Director: Dr. Barbara Ensoli - Curriculum Vitae
phone: (+39) 06 4990 3209
mail: segr-cnaids@iss.it; barbara.ensoli@iss.it
Center activities
Around 40 million people in the world live with HIV. Although retroviral therapy has saved millions of lives, it does not eradicate the infection nor restore the function of the immune system, particularly in those who are not very adherent to therapy or start it late. These people remain vulnerable to infections and complications that undermine their quality of life and need high-cost interventions and treatments for the National Health Service (SSN). It is therefore necessary to develop new preventive and therapeutic interventions to combat the epidemic.
The National AIDS center (CNAIDS) shares with the World Health Organization (WHO) and UNAIDS the goal of stopping the epidemic and ensuring good health-related quality of life for people living with HIV. In this context, CNAIDS is engaged in the development of vaccines (preventive and therapeutic) against HIV / AIDS, innovative therapies for tumors and co-morbidities associated with HIV infection, and in more effective prevention and surveillance methods, with the mission of transferring the knowledge acquired through scientific research to the SSN. The Centre's most advanced products are the therapeutic vaccine against HIV based on the viral protein Tat, and a new therapy for Kaposi's sarcoma, both ready for efficacy clinical studies (phase III). CNAIDS also assesses the prevalence and spread of HIV, HBV and HCV variants in the Italian population and in vulnerable populations infected with HIV, informing them on how these infections are transmitted. CNAIDS "third mission" activities include communication of innovation produced through scientific publications, dissemination activities to the general public, development of patents that open prospects for the creation of spin-offs and industrial partnerships, technology transfer, capacity building and training in the field of HIV / AIDS. The numerous national and international collaborations with public and private bodies strategically place CNAIDS in the European Union (EU) and in developing countries.
The results that CNAIDS aims for are: 1) improvement of public health in the field of HIV / AIDS and sexually transmitted diseases (STDs) in the Italian population, with particular attention to vulnerable populations; 2) production of new knowledge and innovation (research and development) capable of producing tangible benefits for the population in the short and long term; 3) reduction of inequalities in access to care; 4) reduction of costs for the SSN.
Organization of the center
Director: Dr. Barbara Ensoli
phone: (+39) 06 4990 3209
e-mail: segr-cnaids@iss.it
The Directorate coordinates the strategies and research activities of the Center, is responsible for the coordination and management of the technical-scientific, administrative secretariat, support service for laboratory and staff activities, and for activities related to the Center such as: security, anti-corruption, operation of laboratories and information technology, presentation / coordination of projects and patents, networking, communication / dissemination of results.
Operational unit Research and development
Director: Dr. Paolo Monini
phone: (+39) 06 4990 3217
e-mail: paolo.monini@iss.it
The objective of the operating unit is to study the pathogenesis of HIV infection and tumors, co-infections and related pathologies for the pre-clinical development of new products (vaccines, innovative therapies, biomedical products, new assays and biomarkers) with high impact on public health.
