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.