Introduction

The Spanish Aids Research Network (RIS) is one of the Thematic Cooperative Research Networks (RETICs) funded by the Instituto de Salud Carlos III (ISCIII). The RIS aim is to guarantee a high level of quality in the HIV/AIDS research and to promote the continuous improvement of the results in the National Health System through the cooperation of quality research groups of different institutions. The RIS is coordinated by José Mª Gatell (Hospital Clínic-IDIBAPS, Barcelona), Santiago Moreno (Hospital Universitario Ramón y Cajal, Madrid) and Pepe Alcamí (AIDS Immunopathology Unit, ISCIII, Madrid).

The RIS was set up in 2003 and throughout its different stages has undeniably led the research on HIV infection in Spain. The network research not only has strengthened the work of the participating teams but also has allowed to set up collaborative structures not available in Spain until that moment: cohorts, centralised data bases, biobank, coordinated projects, clinical and epidemiological assays, are some of the achievements of the RIS. The RIS has been the best evaluated network of the Spanish research system and, because of the effort of its members, it has helped to improve the contribution of Spain to global HIV/AIDS research.

In 2012, the network was organised in three Programmes:

• Programme 1: Clinical-Epidemiological studies
• Programme 2: Strategic Studies and Clinical Trials
• Programme 3: Immunopathogenesis and Vaccines

The AIDS Immunopathologygroup, led by Pepe Alcamí, participates in the RIS Immunopathogenesis and Vaccine Programme (Programme 3), working in close collaboration with the other Programmes. The Programme 3 is led by Pepe Alcamí together with Manolo Leal from the Hospital Universitario Virgen del Rocío, Seville.

Description and Objectives

Programme 3 (Immunopathogeny and Vaccine Programme) is organised in five work packages (WP):

• WP1. Biobank, Repository and Laboratory Platform

• WP2. Immune Response and Mechanism of Control of HIV Infection

• WP3. Mechanism of Damage and Immune Reconstitution

• WP4. Reservoirs, Latency and Eradication

• WP5. Vaccines development

WP1. Biobank, Repository and Laboratory Platform

This WP is led by María Ángeles Muñoz from Hospital General Universitario Gregorio Marañón, Madrid, and is composed of three structures: the Biobank, the Repository and the Laboratory Platform.

In the Biobank, samples of blood and biopsies from HIV-infected patients belonging to the different RIS cohorts are received and processed, and the resultant tissues, blood, plasma, cells and DNA are stored and cryopreserved. The epidemiological data and the samples stored in the biobank are available to the researchers. The biobank collects samples from HIV patients belonging to the RIS Cohort (CoRIS), an open, prospective and multicentre cohort of patients older than 13 years old with HIV diagnosis and without previous HIV treatment. In addition to CoRIS, the RIS has created other cohorts, among which the next ones stand out: the Long Term Non Progressors cohort (LTNP-RIS), the Elite Controller cohort (EC-RIS), the cohort of patients with recent acute infection (PHI-RIS) and the paediatric cohort (CoRIS-Pe).

In the Repository, other types of biological material are stored: isolated viruses and recombinant viral clones of special interest, viral envelope clones from different groups of patients, immortalized cells from patients with special characteristics, etc.

The objective of the Laboratory Platform is to carry out quality controls to stored samples and to standardise techniques of interest for the RIS projects.

WP2. Immune Response and Mechanism of Control of HIV Infection

This WP is led by Ezequiel Ruiz-Mateos from Hospital Universitario Virgen del Rocío, Seville, and José Miguel Benito from Instituto de Investigación Sanitaria - Fundación Jiménez Díaz. The activity of WP2 is organised around two groups of patients: Elite Controllers and Elite Neutralizers.

The Elite Controllers cohort is formed by patients able to control the infection during at least one year without treatment. This cohort includes more than 400 patients. The objectives to be reached with this group of patients are:           

• To analyse the clinical and immunovirological factors implied in the loss of viral control.
• To study the common mechanisms associated with the spontaneous control of the HIV/ HCV coinfection.
• To analyse the immunological factors associated with the CD4+ loss.

The Elite Neutralizers working group is led by Nuria González from ourgroup and Eloísa Yuste from Hospital Clínic-IDIBAPS, Barcelona. The elite neutralizer patients are characterized by high titers of (>1/200) of broad neutralizing antibodies. The first goal is to create a cohort of these patients. Once the cohort will be established, next objectives to carry out will be:

• To study escape mutants from antibody pressure.
• To study the autologous neutralizing capacity of sera from elite neutralizers patients.
• To study the B lymphocyte maturation and the role of follicular T cells (TFH) in the generation of broad neutralizing antibodies.

