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Madani, Navid

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Madani

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Navid

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Madani, Navid
Author's Publications: search.filters.isAuthorOfPublication.8d816297-632f-41c4-af91-de7c26e69a6a

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Now showing 1 - 9 of 9
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    Evaluation of the contribution of the transmembrane region to the ectodomain conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein
    (BioMed Central, 2017) Nguyen, Hanh; Madani, Navid; Ding, Haitao; Elder, Emerald; Princiotto, Amy; Gu, Christopher; Darby, Patrice; Alin, James; Herschhorn, Alon; Kappes, John C.; Mao, Youdong; Sodroski, Joseph
    Background: The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env), a Type 1 transmembrane protein, assembles into a trimeric spike complex that mediates virus entry into host cells. The high potential energy of the metastable, unliganded Env trimer is maintained by multiple non-covalent contacts among the gp120 exterior and gp41 transmembrane Env subunits. Structural studies suggest that the gp41 transmembrane region forms a left-handed coiled coil that contributes to the Env trimer interprotomer contacts. Here we evaluate the contribution of the gp41 transmembrane region to the folding and stability of Env trimers. Methods: Multiple polar/charged amino acid residues, which hypothetically disrupt the stop-transfer signal, were introduced in the proposed lipid-interactive face of the transmembrane coiled coil, allowing release of soluble cleavage-negative Envs containing the modified transmembrane region (TMmod). We also examined effects of cleavage, the cytoplasmic tail and a C-terminal fibritin trimerization (FT) motif on oligomerization, antigenicity and functionality of soluble and membrane-bound Envs. Results: The introduction of polar/charged amino acids into the transmembrane region resulted in the secretion of soluble Envs from the cell. However, these TMmod Envs primarily formed dimers. By contrast, control cleavage-negative sgp140 Envs lacking the transmembrane region formed soluble trimers, dimers and monomers. TMmod and sgp140 trimers were stabilized by the addition of a C-terminal FT sequence, but still exhibited carbohydrate and antigenic signatures of a flexible ectodomain structure. On the other hand, detergent-solubilized cleaved and uncleaved Envs isolated from the membranes of expressing cells exhibited "tighter” ectodomain structures, based on carbohydrate modifications. These trimers were found to be unstable in detergent solutions, but could be stabilized by the addition of a C-terminal FT moiety. The C-terminal FT domain decreased Env cleavage and syncytium-forming ability by approximately three-fold; alteration of the FT trimerization interface restored Env cleavage and syncytium formation to near-wild-type levels. Conclusion: The modified transmembrane region was not conducive to trimerization of soluble Envs. However, for HIV-1 Env ectodomains that are minimally modified, membrane-anchored Envs exhibit the most native structures and can be stabilized by appropriately positioned FT domains.
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    A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge
    (Nature Publishing Group UK, 2018) Madani, Navid; Princiotto, Amy M.; Mach, Linh; Ding, Shilei; Prevost, Jérémie; Richard, Jonathan; Hora, Bhavna; Sutherland, Laura; Zhao, Connie A.; Conn, Brandon P.; Bradley, Todd; Moody, M. Anthony; Melillo, Bruno; Finzi, Andrés; Haynes, Barton F.; Smith III, Amos B.; Santra, Sampa; Sodroski, Joseph
    The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. The “closed,” antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.
