Projects / Programmes
Interaction of LPS with HIV-1 protein gp120 as a basis for a new type of inhibition of virus binding to T cells
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B230 |
Biomedical sciences |
Microbiology, bacteriology, virology, mycology |
| B510 |
Biomedical sciences |
Infections |
AIDS, HIV-1 virus, glycoprotein gp120, V3 peptide, bacterial superinfection, inhibitor, endotoxin, LPS, lipid A, T cells, pseudo virus, NMR
Researchers (7)
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
21,007 |
Abstract
Prevention of interaction and fusion of HIV-1 virus with T cells is one of the most successful modern strategies to prevent infection. Many antibodies, which neutralize interaction of HIV-1 with target cells, are directed against the viral protein gp120, which lies at the external side of the viral envelope and is responsible for the viral entry into the target cells. The most effective are antibodies against the V3 epitope, which is a surface loop of gp120 protein. This part is exposed at the surface of the protein and is in the crystal structure disordered. A report about the antimicrobial activity of the peptide based on the V3 against the Gram-negative bacteria prompted us to test binding of V3 peptide to the lipopolysaccharide (LPS), which is the characteristic constituent of Gram-negative bacteria. We confirmed this interaction also by NMR and found that V3 binds to the lipid A, which is the conserved part of the LPS. Compounds based on the LPS structure could represent a new lead for the prevention of HIV-1 interaction with the cellular receptors. Within the scope of the project we will determine the structure of V3 bound to the LPS with NMR, using similar approach before for other LPS-binding peptides. We will also measure binding of LPS and its analogues to the integral gp120. We will determine if LPS prevents binding of gp120 to receptors at the surface of T cells, which will be important for the biological relevance of the observed interaction. Besides LPS we will determine activity also for its apyrogenic antagonists – compounds similar to lipid A, which could be applicable for the therapy without the danger of endotoxemia. We will test other compounds that have the similar structural pattern (pharmacophore) as LPS. For the selected compounds we will test the inhibition of pseudoviral infection of T-cells. Since the peptide-LPS represents the pattern recognition type of interaction, we can in comparison to the antibodies expect that it will be much less sensitive to the inactivation by the viral mutations. We expect that the project will establish the base for the rational design of new inhibitors of HIV-1 based on the LPS and at the same time additional insight into the processes during the bacterial superinfections of patients infected with HIV-1.
Significance for science
Infections with HIV-1 represent health problem for all world. On the basis of testing different LPS molecules, LPS anologs and other molecules that have similar structural pattern as LPS we identified some molecules (i.e. lipid IVa and Ec006, nonendotoxic LPS antagonists) that inhibit virus protein gp120 binding to target T cells and will be therefore interesting for further investigations for the development of medicines against HIV-1 on the basis of gp120 inhibition. We expect that such molecules will on the one side reduce HIV-1 load in the organism and on the other side perhaps due to potential apyrogenic characteristics act against infections with opportunistic Gram-negative bacteria.
The role of LPS in HIV-1 infection has not been completely explained. Till now researchers have shown only many indirect effects of LPS on HIV-1 infection, but we have focused on the research of direct interaction between LPS and virus protein gp120 or its V3 peptide segment that is principal for the virus entry into target cells. We expect that our structural model of the interaction of V3 with LPS, based on NMR results, will contribute to the understanding of the mechanisms for inhibition of gp120 interaction with target cells.
Our explicitly interdisciplinary accession with the expertise in structural and cell biology represents innovative and original contribution to the very competitive field of HIV-1 research. The knowledge obtained in the project is important also for the understanding of the role of bacterial infections that accur in patients, infected with HIV-1 virus.
With innovative approach and methods we also expand knowledge spectrum of researchers and undergraduate and graduate students and represent it to the professional public through scientific journals and meetings.
Significance for the country
Accession to foreign knowledge and incorporation into international division of labor: Equality of cooperation with the researchers from different, especially European countries is of importance for national self-confidence and recognition of Slovenia worldwide. The members in the project group have already cooperated with international research community through bilateral cooperation, work with multinational companies from abroad, and European research projects.
Within the frame of the project we continued formal and informal collaboration with research groups at home and abroad. This increased mobility in research society and knowledge exchange.
Education of highly qualified workers: We included graduate and undergraduate students; this contributed to increase of the number of highly qualified researchers with broad knowledge in the field of natural science.
Promotion of natural science: In the period of last four years members of the project team have achieved exceptional successes in the competitions of research projects in the most eminent academic competition (iGEM, described in achievements). Thus, they importantly help to the promotion of natural science in the broad public and Slovenia as the state with the excellent science and education. A wide response of mentioned successes was encountered through all over the world in the newspapers, journals, TV, radio, on web pages. Researchers of the proposed project have also presented other past results and their importance to broad public in press, through interviews and TV emissions and also in the National Assemby of the Republic of Slovenia.
Most important scientific results
Annual report
2008,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2008,
final report,
complete report on dLib.si