The operating unit is engaged in the following research activities:
- study of the structure and biology of the Tat / Env complex and role of anti-Tat / Env antibodies in HIV infection. CNAIDS studies have identified a new HIV entry complex (Tat / Env complex) crucial for the spread of the low multiplicity of virus infection (P Monini, PLoS One, 2012). Studies therefore investigate the role of Tat in residual HIV replication in various cellular models in the presence of suboptimal concentrations of antiretroviral drugs, as well as the ability of the Tat vaccine to block this virus propagation mode. Other studies are aimed at evaluating the effects of Tat on the conformational dynamics of Env and on the vulnerability of HIV to the action of neutralizing and non-neutralizing anti-Env antibodies, for the development of innovative virus neutralization strategies
- role of the HIV-1 Tat protein in the genesis and persistence of viral reservoirs. Phase II therapeutic clinical trials indicated that the Tat vaccine developed at CNAIDS is capable of reducing latent virus reservoirs, opening up new perspectives for functional treatment and for the eradication of HIV in patients being treated (F Ensoli, Retrovirology, 2015). Currently, the studies are aimed at clarifying the mechanism of action of the vaccine on viral reservoirs, in order to develop innovative treatments. In particular, the role and effects of Tat on i) reactivation of latent virus, ii) survival of reservoir cells, iii) inducing productive replication and HIV latency in CD4 + T cells by dendritic, endothelial and monocytes / macrophages cells are being evaluated
- validation of an assay for the quantitative determination of HIV proviral DNA. An easy-to-perform and highly reliable test developed at CNAIDS for the quantitative determination of HIV proviral DNA is currently being validated. The test is essential for the measurement of viral reservoirs and will be applied in clinical practice as it will allow to evaluate the effectiveness of current therapies as well as innovative functional and / or eradicating therapies
New treatments for co-morbidities (associated co-infections and tumors):
- development of innovative vaccines based on attenuated, replicative and non-replicative herpetic vectors against co-infections (Herpes simplex virus type 1 and 2 and tuberculous mycobacterium). These studies, in collaboration with the University of Ferrara, have shown that Tat extrinsic "immunomodulatory" activities capable of promoting the presentation of cryptic and sub-dominant antigenic epitopes, also favoring the development of Th1 type responses and expansion / functionality of cytotoxic lymphocytes. In this way, Tat allows enhanced immunity against intracellular pathogens able to escape the immune response (R Gavioli, J Immunol, 2004). The studies are aimed at developing vaccines against "persistent" infections of relevance to the health system. Currently, vaccines against herpes simplex virus (HSV-1/2) and tuberculous mycobacterium (F Nicoli, PLoS ONE, 2013; M Sicurella, PLos ONE, 2014; F Nicoli, Vaccine, 2016) are being tested. Vaccines are based on attenuated herpetic vectors expressing mycobacterial or herpetic antigens together with Tat. The research has reached the development stage in validated preclinical animal models
- preclinical and clinical studies on the anti-angiogenic and anti-tumor effects of HIV protease inhibitors in the prevention and progression of AIDS associated cervical cancer. CNAIDS studies have shown that HIV protease inhibitors (HIV-PI), currently in use in cART, are able to inhibit angiogenesis and tumor invasion, regardless of their antiviral effects (C Sgadari, Nature Med 2002, Lancet Oncol 2003; P Monini, Nature Cancer Rev 2004; E Toschi, Int J Cancer 2009). Preclinical and clinical studies for the evaluation of efficacy in classical Kaposi's sarcoma (KS) indicate their possible use in cancer patients infected or not with HIV (drug repositioning) (P Monini, AIDS 2009). HIV-PI-based therapies for the treatment of intraepithelial carcinoma of the uterine cervix are currently in the pre-clinical and clinical development phase. Preclinical studies use transgenic mice for the human papillomavirus E6 / E7 onco-proteins, in collaboration with the University of Turin
Clinical development and registration working group for use in humans
Responsible: Dr. Cecilia Sgadari
phone: (+39) 06 4990 6071
e-mail: cecilia.sgadari@iss.it
The objective of the working group is to organize and conduct observational studies and clinical trials aimed at evaluating new vaccine candidates and therapies against HIV / AIDS and associated syndromes up to their registration for clinical use.
