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.
- SourceAvailable from: Eliseo A Eugenin[show abstract] [hide abstract]
ABSTRACT: Human immunodeficiency virus (HIV) infection is associated with accelerated atherosclerosis and vasculopathy, although the mechanisms underlying these findings have not been determined. Hypotheses for these observations include: 1) an increase in the prevalence of established cardiac risk factors observed in HIV-infected individuals who are currently experiencing longer life expectancies; 2) the dyslipidemia reported with certain HIV anti-retroviral therapies; and/or 3) the proinflammatory effects of infiltrating HIV-infected monocytes/macrophages. An unexplored possibility is whether HIV itself can infect vascular smooth muscle cells (SMCs) and, by doing so, whether SMCs can accelerate vascular disease. Our studies demonstrate that human SMCs can be infected with HIV both in vivo and in vitro. The HIV protein p24 was detected by fluorescence confocal microscopy in SMCs from tissue sections of human atherosclerotic plaques obtained from HIV-infected individuals. Human SMCs could also be infected in vitro with HIV by a mechanism dependent on CD4, the chemokine receptors CXCR4 or CCR5, and endocytosis, resulting in a marked increase in SMC secretion of the chemokine CCL2/MCP-1, which has been previously shown to be a critical mediator of atherosclerosis. In addition, SMC proliferation appeared concentric to the vessel lumen, and minimal inflammation was detected, unlike typical atherosclerosis. Our data suggest that direct infection of human arterial SMCs by HIV represents a potential mechanism in a multifactorial paradigm to explain the exacerbated atherosclerosis and vasculopathy reported in individuals infected with HIV.American Journal Of Pathology 05/2008; 172(4):1100-11. · 4.52 Impact Factor
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ABSTRACT: We studied the antiviral activity of carbohydrate-binding agents (CBAs), including several plant lectins and the non-peptidic small-molecular-weight antibiotic pradimicin A (PRM-A). These agents efficiently prevented hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) infection of target cells by inhibiting the viral entry. CBAs were also shown to prevent HIV and HCV capture by DC-SIGN-expressing cells. Surprisingly, infection by other enveloped viruses such as herpes simplex viruses, respiratory syncytial virus and parainfluenza-3 virus was not inhibited by these agents pointing to a high degree of specificity. Mannan reversed the antiviral activity of CBAs, confirming their association with viral envelope-associated glycans. In contrast, polyanions such as dextran sulfate-5000 and sulfated polyvinylalcohol inhibited HIV entry but were devoid of any activity against HCV infection, indicating that they act through a different mechanism. CBAs could be considered as prime drug leads for the treatment of chronic viral infections such as HCV by preventing viral entry into target cells. They may represent an attractive new option for therapy of HCV/HIV coinfections. CBAs may also have the potential to prevent HCV/HIV transmission.Virology 10/2007; 366(1):40-50. · 3.37 Impact Factor
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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;