The Many Faces of Immune Activation in HIV-1 Infection. A Multifactorial Interconnection

Chronic immune activation has a significant role in HIV-1 disease pathogenesis and CD4+ T-cell depletion. The causes of chronic inflammation and immune activation are incompletely understood, but they are likely multifactorial in nature, involving both direct and indirect stimuli. Possible explanations include microbial translocation, coinfection, and continued presence of competent replicating virus. In fact, long-term viral suppression treatments are unable to normalize elevated markers of systemic immune activation. Furthermore, high levels of pro-inflammatory cytokines increase susceptibility to premature aging of the immune system. The phenomenon of "inflammaging" has begun to be evident in the last decades, as a consequence of increased life expectancy due to the introduction of cART. Quality of life and survival have improved substantially; however, PLWH are predisposed to chronic inflammatory conditions leading to age-associated diseases, such as inflammatory bowel disease, neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities, and non-HIV-associated cancers. Several approaches have been studied in numerous uncontrolled and/or randomized clinical trials with the aim of reducing immune activation/inflammatory status in PLWH, none of which have achieved consistent results.