Although cART effectively suppresses HIV replication, it is unable to eradicate the virus and must therefore be taken for life, increasing the risk of non-adherence to therapy and selection and transmission of drug-resistant viral variants. The persistence of the infection is the cause of inflammation and activation of the immune system, which determine an early aging process and the onset of tumors and pathologies typical of the elderly; moreover, a substantial proportion of patients, especially in developing countries but also in Italy, start cART late (CD4 + T cells less than 200 / µl) or do not respond to cART with sufficient immunological recovery. This leads to an increased risk of AIDS- or non-AIDS-associated progression and co-morbidity compared to the general population. The consequences include the reduced quality of life of the infected patients and the high costs for the SSN. Therefore, new therapeutic interventions are needed to improve the effectiveness of cART (ART intensification), and, possibly, eradicate the infection. Studies conducted by CNAIDS indicate that Tat is an optimal target for both preventive and therapeutic vaccination strategies aimed at controlling HIV replication, its propagation in tissues and the formation and maintenance of viral reservoirs (A Cafaro, Expert Opin Biol Ther, 2015; Expert Rev Vaccines 2018; Vaccines 2019). As part of the development of these vaccination strategies, CNAIDS has conducted over the years 5 interventional clinical studies in Italy and South Africa (with a total of 426 volunteers) with funding from the Ministry of Health, the Ministry of Foreign Affairs and the European Commission. These studies have demonstrated the safety, immunogenicity and ability of the vaccine to intensify the effects of cART, bringing the immune system back towards homeostasis and reducing immune-activation and the viral reservoir (B Ensoli, AIDS 2008, Vaccine 2009, PLoSONE 2010, Retrovirology 2016; O Longo, Vaccine 2009; S Bellino, RRCT 2009; F Ensoli, Retrovirology 2015). Very recent studies (C. Sgadari, Frontiers in Immunol 2019) have also shown the long-term effects (8 years) of Tat vaccination resulting in the drastic reduction of the virus reservoirs (90% reduction in the blood) and in the reconstitution of the immune system which has as its best known index the persistent and continuous increase of CD4 cells even in patients who respond poorly to therapy. Furthermore, the results of 3 observational studies conducted in Italy and South Africa indicate that the presence of natural anti-Tat antibodies is associated with a slower progression towards AIDS and a more effective response to therapy (G Rezza, J Inf Dis 2005; S Bellino, Retrovirology 2014; A Cafaro, Expert Opinion Biol Ther, 2015; B Ensoli B, Retrovirology 2016; A Cafaro, Expert Rev Vaccines 2018; Vaccines 2019). These results indicate that the clinical development of the Tat vaccine will continue with final studies of efficacy (phase III) aimed at its approval for use in patients who respond poorly or are poorly adherent to therapy, and to evaluate its use in the pediatric population and in patients at the first diagnosis of infection (Test and Treat). The results obtained were evaluated very positively by the Ministry of Health of South Africa and by UNIDO (United Nations Industrial Development Organization). Both organizations encouraged the continuation of studies until the vaccine was registered. For this purpose, the Tat Vaccine Partnership was created (see Third Mission).
Vaccine clinical trials against HIV/AIDS:
- development of the therapeutic Tat vaccine. The project involves the conduct of: a) Phase III clinical study for the registration of the use of the Tat therapeutic vaccine in HIV-positive adult subjects (> 18 years) who respond poorly to therapy (ART intensification); b) phase II / III clinical study to evaluate the safety, immunogenicity and efficacy of the Tat vaccine in intensifying cART therapy in patients at the first diagnosis of HIV infection (Test & Treat scenario); c) Phase I / II clinical study for the evaluation of the safety, immunogenicity and effective dose of the Tat therapeutic vaccine (ART intensification) in adolescents (12-17 aa) and children (6-11 aa) HIV-positive, preparatory to phase III studies for registration also in the pediatric population. These clinical studies have already been submitted to the South African Health Products Regulatory Authority -SAHPRA, which has encouraged the submission of the related clinical files and protocols and will also be submitted to the EMA / FDA. Conducting these studies can only take place after obtaining the necessary funds
