The Role of HIV-1 genome on biological mechanisms, Molecular function, Interactions between viral and host cell components, Mechanisms of viral entry, Chromosomal integration, and Transcription as potential target for new Preventive HIV-1 Vaccine Development

2021 ◽  
Vol 12 (10) ◽  
pp. 1-19
Author(s):  
Dr. Zelalem Kiros Bitsue
Keyword(s):  
Viral Entry ◽  
Vaccine Development ◽  
Three Dimensional ◽  
Molecular Structures ◽  
Therapeutic Interventions ◽  
Molecular Function ◽  
Biological Mechanisms ◽  
Immunodeficiency Virus ◽  
Cell Components ◽  
Hiv 1

The human immunodeficiency virus (HIV) genome encodes a total of three structural proteins, two envelope proteins, three enzymes, and six accessory proteins. Three-dimensional molecular structures can provide detailed information on biological mechanisms and, for cases in which the molecular function affects human health, can significantly aid in the development of therapeutic interventions.

scholarly journals Broadly neutralizing antibodies and vaccine design against HIV-1 infection

2019 ◽  
Vol 14 (1) ◽  
pp. 30-42 ◽  
Author(s):  
Qian Wang ◽  
Linqi Zhang
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Vaccine Design ◽  
Therapeutic Interventions ◽  
Type I ◽  
Broadly Neutralizing Antibodies ◽  
Dynamic Studies ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Remarkable Progress

AbstractRemarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy. However, vaccine development has remained challenging. Recent discoveries in broadly neutralizing monoclonal antibodies (bNAbs) has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response. Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein (Env) during infection. Our review aims to highlight these discoveries and rejuvenate our endeavor in HIV-1 vaccine design and development.

scholarly journals Challenging the Existing Model of the Hexameric HIV-1 Gag Lattice and MA Shell Superstructure: Implications for Viral Entry

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1515
Author(s):  
Joy Ramielle L. Santos ◽  
Weijie Sun ◽  
Tarana A. Mangukia ◽  
Eduardo Reyes-Serratos ◽  
Marcelo Marcet-Palacios
Keyword(s):  
Viral Entry ◽  
Specific Antigen ◽  
Hexagonal Lattice ◽  
Three Dimensional ◽  
X Ray Crystallography ◽  
Ellipsoidal Shape ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Env Glycoprotein

Despite type 1 human immunodeficiency virus (HIV-1) being discovered in the early 1980s, significant knowledge gaps remain in our understanding of the superstructure of the HIV-1 matrix (MA) shell. Current viral assembly models assume that the MA shell originates via recruitment of group-specific antigen (Gag) polyproteins into a hexagonal lattice but fails to resolve and explain lattice overlapping that occurs when the membrane is folded into a spherical/ellipsoidal shape. It further fails to address how the shell recruits, interacts with and encompasses the viral spike envelope (Env) glycoproteins. These Env glycoproteins are crucial as they facilitate viral entry by interacting with receptors and coreceptors located on T-cells. In our previous publication, we proposed a six-lune hosohedral structure, snowflake-like model for the MA shell of HIV-1. In this article, we improve upon the six-lune hosohedral structure by incorporating into our algorithm the recruitment of complete Env glycoproteins. We generated the Env glycoprotein assembly using a combination of predetermined Env glycoprotein domains from X-ray crystallography, nuclear magnetic resonance (NMR), cryoelectron tomography, and three-dimensional prediction tools. Our novel MA shell model comprises 1028 MA trimers and 14 Env glycoproteins. Our model demonstrates the movement of Env glycoproteins in the interlunar spaces, with effective clustering at the fusion hub, where multiple Env complexes bind to T-cell receptors during the process of viral entry. Elucidating the HIV-1 MA shell structure and its interaction with the Env glycoproteins is a key step toward understanding the mechanism of HIV-1 entry.

scholarly journals Rhabdo-immunodeficiency virus, a murine model of acute HIV-1 infection

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Rachel A Liberatore ◽  
Emily J Mastrocola ◽  
Elena Cassella ◽  
Fabian Schmidt ◽  
Jessie R Willen ◽  
...  
Keyword(s):  
Viral Entry ◽  
Murine Model ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Small Animal ◽  
Immunodeficiency Virus ◽  
Acute Hiv ◽  
Humoral Responses ◽  
Hiv 1

