Description

Entry of HIV-1 into target cells requires the sequential interaction of the viral envelope glycoprotein gp120 with the CD4 receptor and either CCR5 or CXCR4 acting as co-receptors. The viral envelope is under strong evolutionary pressure along HIV-1 infection due to both innate and adaptive immune responses: chemokines binding HIV-1 co-receptors, neutralizing antibodies and probably class I Interferon, are mechanisms driving important changes in the structure of the HIV-1 envelope in a particular HIV-1 infected patient. In support of this hypothesis it is well known that viral strains binding CCR5 (R5-tropic) and with a resistance to Interferon are preferentially transmitted, and R5-tropic viruses predominate in the early phases of infection. In contrast, those strains that use CXCR4 for entry emerge after years of infection, and this emergence correlates with a poor clinical outcome and development of AIDS. However, up to 50% of the infected individuals progress to AIDS in the presence of only R5 viruses and the mechanisms driving this selection are not fully understood so far.

In the lab we have addressed the study of the HIV-1 envelope from different perspectives and we consider the viral envelope as both a major determinant of HIV pathogenesis and a mirror of the innate and adaptive immune response elicited against HIV.

Different projects and approaches to get a better insight on the characteristics of the HIV-1 envelope are developed by Mayte Pérez-Olmeda (Senior researcher), Javier García-Pérez (Tenure Post-doc) and Nuria González (Tenure Post-doc) with the support of the technicians Almudena Cascajero, Amparo Álvarez and Laura Jiménez.

Our main contributions to this field have been:

• The demonstration of the production of CXCL12 by mature dendritic cells, a process that favors the transmission of R5 over X4-tropic variants in the immune synapse (González N, et al. J Virol. 2010 May;84(9):4341-51.).
• In collaboration with Bernard Lagane and Fernando Arenzana-Seisdedos at Institut Pasteur, we have contributed to the study of HIV-1 escape from CCR5 chemokines (Colin P, et al. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9475-80.) and the mechanisms of resistance to Maraviroc - a CCR5 antagonist - at molecular level (García-Pérez J, et al. J Biol Chem. 2011 Sep 23;286(38):33409-21. and García-Pérez J, et al. J Biol Chem. 2011 Feb 18;286(7):4978-90.).
• Also we have developed specific systems to assess the viral tropism and titration of neutralizing activity in the sera from HIV-1 infected patients (González N, et al. J Antimicrob Chemother. 2010 Dec;65(12):2493-501., Fenyö EM, et al. PLoS One. 2009;4(2):e4505. and Heyndrickx L, et al. PLoS One. 2012;7(5):e36438.). These systems have been validated with the gold standards in the field (Monogram, Montefiori´s lab) and are available for clinical practice. These technologies have been used in academic studies (Medina-Ramírez M, et al. J Virol. 2011 Jun;85(12):5804-13.) and in the assessment of vaccine trials in which we participate as reference laboratory in the evaluation of neutralizing antibodies: trials DCV1, DCV2, RISVAC 02 and RISVAC 03 (García F, et al. J Infect Dis. 2005 May 15;191(10):1680-5., García F, et al. J Infect Dis. 2011 Feb 15;203(4):473-8. and García F, et al. Vaccines. 2011 Oct 26;29(46):8309-16.)

 

Finally, we have written different reviews on this issue and participated in clinical guidelines:

• Determination of HIV tropism and its use in the clinical practice (Pérez-Olmeda M, et al. Expert Rev Anti Infect Ther. 2013 Dec;11(12):1291-302.).
• Update on clinical and methodological recommendations for genotypic determination of HIV tropism to guide the usage of CCR5 antagonists (Poveda E, et al. AIDS Rev. 2012 Jul-Sep;14(3):208-17.).
• Broadly neutralizing antibodies and their significance for HIV-1 vaccines (González N, et al. Curr HIV Res. 2010 Dec;8(8):602-12.).

