Evaluation of current approaches to inhibit HIV entry.
ABSTRACT Highly active inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and protease have made it possible to dramatically reduce virus load in HIV-positive individuals. However, the presence of viral reservoirs, the emergence of drug-resistant HIV variants and the side effects of these compounds call for research into new drugs that target different stages of the viral life cycle. One attractive target is the first step in HIV replication: entry of virus into cells. HIV entry is initiated by the attachment of the virus to the host cell membrane, which is some cases involves binding to attachment factors such as DC-SIGN. Subsequent interaction of the envelope protein (Env) with the CD4 receptor causes conformational changes that enable Env to interact with a coreceptor, generally the chemokine receptors CCR5 or CXCR4. Coreceptor engagement triggers the final conformational changes in Env, which mediate lipid mixing between the viral and cellular membranes. All of these steps are potential targets for therapeutic intervention: targeting proteins that mediate viral attachment may reduce HIV transmission, while receptor blockade will inhibit virus entry. Highly conserved domains in Env which bind to CD4 and coreceptor are promising targets for broadly neutralizing antibodies, and peptide inhibitors that bind to Env and that block membrane fusion are in advanced clinical trials. These new approaches may supplement current HIV therapy and may assist in the development of an HIV vaccine.
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ABSTRACT: In the late nineteenth century, Paul Langerhans discovered Langerhans cells, a form of dendritic cell (DC) found on the skin. However, the term DC was first described in 1973 by Ralph M. Steinman after identifying a population of dendritic-shaped cells in the spleen of mice. Increased research on DC lead to the recognition of DCs as professional antigen presenting cells (APCs). DCs can be classified into different subsets based on their location, marker expression, immune function, and cytokine secretion. To date, four major DC subtypes have been identified: myeloid (mDCs) and plasmacytoid (pDCs) in the blood, follicular dendritic cells (FDCs) in lymph follicles, and Langerhans cells in tissues such as the skin and mucosal epithelial. DCs comprise ≤2% of total peripheral-blood mononuclear cells (PBMCs). However, due to their role in the regulation of the adaptive immune response and their localization, DCs have been recognized as the first line of defense against any pathogen including Human Immunodeficiency Virus (HIV). DCs can harbor HIV and mediate its spread to other immune cells. The ability of HIV-1 to use DCs for propagation and to transfer virus to activated T cells is crucial in the early stages of HIV-1 pathogenesis. Furthermore, several research studies have been focusing on targeting HIV binding receptors on host cells such as DCs as an alternative therapeutic strategy. A major breakthrough in this research area was the discovery of a membrane associated C-type lectin, DC Specific Intercellular adhesion molecule-3 (ICAM-3) Grabbing Nonintegrin, (DC-SIGN or CD209), which facilitates HIV infection independent of the main receptor (CD4) or HIV-1 co-receptors (CCR5/CXCR4) and is The exclusive license for this PDF is limited to personal printing only. No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.01/2010: pages 167-177;
Article: Analysis of binding sites for the new small-molecule CCR5 antagonist TAK-220 on human CCR5.[show abstract] [hide abstract]
ABSTRACT: G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.Antimicrobial Agents and Chemotherapy 12/2005; 49(11):4708-15. · 4.84 Impact Factor
Article: Oligosaccharide and glycoprotein microarrays as tools in HIV glycobiology; glycan-dependent gp120/protein interactions.[show abstract] [hide abstract]
ABSTRACT: Defining HIV envelope glycoprotein interactions with host factors or binding partners advances our understanding of the infectious process and provides a basis for the design of vaccines and agents that interfere with HIV entry. Here we employ carbohydrate and glycoprotein microarrays to analyze glycan-dependent gp120-protein interactions. In concert with new linking chemistries and synthetic methods, the carbohydrate arrays combine the advantages of microarray technology with the flexibility and precision afforded by organic synthesis. With these microarrays, we individually and competitively determined the binding profiles of five gp120 binding proteins, established the carbohydrate structural requirements for these interactions, and identified a potential strategy for HIV vaccine development.Chemistry & Biology 07/2004; 11(6):875-81. · 5.83 Impact Factor