Numerous challenges have impeded HIV-1 vaccine development. Among these is the lack of a convenient small animal model in which to study antibody elicitation and efficacy. We describe a chimeric Rhabdo-Immunodeficiency virus (RhIV) murine model that recapitulates key features of HIV-1 entry, tropism and antibody sensitivity. RhIVs are based on vesicular stomatitis viruses (VSV), but viral entry is mediated by HIV-1 Env proteins from diverse HIV-1 strains. RhIV infection of transgenic mice expressing human CD4 and CCR5, exclusively on mouse CD4+ cells, at levels mimicking those on human CD4+ T-cells, resulted in acute, resolving viremia and CD4+ T-cell depletion. RhIV infection elicited protective immunity, and antibodies to HIV-1 Env that were primarily non-neutralizing and had modest protective efficacy following passive transfer. The RhIV model enables the convenient in vivo study of HIV-1 Env-receptor interactions, antiviral activity of antibodies and humoral responses against HIV-1 Env, in a genetically manipulatable host.

scholarly journals Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist

2004 ◽  
Vol 78 (23) ◽  
pp. 12996-13006 ◽  
Author(s):  
Katrien Princen ◽  
Sigrid Hatse ◽  
Kurt Vermeire ◽  
Stefano Aquaro ◽  
Erik De Clercq ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Entry ◽  
Mononuclear Cells ◽  
Human Immunodeficiency Virus Replication ◽  
Cxcr4 Antagonist ◽  
Peripheral Blood Mononuclear ◽  
Transfected Cells ◽  
Immunodeficiency Virus ◽  
Intracellular Ca ◽  
Hiv 1

ABSTRACT Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC50] ranging from 1.2 to 26.5 μM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC50, 1.8 to 7.3 μM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca2+ signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca2+ flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca2+ signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca2+ signaling by itself at concentrations up to 400 μM. In freshly isolated monocytes, AMD3451 inhibited the Ca2+ flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.

scholarly journals HIV-1 requires Arf6-mediated membrane dynamics to efficiently enter and infect T lymphocytes

2011 ◽  
Vol 22 (8) ◽  
pp. 1148-1166 ◽  
Author(s):  
Laura García-Expósito ◽  
Jonathan Barroso-González ◽  
Isabel Puigdomènech ◽  
José-David Machado ◽  
Julià Blanco ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
T Lymphocytes ◽  
Viral Entry ◽  
Membrane Trafficking ◽  
Membrane Dynamics ◽  
Viral Fusion ◽  
Viral Attachment ◽  
Immunodeficiency Virus ◽  
Vesicular Stomatitis ◽  
Hiv 1

As the initial barrier to viral entry, the plasma membrane along with the membrane trafficking machinery and cytoskeleton are of fundamental importance in the viral cycle. However, little is known about the contribution of plasma membrane dynamics during early human immunodeficiency virus type 1 (HIV-1) infection. Considering that ADP ribosylation factor 6 (Arf6) regulates cellular invasion via several microorganisms by coordinating membrane trafficking, our aim was to study the function of Arf6-mediated membrane dynamics on HIV-1 entry and infection of T lymphocytes. We observed that an alteration of the Arf6–guanosine 5′-diphosphate/guanosine 5′-triphosphate (GTP/GDP) cycle, by GDP-bound or GTP-bound inactive mutants or by specific Arf6 silencing, inhibited HIV-1 envelope–induced membrane fusion, entry, and infection of T lymphocytes and permissive cells, regardless of viral tropism. Furthermore, cell-to-cell HIV-1 transmission of primary human CD4+T lymphocytes was inhibited by Arf6 knockdown. Total internal reflection fluorescence microscopy showed that Arf6 mutants provoked the accumulation of phosphatidylinositol-(4,5)-biphosphate–associated structures on the plasma membrane of permissive cells, without affecting CD4-viral attachment but impeding CD4-dependent HIV-1 entry. Arf6 silencing or its mutants did not affect fusion, entry, and infection of vesicular stomatitis virus G–pseudotyped viruses or ligand-induced CXCR4 or CCR5 endocytosis, both clathrin-dependent processes. Therefore we propose that efficient early HIV-1 infection of CD4+T lymphocytes requires Arf6-coordinated plasma membrane dynamics that promote viral fusion and entry.