- development of the Tat and Tat / Env preventive vaccine. Phase I preventive vaccine trials have already been successfully conducted by CNAIDS with the Tat and Tat / Env vaccine in Italy after experiments in a primate model (B Ensoli, Vaccine 2009; S Bellino, Reviews on Rec. Clinical Trials 2009; A Cafaro J Virol 2010; Expert Opinion Biol Ther 2015; Expert Rev Vaccines 2018; Vaccines 2019). The clinical development of these preventive vaccination approaches will be pursued in countries with a high incidence of infection (South Africa) in order to evaluate their effectiveness in preventing HIV infection. In particular, if funds are available, a phase IIB study is expected to be conducted in healthy subjects at risk of infection
Observational clinical trials:
- observational studies for the clinical, immunological and virological monitoring of HIV-1 infection and the effects of the presence of natural or vaccination-induced anti-Tat antibodies on the disease in naive subjects and in cART therapy. Analyzes are underway for the 3 observational studies conducted by CNAIDS in cART (ISS OBS T-002 and T-004) and asymptomatic (ISS OBS T-003 and T-004) patients in Italy and South Africa, and longitudinal observational studies for the extension of the monitoring of cART patients vaccinated with Tat enrolled in the phase II clinical studies ISS T-002 and ISS T-003 conducted in Italy and South Africa. A longitudinal observational study (OBS T-005) was also activated in Italy to evaluate the effect of natural or vaccine-induced anti-Tat antibodies on viral reservoirs, apoptosis or peripheral blood cell infection of HIV+ patients, both naive and in cART therapy
- cardiovascular risk biomarkers (CVD) and study of the metabolome after intensification of Tat vaccination therapy and in natural infection. The role of Tat and HIV infection on the increased risk of CVD that is found in HIV+ subjects and in lipid metabolism will be assessed by studying serum biomarkers of fat metabolism and immune and vascular activation in subjects vaccinated with Tat. These data will generate an algorithm aimed at improving the assessment and monitoring of risk for CVD and premature aging in the population studied, potentially extendable to the general population
- characterization of the pharmacokinetic and pharmacogenetic profile of antiretroviral drugs to support the clinical management of HIV+ patients in developing countries. Given that the plasma dosage of antiretroviral drugs (ARV) is the only reliable and objective means to ascertain the achievement of effective pharmacological levels, the study of the pharmacodynamic profile of ARV in populations other than the western ones infected with non-B viruses will provide information important for the evaluation of clinical therapeutic studies in those populations
Clinical oncology trials:
- clinical studies for the treatment of (KS) with HIV-PI in monotherapy or in combination with conventional chemotherapy. Based on the demonstration of the anti-angiogenic and anti-tumor activity of HIV-PI (C Sgadari, Nature Med 2002, Lancet Oncol 2003; P Monini, Nature Cancer Rev 2004) the Center conducted two phase II clinical trials with the HIV-PI in patients with classical KS obtaining efficacy results (P Monini, AIDS 2009 and manuscript in preparation). These studies, financed so far by the Ministry of Health and AIFA, will continue if the funds are available with a phase III clinical trial with the aim of achieving registration for the use of HIV-PI in KS associated or not with HIV. KS is included among rare diseases. These studies will allow to transfer to the SSN new therapeutic approaches and protocols based on antiretroviral drugs in monotherapy or in combination with cytotoxic drugs for the therapy of early or advanced tumors (drug repositioning)
Working group: Surveillance and pathogenesis of HIV variants and associated co-infections
Responsible: Dr. Stefano Buttò
phone: (+39) 06 4990 3249
e-mail: stefano.buttò@iss.it
The aim of the working group is to carry out studies for the control and prevention of the spread of HIV variants and hepatitis viruses associated with HIV infection in vulnerable populations and in the indigenous population in Italy.
