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
     

The "latent" HIV reservoirs

Despite antiretroviral therapy (ART), HIV persists in the form of a "latent" virus that is resistant to drugs and invisible to the immune system. 

Although antiretroviral drugs suppress HIV-1 replication in treated patients, the virus persists indefinitely in cell "reservoirs" that house HIV in a silent (latent) form. In this context, vaccination with the HIV Tat vaccine developed at CNAIDS has shown to induce the progressive decline of the reservoirs. Therefore, CNAIDS is conducting studies aimed at understanding the role of the HIV-1 Tat protein in the genesis and persistence of the HIV reservoirs, in the effort to set up new treatments toward virus eradication.  

Acute HIV infection is characterized by high viremia and sudden drop of CD4+ T lymphocytes. Subsequently, nevertheless, the immune system reacts to "control" the infection by lowering the viremia and partly restoring the number of CD4+ T cells. ART administration, on the other hand, is capable to fully suppress virus replication. However, HIV is able to "hide" in cellular and tissue "compartments" where it persists in the form of "silent" proviral DNA, a form of the virus that does not produce any of the viral proteins (latent virus). The reservoirs are generated early in the infection and remain invisible to the immune system and ART, which both target only the replicating virus. The latent virus reservoirs thus persist indefinitely, even after the start of ART. 

The main virus reservoir is the “resting” naïve and CD4+ "memory" T cell compartment. In addition, macrophages and dendritic cells can accumulate and store HIV viral particles for long time, protecting them from the immune system. Therefore, also these cells represent important HIV reservoirs. 

Latent HIV reservoirs are not static but continuously reshaped; in fact, some of the cells containing latent virus die ("depletion" of the reservoir) but are continuously replaced by new latently infected cells ("replenishment" of the reservoir). This dynamic process ensures the constant and indefinite balance of viral reservoirs, even in subjects under treatment with antiretroviral drugs. It is believed that the death of reservoir cells is mainly determined by their natural caducity, as well as by the sporadic and random spontaneous reactivation of the virus, a process for which latent HIV "wakes up" and starts to replicate again. The sporadic reactivation of the virus causes "cytopathic" effects that lead to cell death or make the infected cells visible to the immune system, which, eventually, will eliminate them. On the other hand, it is believed that virus replication in the reservoir cells is determined by the continuous proliferation of some of the latently infected cells as well as “de novo” HIV replication and transmission in certain areas of lymphoid organs characterized by low penetration of antiretroviral drugs that, therefore, become insufficient to suppress viral replication. 

Specific strategies have been recently developed to eradicate HIV reservoirs, based on the administration of compounds capable of reactivating latent virus in patients treated with antiretroviral drugs ("shock-and-kill" strategies). The objective of these treatments is to reactivate the virus to make it a visible target for both the immune system and antiretroviral drugs. Clinical trials based on this strategy, however, have so far produced disappointing results. On the other hand, the phase II vaccine trial conducted by CNAIDS has indicated that the Tat therapeutic vaccine induces a significant reduction of proviral DNA (i.e. latent virus) in blood. Eight years after vaccination, the proviral DNA was reduced by up to 90%, and fell below the detection threshold in one or more measurements in 33% of vaccinated volunteers. These results open new perspectives for the development of the so-called "functional" therapies and for the eradication of the virus. With these studies, CNAIDS proposes to clarify the mechanisms by which the Tat vaccine acts on reservoirs, in order to identify new treatments against HIV capable of "attacking" the latent virus reservoirs and eradicating HIV infection.