scholarly journals A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans

2004 ◽  
Vol 85 (4) ◽  
pp. 911-919 ◽  
Author(s):  
Matilu Mwau ◽  
Inese Cebere ◽  
Julian Sutton ◽  
Priscilla Chikoti ◽  
Nicola Winstone ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Vaccinia Virus ◽  
Mononuclear Cells ◽  
Vaccine Development ◽  
Cell Mediated Immunity ◽  
Phase I Clinical Trials ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus ◽  
Hiv 1

The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)-vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own and in a prime–boost regimen in phase I clinical trials in healthy uninfected individuals in the United Kingdom. Given the current lack of approaches capable of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA vaccines focus solely on the induction of cell-mediated immunity. The vaccines expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag p24/p17 proteins fused to a string of clade A-derived epitopes recognized by cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear cells were tested for HIV-specific responses in a validated gamma interferon enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools across the Gag domain and three pools of known CTL epitopes present in all of the HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime–MVA boost combination were safe and induced HIV-specific responses in 14 out of 18, seven out of eight and eight out of nine volunteers, respectively. These results are very encouraging and justify further vaccine development.

scholarly journals Construction of A Preliminary Three-Dimensional Structure Simian betaretrovirus Serotype-2 (SRV-2) Reverse Transcriptase Isolated from Indonesian Cynomolgus Monkey

2020 ◽  
Vol 31 (3) ◽  
pp. 47-61
Author(s):  
Uus Saepuloh ◽  
Diah Iskandriati ◽  
Joko Pamungkas ◽  
Dedy Duryadi Solihin ◽  
Sela Septima Mariya ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Cynomolgus Monkey ◽  
Tertiary Structure ◽  
Vaccine Development ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Nucleotide Position ◽  
Structure Model ◽  
Three Dimensional Structure ◽  
Hiv 1

Simian betaretrovirus serotype-2 (SRV-2) is an important pathogenic agent in Asian macaques. It is a potential confounding variable in biomedical research. SRV-2 also provides a valuable viral model compared to other retroviruses which can be used for understanding many aspects of retroviral-host interactions and immunosuppression, infection mechanism, retroviral structure, antiretroviral and vaccine development. In this study, we isolated the gene encoding reverse transcriptase enzyme (RT) of SRV-2 that infected Indonesian cynomolgus monkey (Mf ET1006) and predicted the three dimensional structure model using the iterative threading assembly refinement (I-TASSER) computational programme. This SRV-2 RT Mf ET1006 consisted of 547 amino acids at nucleotide position 3284–4925 of whole genome SRV-2. The polymerase active site located in the finger/palm subdomain characterised by three conserved catalytic aspartates (Asp90, Asp165, Asp166), and has a highly conserved YMDD motif as Tyr163, Met164, Asp165 and Asp166. We estimated that this SRV-2 RT Mf ET1006 structure has the accuracy of template modelling score (TM-score 0.90 ± 0.06) and root mean square deviation (RMSD) 4.7 ± 3.1Å, indicating that this model can be trusted and the accuracy can be seen from the appearance of protein folding in tertiary structure. The superpositionings between SRV-2 RT Mf ET1006 and Human Immunodeficiency Virus-1 (HIV-1) RT were performed to predict the structural in details and to optimise the best fits for illustrations. This SRV-2 RT Mf ET1006 structure model has the highest homology to HIV-1 RT (2B6A.pdb) with estimated accuracy at TM-score 0.911, RMSD 1.85 Å, and coverage of 0.953. This preliminary study of SRV-2 RT Mf ET1006 structure modelling is intriguing and provide some information to explore the molecular characteristic and biochemical mechanism of this enzyme.

scholarly journals Use of Coreceptors Other Than CCR5 by Non-Syncytium-Inducing Adult and Pediatric Isolates of Human Immunodeficiency Virus Type 1 Is Rare In Vitro