 

Projects and funding

Spanish Ministry of Health. Instituto de Salud Carlos III:

• Characterisation of broadly neutralizing antibodies in Long Term Non-Progressors (LTNPs) and Elite Neutralizers patients. Activity against founder viruses (EC-11-278). Principal investigator: P Alcamí. 2012-2013.
• Development of a vaccine against HIV: Isolation and characterisation of new broad neutralizing antibodies. Design of immunogens able to generate these antibodies (FIS PS09/01459). Principal investigators: P Alcamí and E Yuste (Hospital Clínic, Barcelona). 2010-2012.
• Phase I open study to evaluate safety and immunogenicity of MVA-B vaccine against HIV, in chronic HIV infected patients on antiretroviral treatment: RISVAC03 (FIS TRA-094). Principal investigators: P Alcamí and F García (Hospital Clínic, Barcelona). 2010-2011.
• Study of the regulation of CXCR4 coreceptor in peripheral blood lymphocytes and its relationship with HIV infection (FIS 98/0337). Principal investigator: P Alcamí. 1998-2000.

Foundation for Research and Prevention of AIDS in Spain (FIPSE):

• Genotypic and phenotypic HIV evolution in patients treated with CCR5 antagonists (FIPSE 36630/07). Principal investigator: P Alcamí. 2008-2010.
• Analysis of the regulation of SDF-1 chemokine in dendritic cells and its impact on HIV-1 infection (FIPSE 36453/03). Principal investigator: P Alcamí. 2004-2006.
• Phase II study of use of autologous myeloid dendritic cells as cellular adjuvant for a therapeutic vaccine against HIV-1 in patients in early stages of HIV-1 infection (FIPSE   36536/05). Principal investigators: P Alcamí and T Gallart (Hospital Clínic, Barcelona). 2006-2008.

French Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS):

• Comparative study of the influence of chemokines on the evolution of phenotypic properties of R5 and X4. Principal investigators: B Lagane (Institut Pasteur) and P Alcamí. 2013-2016. FALTA EL NÚMERO DE PROYECTO
• Genotypic evolution, phenotypic tropism and study of the mechanisms of viral adaptation in subjects treated with a CCR5 antagonist (A.N.R.S. 2008). Principal investigators: P Alcamí and F Arenzana-Seisdedos (Institut Pasteur). 2008-2010.

European Commission:

• European Network of Excellence on HIV/AIDS. Development of new vaccines and viricides against HIV, 6^th Framework Programme EUROPRISE Network (037611). Principal investigator (ISCIII node): P Alcamí. 2006-2010.

 

Scientific collaborations

Thanks to the development of a new recombinant virus system carrying specific genetic sequences from patients, we had the opportunity of participating in the NEUTNET and EUROPRISE Networks supported by the European Commission. In this initiative we validated our model with gold standards in the field and collaborated closely with Gabriella Scarlatti from Università Vita-Salute San Raffaele, Milan, and Leo Heyndrick from the Instituut voor Tropische Geneeskunde, Antwerp (Fenyö EM, et al. PLoS One. 2009;4(2):e4505. and Heyndrickx L, et al. PLoS One. 2012;7(5):e36438.).

In the vaccine field, our group is the reference laboratory in the Spanish AIDS Research Network (RIS) for titration and characterization of neutralizing antibodies. We have participated in vaccine clinical trials and develop very close collaborations with teams from Hospital Clínic of Barcelona, José María Gatell, Eloisa Yuste and Sonsoles Sánchez-Palomino (Medina-Ramírez M, et al. J Virol. 2011 Jun;85(12):5804-13. and Álvarez-Fernández C, et al. PLoS One. 2012;7(11):e48848.).

We collaborate with Bernard Lagane and Fernando Arenzana-Seisdedos from Unité de Patologie Virale Molléculaire at Pasteur Institute in the study of the mechanisms driving HIV-1 evolution in vivo, and in particular, the role of chemokines in this process. These projects are funded by the French Agency on AIDS Research, ANRS, (Colin P, et al. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9475-80.).

Finally, we have set up a tropism assay that has been validated with other tests in the field and gave us the opportunity to collaborate with the company Pfizer in the study of tropism in clinical samples and the mechanisms of resistance to Maraviroc (González N, et al. J Antimicrob Chemother. 2010 Dec;65(12):2493-501., (García-Pérez J, et al. J Biol Chem. 2011 Sep 23;286(38):33409-21. and García-Pérez J, et al. J Biol Chem. 2011 Feb 18;286(7):4978-90.).