Trkola
Fakultäten » Medizinische Fakultät » Medizinische Virologie, Institut für » Prof. Dr. Alexandra Trkola » Trkola
Completed research project
| Title / Titel | HIV entry: a target for the host immune response and antiviral approaches | ||||||
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| Abstract (PDF, 14 KB) | |||||||
| Summary / Zusammenfassung | Over recent years it has become increasingly apparent that the potency of the antiretroviral drug regimens used in the treatment of HIV-1 infection does not allow for complete elimination of the virus and that long term toxicity of these drugs is considerable. Thus, novel therapeutic treatment forms to supplement or replace current therapies are urgently needed. Amongst other strategies a strong emphasis has been put towards the development of vaccines based on the induction of an anti-HIV humoral immune response and on engineered inhibitors both of which target the HIV entry process. The project aims to define the role and underlying mechanisms of the host immune responses directed against the viral entry process and to gain further insights into the early steps of the HIV infection process. The project is divided into two individual projects: Project A focuses on the characterization of the humoral immune response directed against HIV-1. In particular we aim here to define the protective potential of antibodies in vivo. To date our understanding of the role that neutralizing antibodies play in vivo is largely based on in vitro data, anecdotal case reports and animal studies. Although particularly the latter studies gave strong evidence that neutralizing antibodies can in fact protect against infection or at least significantly reduce infection rates, we have yet to find formal proof that neutralizing antibodies are indeed also a correlate of protection in man. Project B focuses on aspects of virus - target cell interactions and their consequence for the HIV infection process in vivo. Here we will continue our efforts on elucidating inhibitory and immunmodulatory functions of chemokines and their influence on viral infectivity and pathogenesis. A detailed knowledge of chemokine function, including both, their activity as chemoattractant and HIV inhibitors, is pivotal for our understanding of the HIV entry process and the influence of chemokines in pathogenesis as well as the development of antiviral strategies that target the HIV entry process by interfering with the coreceptors. We will also expand our research on the role that glycosaminoglycans play in the interaction with chemokines and their role in virus attachment and entry. More than twenty years after its discovery, HIV remains a major threat to public health, particularly in developing countries, infecting more than 40 million people world wide. Available drug therapies are costly and succeed only in suppressing but not eradicating infection. In addition resistance of the virus to drugs develops frequently and some of the medications lead to severe side effects preventing the necessary lifelong application. Thus, there is an increasing demand on novel therapeutics that are potent and cost-effective and overcome the limitations of the current available drugs. Despite the clear benefits of drug therapy, a successful control of the HIV- 1 pandemic will require effective protective and therapeutic vaccines that can be made available globally. However, despite considerable research efforts over the past decades, it has become evident that the development of a successful vaccine against HIV-1 faces enormous difficulties and may require many more years. As long as no effective vaccine is available other measures to limit the vast spread of HIV are urgently sought for. HIV infection is predominantly acquired through sexual transmission across mucosal surface. Thus, strategies that prevent mucosal transmission could significantly impact on diminishing viral spread. One very compelling approach is the use of microbicides, agents that by topical application on mucosal surfaces inhibit infection by either inactivating incoming virus, or by preventing HIV from entering or replicating in target cells directly at the initial site of exposure. Although our understanding of the mechanisms involved in mucosal infection are incomplete, inhibitors of this process, as for instance based on blocking viral entry into target cells, can be developed. Here we aim to identify novel protein-based inhibitors of the HIV entry process that may have potential as future therapeutic and preventive agents. We are applying together with our collaborators Molecular Partners a novel approach to identify inhibitors of HIV entry by using designed ankyrin repeat protein (DARPin) libraries. DARPins are attractive candidates for protein-based inhibitors as they share many features of antibodies while having a higher chemical and physical stability and displaying a different binding mode compared to antibodies. One focus will be on identifying DARPins that specifically bind to the viral envelope proteins gp41 and gp120. We will particularly concentrate our screening on the identification of DARPins that are able to recognize the oligomeric forms of the viral envelope as present on intact virions. A further aim will be to select DARPins that specifically bind to the viral receptors CD4, CCR5 and CXCR4. DARPins that recognize viral envelope proteins or viral receptors will then be screened for their capacity to inhibit HIV-1 infection in vitro. We will characterize the mode of action of the identified proteins with inhibitory activity and define the epitopes on the viral and cellular proteins they recognize. The overall aim is to identify DARPin-based inhibitors of viral entry that merit further investigation as potential agents for clinical application. |
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| Publications / Publikationen | Trkola A, Kuster H, Leemann C, Oxenius A, Fagard C, Furrer H, Battegay M, Vernazza P, Bernasconi E, Weber R, Hirschel B, Bonhoeffer A, Günthard HF, and the Swiss HIV cohort study. Humoral immunity to HIV-1: Kinetics of antibody responses in chronic infection reflect capacity of immune system to improve viral set point. Blood. 2004;104(6):1784-92Rusert P, Fischer M, Leemann C, Kuster H., Flepp M, Weber R, Gunthard H, Trkola A. Quantification of infectious HIV-1 plasma viral load using a boosted in vitro infection protocol. Virology 2004. 326:113-29Rusert P, Kuster H, Misselwitz B, Joos B, Gujer C, Fischer M, Leemann C, Stiegler G, Katinger H, Olson W, Aceto L, Günthard HF, Trkola A. Virus isolates during acute and chronic HIV infection show distinct pattern of sensitivity to entry inhibitors. Journal of Virology. 2005. 79(13):8454-69.Joos B, Trkola A, Fischer M, Kuster H, Leemann C, Böni J, Oxenius A, Wong J, Weber R, Günthard HF and the Swiss HIV Cohort Study. Low Pretreatment Diversity of HIV-envelope Sequences in Chronically Infected Patients Predicts Spontaneous Control of Plasma Viremia after Structured Treatment Interruptions. J Virol. 2005;79(14):9026-37.Cilliers T, Willey S,. Sullivan MW, Patience T, Pugach P, Coetzer M, Papathanasopoulos M; Moore JP, Trkola A, Clapham P, Morris L. Use of alternate coreceptors on primary cells by two HIV-1 isolates. Virology. 2005;339(1):136-44.Trkola A, Kuster H, Rusert P, Joos B, Fischer M, Leemann C, Manrique A, Huber M, Rehr M, Oxenius A, Weber R, Stiegler G, Vcelar B, Katinger H, Aceto L, Günthard HF. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nature Medicine. 2005; 11(6):615-22. | ||||||
| Keywords / Suchbegriffe | HIV-1, entry, neutralizing antibodies, entry inhibitors | ||||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
SNF (Personen- und Projektförderung), Foundation SNF PP00B-102647 Swiss National Fonds Professorship; Hartmann-Müller StiftungNovartis FoundationStiftung für wissenschaftliche ForschungVelux FoundationVontobel Foundation |
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| In collaboration with / In Zusammenarbeit mit |
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| Duration of Project / Projektdauer | Mar 2004 to Dec 2008 |