1998 ◽  
Vol 72 (11) ◽  
pp. 9337-9344 ◽  
Author(s):  
Yi-jun Zhang ◽  
Tatjana Dragic ◽  
Yunzhen Cao ◽  
Leondios Kostrikis ◽  
Douglas S. Kwon ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Entry ◽  
Infected Infant ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We have tested a panel of pediatric and adult human immunodeficiency virus type 1 (HIV-1) primary isolates for the ability to employ the following proteins as coreceptors during viral entry: CCR1, CCR2b, CCR3, CCR4, CCR5, CCR8, CXCR4, Bonzo, BOB, GPR1, V28, US28, and APJ. Most non-syncytium-inducing isolates could utilize only CCR5. All syncytium-inducing viruses used CXCR4, some also employed V28, and one (DH123) used CCR8 and APJ as well. A longitudinal series of HIV-1 subtype B isolates from an infected infant and its mother utilized Bonzo efficiently, as well as CCR5. The maternal isolates, which were syncytium inducing, also used CXCR4, CCR8, V28, and APJ.

Genetically identical primate modelling systems for HIV vaccines

1998 ◽  
Vol 10 (8) ◽  
pp. 651 ◽  
Author(s):  
Stephen J. Kent ◽  
Ian M. Lewis
Keyword(s):  
Immune Responses ◽  
Hiv Infection ◽  
Vaccine Development ◽  
Careful Consideration ◽  
Hiv Vaccine ◽  
Effective Vaccine ◽  
Hiv Vaccines ◽  
Major Step ◽  
Immunodeficiency Virus ◽  
Hiv 1

There is an urgent need for a safe and effective vaccine to prevent human immunodeficiency virus (HIV) infection. Several HIV vaccine candidates have shown promise, but many concerns regarding the safety and efficacy of current vaccines remain. A major hindrance in HIV vaccine development is a poor understanding of precisely what functions HIV vaccines are required to perform in order to protect humans from HIV-1. Only higher primates (i.e. macaques, chimpanzees and humans) are susceptible to HIV-1 or the closely related virus ‘simian immunodeficiency virus’. These species are outbred and there are remarkable genetic differences in both the immune responses to vaccines and their susceptibility to infection. The development of genetically identical macaques would be a major step towards dissecting what immune responses are required to protect from HIV infection. For example, live attenuated HIV-1 vaccines are likely to be highly efficacious, but will induce disease in a substantial proportion of recipients. Defining why a live attenuated vaccine is effective should allow safer vaccines to be developed, retaining only the immunologic properties of an effective vaccine. The reduction in ‘background genetic noise’ obtained by studying genetically identical primates would provide concise answers to critical HIV vaccine issues, by studying a minimal number of animals. Such an approach could potentially be employed in other diseases where non-human primates are the only available model. Small studies can be performed where identical twins are generated by embryo bisection; however, larger studies where multiple immune parameters are simultaneously evaluated would be facilitated by cloning technology. Despite the technical difficulties to be overcome, the potential gains in human health from the development of genetically identical non-human primates are worthy of careful consideration.

scholarly journals Human Immunodeficiency Virus Env-Independent Infection of Human CD4− Cells

2000 ◽  
Vol 74 (23) ◽  
pp. 10994-11000 ◽  
Author(s):  
Shen Pang ◽  
Duan Yu ◽  
Dong Sung An ◽  
Gayle C. Baldwin ◽  
Yiming Xie ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Lines ◽  
Fluorescent Protein ◽  
Vaccine Development ◽  
Alternative Pathway ◽  
Neutralizing Antibody ◽  
Green Fluorescent Protein Gene ◽  
Immunodeficiency Virus ◽  
Green Fluorescent ◽  
Hiv 1

ABSTRACT CD4− epithelial cells covering mucosal surfaces serve as the primary barrier to prevent human immunodeficiency virus type 1 (HIV-1) infection. We used HIV-1 vectors carrying the enhanced green fluorescent protein gene as a reporter gene to demonstrate that HIV-1 can infect some CD4− human epithelial cell lines with low but significant efficiencies. Importantly, HIV-1 infection of these cell lines is independent of HIV-1 envelope proteins. The Env-independent infection of CD4− cells by HIV-1 suggests an alternative pathway for HIV-1 transmission. Even on virions bearing Env, a neutralizing antibody directed against gp120 is incapable of neutralizing the infection of these cells, thus raising potential implications for HIV-1 vaccine development.

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