its ability to manipulate T-cell function by targeting cellular signal transduction proteins. We reported that Nef coprecipitates a multiprotein complex from cells which contains tumor suppressor protein p53. We now show that Nef interacts directly with p53. Binding assays showed that an N-terminal, 57-residue fragment of Nef (Nef 1-57) contains the p53-binding domain. Nef also interacted with p53 during HIV-1 infection in vitro. As p53 plays a critical role in the regulation of apoptosis, we hypothesized that Nef may alter this process. Nef inhibited UV light-induced, p53-dependent apoptosis in MOLT-4 cells, with Nef 1-57 being as effective as its full-length counterpart. The inhibition by Nef of p53 apoptotic function is most likely due its observed ability to decrease p53 protein half-life and, consequently, p53 DNA binding activity and transcriptional activation. These data show that HIV-1 Nef may augment HIV replication by prolonging the viability of infected cells by blocking p53-mediated apoptosis.

scholarly journals Human Immunodeficiency Virus Type 1 Matrix Protein Interacts with Cellular Protein HO3

1998 ◽  
Vol 72 (2) ◽  
pp. 1671-1676 ◽  
Author(s):  
Juan Lama ◽  
Didier Trono
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Matrix Protein ◽  
Critical Role ◽  
Trna Synthetase ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The matrix (MA) protein of human immunodeficiency virus type 1 (HIV-1) plays a critical role in virion morphogenesis and fulfills important functions during the early steps of infection. In an effort to identify cellular partners of MA, a Saccharomyces cerevisiae two-hybrid screen was utilized. A specific interaction between MA and HO3, a putative histidyl-tRNA synthetase, was demonstrated in this system. HO3-specific mRNA was detected in several tissues relevant for HIV infection, such as spleen, thymus, and peripheral blood lymphocytes, as well as in a number of T-lymphoid-cell lines. The binding of MA to HO3 was confirmed in transfected cells by coimmunoprecipitation. This interaction was abrogated by replacing two lysine residues at positions 26 and 27 of MA by threonine (MAKK27TT ). HO3 localized both to the cytoplasm and to the nucleus of acutely transfected 293T cells. When overexpressed in HIV-1-producing cells, HO3 was incorporated into wild-type virions but not in ones containing the dilysine-mutated variant of MA. Correspondingly, overexpression of HO3 in virus producer cells enhanced the infectivity of wild-type but not MAKK27AA HIV-1 particles. The stimulating effect of HO3 was independent from the presence of Envelope, Vpr, or Vpu. Taken together, these results suggest that HO3, through its recognition of MA, plays a role in the life cycle of HIV-1.

scholarly journals Human immunodeficiency virus type 1 Vpr: functions and molecular interactions

2009 ◽  
Vol 90 (8) ◽  
pp. 1795-1805 ◽  
Author(s):  
Bizhan Romani ◽  
Susan Engelbrecht
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Critical Role ◽  
Cellular Proteins ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Hiv 1

Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) is an accessory protein that interacts with a number of cellular and viral proteins. The functions of many of these interactions in the pathogenesis of HIV-1 have been identified. Deletion of the vpr gene reduces the virulence of HIV-1 dramatically, indicating the importance of this protein for the virus. This review describes the current findings on several established functions of HIV-1 Vpr and some possible roles proposed for this protein. Because Vpr exploits cellular proteins and pathways to influence the biology of HIV-1, understanding the functions of Vpr usually involves the study of cellular pathways. Several functions of Vpr are attributed to the virion-incorporated protein, but some of them are attributed to the expression of Vpr in HIV-1-infected cells. The structure of Vpr may be key to understanding the variety of its interactions. Due to the critical role of Vpr in HIV-1 pathogenicity, study of the interactions between Vpr and cellular proteins may help us to understand the mechanism(s) of HIV-1 pathogenicity.

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