HIV, HBV and HCV viruses are characterized by an extensive genetic variability responsible for the extreme diversification of variants whose distribution, depending on the geographical area, continues to change due to migratory flows and risky behaviors. These variants present a different pathogenicity and sensitivity to drugs and diagnostic tests. Viral variants with mutations capable of conferring resistance to therapies can also be selected. Therefore, their distribution in the general population and in vulnerable populations must be kept under control through continuous surveillance. For this reason, the European Center for Disease Prevention and Control (ECDC) foresees programs of intervention and control of the viral variants circulating in the general population and in vulnerable populations, such as migrants, prisoners, MSM (males having sex with males), drug addicts and sex workers. Similarly, the European Action Plan against Antimicrobial Resistance approved by the European Parliament (2017), recommends that Member States implement appropriate surveillance strategies for microorganisms to control the emergence of forms resistant to therapies. Finally, for the surveillance of genetic forms of HIV globally, WHO has created an international network, of which CNAIDS has been an integral part for years. In line with these recommendations, many European and non-European countries have implemented surveillance systems for circulating variants of the HIV, HBV and HCV viruses. In Italy, at present, no surveillance is being implemented. The Working group therefore proposes to develop a system for monitoring the dynamics of the genetic forms of HIV, HBV and HCV in vulnerable populations as well as in the general population in Italy, making use of the network of 19 clinical centers already created by CNAIDS in previous projects (N Sanarico, Ann Ist Super. Sanità, 2015; N Sanarico, Medicine, 2016), and with European and non-European institutions and clinical centers. The group's scientific research activity is therefore focused on the pathogenetic, clinical, virologic and epidemiological / molecular aspects of HIV infection and of the HBV and HCV infections associated with it in the "vulnerable" populations in our country, which will increase knowledge of their natural history in economically disadvantaged social contexts and / or characterized by peculiar environmental, cultural and hygienic aspects.
Scientific research activities are:
- multicenter studies of the molecular and epidemiological characteristics of HIV, HBV and HCV in HIV-infected prisoners, migrants and autochthonous populations in Italy
- biological and molecular characterization of genetic variants of HIV in developing countries
- effects of anti-HCV therapy with DAAs drugs on virologic and immunological outcome in ART patients co-infected with HIV / HCV
Third mission activities
CNAIDS is engaged in various third mission activities, such as:
Support to the ISS in the preparation of technical documents relating to HIV / AIDS, such as the report to Parliament on the activities of the ISS in the context of HIV infection to be submitted annually to the Ministry of Health;
Inspection activity within the quality management system and control of good laboratory practices and technical evaluation of in vitro diagnostic devices for HIV-1/2 and HTLV-I / II (NBOG IVD0201 and IVD0202), implemented by the Notified Body for Medical Devices and Cosmetics Evaluation (ONDICO) of the ISS.
Training: CNAIDS trains health and penitentiary staff on the health organization and clinical management of vulnerable populations and patients with HIV and / or STD, provides health education to vulnerable populations (prisoners, migrants) in collaboration with the Italian Society of Medicine and Penitentiary Health (SIMSPE), carries out training activities for operators in the field of infectious diseases within the framework of Law 135/90, is actively involved in the training of undergraduate and graduate students.
Capacity building: national and international projects have led to the development of specific clinical-laboratory platforms for the conduct of clinical research in the public sector, in Italy and in sub-Saharan Africa; in particular, in the framework of the bilateral program financed by the EAW, a platform for interventional studies was implemented in three provinces of South Africa.
Scientific disclosure: since its inception (2005), CNAIDS has produced 296 publications in international peer-reviewed scientific journals and numerous presentations at scientific meetings.
Research projects and with third parties: CNAIDS has obtained over the years national and international funds from the Ministry of Health, Ministry of Foreign Affairs, Ministry of University and Research, AIFA, European Commission, private agencies (AIRC), and industry (Merck, Novartis, Gilead).
Collaborations: CNAIDS collaborates with national and international public and private bodies (20 regions in Italy, 12 European nations, South Africa, Swaziland, Uganda, USA).
Technology transfer: projects relating to observational clinical studies and experimentation for the production of new vaccines, innovative therapies and advanced diagnostic tools allow the transfer of specific technologies, knowledge and skills to centers and institutes; the know-how for the Tat vaccine production process has already been transferred to BIOVAC, Cape Town, as part of the MAE-funded Italy-South Africa cooperation program.
Patents: CNAIDS currently has a portfolio of 7 patent families.
Spin-Off / Industrial partnership: various projects of the Center described above have potential for spin-off / industrial partnership that will be pursued in the modalities. For this purpose CNAIDS has promoted, with national and international public and private partners, the Tat Vaccine Partnership (TVP), coordinated by the Medical Research Council of South Africa (SAMRC); DVT's mission is the aggregation of public and private implementation and financing entities for the completion of the Tat vaccine experimentation and its registration for distribution to the population.