WP3. Mechanism of Damage and Immune Reconstitution

This WP is led by Julià Blanco from Instituto de Investigación del Sida IrsiCaixa, Barcelona, and Yolanda Pacheco from Hospital Universitario Virgen del Rocío, Seville.

WP3 is based on the study of two types of patients with potentially important immune damage (patients with discordant immunological response and adolescent patients infected by vertical transmission) and the study of the pathogenic properties of the HIV envelope.

The patients with discordant immunological response have a poor CD4+ T lymphocyte recovery after antiretroviral treatment. Numerous studies have been carried out with this group of patients allowing to define mechanisms of immune damage: immunosenescence, immune activation and inflammation. The first objective to be carried out will be to create a cohort with these patients allowing their prospective monitoring. Once the cohort will be constituted, the determinants of poor response to antiretroviral treatment will be studied in these patients.

The cohort of patients infected by vertical transmission (CoRIS-Pe): In this group of patients an immunosenescence study has been performed, and nowadays new goals are being defined.

Role of HIV envelope in immunological damage: Several groups of Programme 3 are studying different aspects of viral entry and the properties of the envelope. Next objectives have been set out:

• To create an envelope bank.
• To study the properties of the envelopes in cohorts of patients with different progression and in different viral subtypes
• To perform functional and structural studies of envelopes and their association with high or low pathogenicity models.
• To develop and apply new algorithms of tropism prediction.

WP4. Reservoirs, Latency and Eradication

This WP is led by Santiago Moreno from Hospital Universitario Ramón y Cajal, Madrid, and by Mayte Coirasfrom our group.

The eradication or functional cure of HIV constitutes one of the huge global initiatives to combat AIDS. The objectives of this WP are:

• To develop latency models.
• To standardise techniques to allow the quantification of reservoir and low level replication.
• To study in vitro the mechanism of action of different drug families.

 Vaccines development

This WP is led by Eloísa Yuste and Felipe García from Hospital Clínic-IDIBAPS, Barcelona.

The objectives of this WP are:

• To improve prototypes currently under development at different stages (in vitro, animal models, clinical trials).
• To study the immunogenicity of the different prototypes ex vivo and in vivo.
• To provide support to vaccine clinical trials and studies performed by Programme 2.

Research groups

The groups participating of RIS Programme 3 are the following:

Group	Group leader	Leading researchers
AIDS Immunopathology, ISCIII (Madrid)	Pepe Alcamí	WP4: Mayte Coiras
Hospital Universitario Virgen del Rocío (Seville)	Manolo Leal	WP2: Ezequiel Ruiz-Mateos WP3: Yolanda Pacheco
Hospital General Universitario Gregorio Marañón (Madrid)	María Ángeles Muñoz	WP1: María Ángeles Muñoz
Hospital Clínic-IDIBAPS (Barcelona)	José María Gatell	WP5: Eloísa Yuste WP5: Felipe García
Instituto de Investigación del Sida IrsiCaixa (Barcelona)	Bonaventura Clotet	WP3: Julià Blanco
Hospital Universitario Ramón y Cajal (Madrid)	Santiago Moreno	WP4: Santiago Moreno
Instituto de Investigación Sanitaria-Fundación Jiménez Díaz UAM	José Miguel Benito	WP2: José Miguel Benito
Hospital Universitario 12 de Octubre (Madrid)	Rafael Delgado
HIV Biology and Variability, ISCIII (Madrid)	Lucía Pérez-Álvarez
Viral Infection and Immunity, ISCIII (Madrid)	Salvador Resino
Molecular Virology, ISCIII (Madrid)	Cecilio López-Galíndez
Hospital Universitario Joan XXIII (Tarragona)	Francesc Vidal
Hospital de Sant Pau (Barcelona)	Pere Domingo
Universidad de Valencia	Rafael Sanjuán
Universidad de la Laguna	Agustín Valenzuela
Centro Nacional de BiotecnologÍa (Madrid)	Mariano Esteban
Centro Nacional de EpidemiologÍa, ISCIII (Madrid)	Julia del Amo	Vicky Hernando
Centro Sandoval (Madrid)	Jorge del Romero

Links

RIS:

www.retic-ris.net

Newsletters:

www.retic-ris.net/CoordinaciónyDocencia/Newsletter.aspx