The introduction of combination antiretroviral therapy (cART) in the 1990s has dramatically changed the course of HIV infection, decreasing the risk for both AIDS- and non-AIDS-related events. Cancers, cardiovascular disease (CVD), liver and kidney disease, neurological disorders and frailty have become of great importance lately in the clinical management as they represent the principal cause of death in people living with HIV who receive cART (Kirk et al. in Clin Infect Dis 45(1):103-10, 2007; Strategies for Management of Antiretroviral Therapy Study et al. N Engl J Med 355(22):2283-2296, 2006; Ances et al. J Infect Dis 201(3):336-340, 2010; Desquilbet et al. J Gerontol A Biol Sci Med Sci 62(11):1279-1286, 2007; Lifson et al. HIV Clin Trials 9(3):177-185, 2008). Despite the undeniable achievements of cART, we are now faced with its limitations: a considerable proportion of individuals, referred as to immunological non-responders, fails to reconstitute the immune system despite optimal treatment and viral suppression (Kelley et al. Clin Infect Dis 48(6):787-794, 2009; Robbins et al. Clin Infect Dis 48(3):350-361, 2009) and remains at high risk for opportunistic infections and non-AIDS-related events (Strategies for Management of Antiretroviral Therapy Study et al. N Engl J Med 355(22):2283-2296, 2006). Moreover, the generalized state of immune activation and inflammation, linked to serious non-AIDS events, persists despite successful HIV suppression with cART. Finally, the current strategies have so far failed to eradicate the virus, and inflammation appears a driving force in viral persistence. In the light of all this, it is of fundamental importance to investigate the pathophysiological processes that link incomplete immune recovery, immune activation and HIV persistence to design targeted therapies that could impact on the three.