TOPIC

Infectious diseases, HIV

HIV/AIDS

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
     

Innovative vaccines against herpetic virus co-infections that exploit the adjuvant properties of Tat

Herpes simplex viruses (HSV) 1 and 2 are causes of disease worldwide. These are mainly mucocutaneous pathologies, with perioral localization (HSV-1), or to the genitals (HSV-2), but they can also affect the conjunctiva and cornea (neonatal herpetic keratitis), and the central nervous system (encephalitis, meningitis). Herpetic infection persists throughout life, so it can relapse, become chronic and spread, especially in people with immature (newborn) or immunosuppressed (elderly) immune systems, or compromised by other infections (HIV) or conditions (malnutrition, stress, radiological and chemotherapy treatments, etc.). WHO has identified the development of HSV vaccines as an important global goal, especially for low- and middle-income countries, with the aim of reducing the burden of HSV-associated diseases, including: i) mortality and morbidity due to neonatal herpes; ii) the impact on sexual and reproductive health and iii) the acquisition and transmission of HIV associated with HSV-2 infection in high prevalence populations. Despite scientific advances and numerous attempts, there is currently no preventive or therapeutic vaccine against the HSV-1 and HSV-2 viruses. CNAIDS is conducting preclinical studies with the aim of developing a vaccine against HSV, exploiting the ability of HIV Tat to induce cell-type immune responses, essential for the control of HSV infection. 

 The chronicity of herpetic infections and the periodic reactivations are considered important factors in the aging process. Recent data indicate that the control of HSV infections requires the presence of CD8+ T cells that recognize regions (epitopes) of HSV associated with protection in natural infections. In order to develop an anti-herpetic vaccine capable of inducing CD8+ T lymphocytes with these properties, CNAIDS, in collaboration with the University of Ferrara, has chosen to exploit the immunomodulatory properties of the HIV-1 Tat protein that promotes development of Th-1 responses required for induction of CD8+ T cells. Therefore, the HIV-1 tat gene was introduced into attenuated or replicating HSV-1 vectors (herpes vectors). In mice, vaccination with these Tat-expressing herpes vectors induces extensive and prolonged HSV-specific CD8+ T cell responses and anti-HSV antibodies that are associated with viral load reduction and protection from death after experimental infection with lethal doses of the virus. These studies, conducted in collaboration with the University of Ferrara, show that Tat has extrinsic "immunomodulatory" activity capable of enhancing immunity against intracellular pathogens capable of escaping the immune response. 

The goal of the project is the preclinical development for the approval for human testing of preventive and therapeutic anti-herpes vaccines based on attenuated and/or replication-defective HSV-1 vectors expressing the HIV-1 tat gene. If successful, the project will continue with the evaluation in humans (clinical trial). In perspective, this innovative strategy could be used for the development of vaccines against other "persistent" infections, such as those from Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Varicella-Zoster virus (VZV), as well as tuberculosis. 

The project has been founded by the Ministry of Health (Ricerca Finalizzata RF-2019-12368996).