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
     

Can the Tat vaccine reduce the cardiovascular risk?

This study conducted by CNAIDS will determine whether the Tat therapeutic vaccine reduces metabolic changes that are very frequent in subjects under effective cART.

Despite the effectiveness of cART in suppressing viral replication, residual viral replication persists in treated subjects due to either incomplete suppression or reactivation of the virus. This replication contributes significantly to chronic inflammation and dysregulation of the immune system. In turn, chronic inflammation and dysregulation of the immune system fuel viral replication, in a vicious circle that ensures the maintenance of viral reservoirs and consumes the host, exposing it to an increased risk of developing diseases generally prevalent in the elderly, therefore promoting the early aging of HIV+ persons under effective cART. Among these diseases, cardiovascular diseases (CVD) are particularly important and frequent. In fact, many of the markers associated with an increased risk of CVD in the general population are elevated in the HIV+ population under effective cART.

Among the factors responsible for residual viral replication, the HIV-1 Tat protein is of particular importance because Tat is the first HIV protein to be produced and is essential for efficient viral replication. Moreover, released from infected cells, Tat promotes the recall and activation of CD4+ lymphocytes and promotes the entry of the virus into new cells, facilitating the spread and maintenance of the infection.

Furthermore, Tat profoundly alters the functions and morphology of endothelial cells (EC) lining blood and lymphatic vessels, and it is plausible that it contributes to the inflammatory response observed in the vascular endothelium. This  leads to recruitment of leukocytes, increased platelet adhesiveness and activation of the coagulation system, an alteration considered crucial in the pathogenesis of atherosclerotic disease, even in the uninfected subject. Tat therefore appears to be a key protein to block in order to break the vicious circle triggered by the residual viral replication and therefore to reduce inflammation, immune activation and  CVD risk. The results obtained with the intensification of cART with the Tat vaccine in phase I and II therapeutic clinical trials support this hypothesis and provide the opportunity to verify the contribution of Tat to the increased risk of CVD found in HIV+ subjects. To this end, a large group of immune and vascular activation markers associated with CVD risk will be evaluated in a cohort of subjects who participated in a cART intensification trial by vaccination with the Tat protein of HIV-1 (ISS T-002) and in subjects in effective cART but not vaccinated with Tat who participated in observational studies (ISS OBS-T002, ISS OBS T-005) conducted at the same clinical centers. After identification of the biomarkers associated with the increased CVD risk, an algorithm will be generated to assess and monitor more accurately the risk for CVD in HIV+ subjects.

The results of the study may also have positive effects on the prevention and management of CVD risk in the general population, with obvious social and public health benefits, as well as on the advancement  of scientific knowledge.