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.