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    Tackling HIV in MENA: Talk Is Not Enough–It Is Time for Bold Actions: A Response to Recent Commentaries
    (Kerman University of Medical Sciences, 2018) Karamouzian, Mohammad; Madani, Navid; Doroudi, Fardad; Haghdoost, Ali Akbar
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    Women, culture and the HIV epidemic in MENA
    (International AIDS Society, 2014) Chahil-Graf, Renu; Madani, Navid
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    Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity
    (Elsevier, 2016) Bradley, Todd; Trama, Ashley; Tumba, Nancy; Gray, Elin; Lu, Xiaozhi; Madani, Navid; Jahanbakhsh, Fatemeh; Eaton, Amanda; Xia, Shi-Mao; Parks, Robert; Lloyd, Krissey E.; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy M.; Barnett, Susan; Abdool-Karim, Salim S.; Boyd, Scott D.; Melillo, Bruno; Smith, Amos B.; Sodroski, Joseph; Kepler, Thomas B.; Alam, S.Munir; Gao, Feng; Bonsignori, Mattia; Liao, Hua-Xin; Moody, M. Anthony; Montefiori, David; Santra, Sampa; Morris, Lynn; Haynes, Barton F.
    Most HIV-1 vaccines elicit neutralizing antibodies that are active against highly sensitive (tier-1) viruses or rare cases of vaccine-matched neutralization-resistant (tier-2) viruses, but no vaccine has induced antibodies that can broadly neutralize heterologous tier-2 viruses. In this study, we isolated antibodies from an HIV-1-infected individual that targeted the gp41 membrane-proximal external region (MPER) that may have selected single-residue changes in viral variants in the MPER that resulted in neutralization sensitivity to antibodies targeting distal epitopes on the HIV-1 Env. Similarly, a single change in the MPER in a second virus from another infected-individual also conferred enhanced neutralization sensitivity. These gp41 single-residue changes thus transformed tier-2 viruses into tier-1 viruses that were sensitive to vaccine-elicited tier-1 neutralizing antibodies. These data demonstrate that Env amino acid changes within the MPER bnAb epitope of naturally-selected escape viruses can increase neutralization sensitivity to multiple types of neutralizing antibodies, and underscore the critical importance of the MPER for maintaining the integrity of the tier-2 HIV-1 trimer.
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    Structure-Based Design, Synthesis and Validation of CD4-Mimetic Small Molecule Inhibitors of HIV-1 Entry: Conversion of a Viral Entry Agonist to an Antagonist
    (American Chemical Society, 2014) Courter, Joel R.; Madani, Navid; Sodroski, Joseph; Schön, Arne; Freire, Ernesto; Kwong, Peter D.; Hendrickson, Wayne A.; Chaiken, Irwin M.; LaLonde, Judith M.; Smith, Amos B.
    Conspectus This Account provides an overview of a multidisciplinary consortium focused on structure-based strategies to devise small molecule antagonists of HIV-1 entry into human T-cells, which if successful would hold considerable promise for the development of prophylactic modalities to prevent HIV transmission and thereby alter the course of the AIDS pandemic. Entry of the human immunodeficiency virus (HIV) into target T-cells entails an interaction between CD4 on the host T-cell and gp120, a component of the trimeric envelope glycoprotein spike on the virion surface. The resultant interaction initiates a series of conformational changes within the envelope spike that permits binding to a chemokine receptor, formation of the gp41 fusion complex, and cell entry. A hydrophobic cavity at the CD4–gp120 interface, defined by X-ray crystallography, provided an initial site for small molecule antagonist design. This site however has evolved to facilitate viral entry. As such, the binding of prospective small molecule inhibitors within this gp120 cavity can inadvertently trigger an allosteric entry signal. Structural characterization of the CD4–gp120 interface, which provided the foundation for small molecule structure-based inhibitor design, will be presented first. An integrated approach combining biochemical, virological, structural, computational, and synthetic studies, along with a detailed analysis of ligand binding energetics, revealed that modestly active small molecule inhibitors of HIV entry can also promote viral entry into cells lacking the CD4 receptor protein; these competitive inhibitors were termed small molecule CD4 mimetics. Related congeners were subsequently identified with both improved binding affinity and more potent viral entry inhibition. Further assessment of the affinity-enhanced small molecule CD4 mimetics demonstrated that premature initiation of conformational change within the viral envelope spike, prior to cell encounter, can lead to irreversible deactivation of viral entry machinery. Related congeners, which bind the same gp120 site, possess different propensities to elicit the allosteric response that underlies the undesired enhancement of CD4-independent viral entry. Subsequently, key hotspots in the CD4–gp120 interface were categorized using mutagenesis and isothermal titration calorimetry according to the capacity to increase binding affinity without triggering the allosteric signal. This analysis, combined with cocrystal structures of small molecule viral entry agonists with gp120, led to the development of fully functional antagonists of HIV-1 entry. Additional structure-based design exploiting two hotspots followed by synthesis has now yielded low micromolar inhibitors of viral entry.
