Infectious diseases, HIV


The Italian National Institute of Health (ISS) is at the forefront in the fight against infectious agents which, constantly changing over time, make it necessary the frequent updating  of priority actions.

The ISS implements surveillance, prevention and control measures against emerging diseases such as those deriving from the spread of antibiotic-resistant biological agents commonly found in hospital environment, and those transmitted by vectors, such as chikungunya, dengue and West Nile.

Vaccine preventable diseases, although they have been reduced due to effective interventions, represent a significant burden of diseases which require to maintain a high level of attention.

Viral hepatitis and sexually transmitted infections, as human papillomavirus (HPV) infection, are a paradigmatic example of how chronic infections can result in degenerative diseases and even cancers. A vaccine is available for hepatitis B virus (HBV) and HPV infection.

Infectious diseases include also neglected tropical diseases, as intestinal parasitosis and echinococcosis, found in many parts of the world.

With regard to HIV / AIDS, the antiretroviral therapy (ART), although it has saved millions of lives, does not eliminate the HIV from the body nor restore the immune system completely back to normal. Furthermore, it has limited effects if started late or not taken regularly.

In order to stop the HIV epidemic and assure those living with the infection (about 38 million people with HIV / AIDS in the world, including 20.6 million in Africa) better quality of life and life expectancy, the ISS develops surveillance, prevention and treatment strategies, working in cooperation with the National Health Service (SSN), Regions, developing countries and international bodies.

General aims of ISS research activities on HIV/AIDS include:

  • study and surveillance of the spread of HIV and its variants, and of co-infections in general and vulnerable populations
  • study of the mechanisms of infection, of development of AIDS and associated diseases
  • facilitating ART adherence by improving its effectiveness and reducing its side effects
  • development of new strategies capable of preventing infection, reducing its progression and enhancing the effectiveness of ART, in particular preventive and therapeutic vaccines

The Tat-based vaccine enhances the effects of combined antiretroviral therapy (cART) The therapeutic Tat vaccine improves cART effects.

Although cART effectively suppresses HIV replication, it cannot eradicate the virus, which persists in reservoirs resistant to therapy. Therefore, cART must be taken for life, increasing the risk of non-adherence and of the selection and transmission of drug-resistant viral variants. New therapeutic interventions are therefore necessary to improve cART effectiveness and, possibly, eradicate the infection. Studies conducted by CNAIDS indicate that Tat is an optimal target for vaccine strategies aimed at controlling HIV replication, its propagation in tissues, and the establishment  and maintenance of viral reservoirs.

The persistence of  HIV infection under effective cART causes inflammation and activation of the immune system, which leads to premature-aging and to the onset of tumors and diseases typical of the elderly. In addition, a substantial proportion of patients, particularly in developing countries but also in Italy, starts late cART (T cells CD4+ <200/µl) and can respond poorly to therapy, resulting in an increased risk of progression and of co-morbidities, as compared to the general population. The consequences are the reduced quality of life of infected patients and high costs for the National Health System (NHS). New therapeutic interventions are therefore necessary to improve the effectiveness of cART (ART intensification), and, possibly, eradicate the infection. Studies conducted by CNAIDS indicate that Tat represents an optimal target for both preventive and therapeutic vaccine strategies aimed at controlling HIV replication, its propagation in tissues and the establishment and maintenance of viral reservoirs. In particular, 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.
In the effort to develop new therapeutic vaccine strategies, CNAIDS has conducted, over the years, 5 Tat-based vaccine trials in Italy and South Africa (for a total of 426 volunteers), funded by the European Commission, the Italian Ministry of Health, and the Ministry of Foreign Affairs.
These studies have demonstrated the Tat-vaccine safety, immunogenicity and capability of intensifying cART effects, normalizing the immune system, and reducing immunoactivation and viral reservoirs, even in patients poorly responding to therapy. Very recent studies also demonstrated the long-term effects of Tat vaccination, culminating in a drastic reduction of virus reservoirs (90% mean reduction in blood) after 8 years from Tat vaccination, with a rate that is 4 to 7 times faster as compared to similar cohorts of cART-treated patients. Moreover, in vaccinated volunteers the reduction of latent virus reservoirs was associated with an increase in CD4+ T cells and the CD4+/CD8+ T-cell ratio. These features are also found in those rare patients called "post-treatment controllers", who spontaneously control the reactivation of viral replication after therapy interruption. This suggests that Tat-vaccinated patients might control the virus without taking drugs for periods of time whose duration should be evaluated in dedicated trials, which are currently being planned to verify this hypothesis.
CNAIDS is now actively seeking funds to conduct the following clinical trials:

  • Phase 2 trial to assess whether Tat immunization in cART-treated patients allows prolonged treatment interruption in the absence of viral replication. This study, which will be conducted in volunteers vaccinated as part of the ISS T-002 and/or ISS T-003 trials, could lead to a reduction of cART cumulative-toxicity and open new perspectives for a functional cure and eradication strategies.
  • Phase 3 trial for the registration of the use of Tat therapeutic vaccine in HIV+ adult subjects (>18 aa). The trial is aimed at confirming Tat vaccine efficacy in intensifying the immunological reconstitution promoted by cART on a larger number of volunteers, in support of its registration for the use in patients poorly responding to therapy (CD4+ T cells ≤500/µl). 
  • Phase 2/3 study to evaluate Tat vaccine safety, immunogenicity and efficacy in intensifying cART in patients at the first diagnosis of HIV infection, in accordance with the new international guidelines that recommend to start cART at diagnosis (Test & Treat), regardless of the immunological status of the patient. The study will be conducted in South Africa and is aimed at confirming Tat vaccine effectiveness in improving CD4+ T lymphocyte-recovery and reducing plasma viremia. 
  • Phase 1/2 trial of Tat therapeutic vaccine in HIV+ adolescents (12-17 aa) and children (6-11 aa), in preparation for the conduct of phase 3 trials for vaccine registration also in the pediatric population. The trial will be conducted in South Africa and is aimed at assessing the safety and effective dose of the Tat vaccine in these age groups.