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    Improving the Quality and Quantity of HIV Data in the Middle East and North Africa: Key Challenges and Ways Forward
    (Kerman University of Medical Sciences, 2017) Karamouzian, Mohammad; Madani, Navid; Doroudi, Fardad; Haghdoost, Ali Akbar
    Although the HIV pandemic is witnessing a decline in the number of new infections in most regions of the world, the Middle East and North Africa (MENA) has a rapidly growing HIV problem. While generating HIV data has been consistently increasing since 2005, MENA’s contribution to the global HIV literature is just over 1% and the existing evidence often falls behind the academic standards. Several factors could be at play that contribute to the limited quantity and quality of HIV data in MENA. This editorial tries to explore and explain the barriers to collecting high-quality HIV data and generating precise estimates in MENA. These barriers include a number of logistic and socio-political challenges faced by researchers, public health officials, and policy-makers. Looking at successful regional HIV programs, we explore examples were policies have shifted and lessons could be learned in developing appropriate responses to HIV across the region.
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    Thermal Stability of the Human Immunodeficiency Virus Type 1 (HIV-1) Receptors, CD4 and CXCR4, Reconstituted in Proteoliposomes
    (Public Library of Science, 2010) Zhukovsky, Mikhail A.; Basmaciogullari, Stéphane; Schwartz, Olivier; Pacheco, Beatriz; Wang, Jiping; Madani, Navid; Haim, Hillel; Sodroski, Joseph
    Background: The entry of human immunodeficiency virus (HIV-1) into host cells involves the interaction of the viral exterior envelope glycoprotein, gp120, and receptors on the target cell. The HIV-1 receptors are CD4 and one of two chemokine receptors, CCR5 or CXCR4. Methodology/Principal Findings: We created proteoliposomes that contain CD4, the primary HIV-1 receptor, and one of the coreceptors, CXCR4. Antibodies against CD4 and CXCR4 specifically bound the proteoliposomes. CXCL12, the natural ligand for CXCR4, and the small-molecule CXCR4 antagonist, AMD3100, bound the proteoliposomes with affinities close to those associated with the binding of these molecules to cells expressing CXCR4 and CD4. The HIV-1 gp120 exterior envelope glycoprotein bound tightly to proteoliposomes expressing only CD4 and, in the presence of soluble CD4, bound weakly to proteoliposomes expressing only CXCR4. The thermal stability of CD4 and CXCR4 inserted into liposomes was examined. Thermal denaturation of CXCR4 followed second-order kinetics, with an activation energy (E\(_a\)) of 269 kJ/mol (64.3 kcal/mol) and an inactivation temperature (T\(_i\)) of 56°C. Thermal inactivation of CD4 exhibited a reaction order of 1.3, an E\(_a\) of 278 kJ/mol (66.5 kcal/mol), and a T\(_i\) of 52.2°C. The second-order denaturation kinetics of CXCR4 is unusual among G protein-coupled receptors, and may result from dimeric interactions between CXCR4 molecules. Conclusions/Significance: Our studies with proteoliposomes containing the native HIV-1 receptors allowed an examination of the binding of biologically important ligands and revealed the higher-order denaturation kinetics of these receptors. CD4/CXCR4-proteoliposomes may be useful for the study of virus-target cell interactions and for the identification of inhibitors.