INCREASED LEVELS OF PLASMATIC MITOCHONDRIAL DNA DURING HIV INFECTION REVEAL A NEW ROLE FOR MITOCHONDRIAL DAMAGE-ASSOCIATED MOLECULAR PATTERNS

Recently, it has been shown that mtDNA or degraded mitochondrial peptides can act as “damage-associated molecular patterns" (DAMPs), that are conceptually and functionally similar to PAMPs. Mitochondrial DAMPs, defined MTDs, can be involved in the pathogenesis of the systemic inflammatory response syndrome (SIRS), a condition that often affects patients who survive a trauma, characterized by the presence of shock and compromised function of several organs. During SIRS, mtDNA released from damaged or dead cells can bind TLR-9, whose activation causes a potent inflammatory reaction, with the production of proinflammatory cytokines. Since HIV infection is characterized by a proinflammatory status, and by a hyperproduction of proinflammatory cytokines, we asked whether soluble mtDNA circulating in the plasma could play a role in determining such condition.Thus, we have studied plasma levels of mtDNA in HIV+ patients showing a different course of the infection, and have correlated such levels to the activation of the immune system and to the plasma viremia. We analyzed individuals during acute, primary HIV infection (AHI), patients with an advanced infection (including those with full blown acquired immunodeficiency syndrome, AIDS) but still naive for antiretroviral therapy (ART), and those defined “long term non progressors” (LTNPs), who had been infected since at least 8 years, always out of treatment, but with a normal number of CD4+ T cells, a low grade of apoptosis and a good immunological control of the virus.In all HIV+ patients but LTNP plasma levels of mtDNA were significantly higher than in healthy controls. Furthermore, in naive patients, 6 months of efficient ART (able to increase CD4+ T cell count, decrease viral load and reduce T cell activation) did not modify mtDNA plasma levels. These levels were not correlated to CD4+ T cell count, nor to markers of immune activation, but had a significant correlation with plasma viral load, revealing a possible role for mtDNA not only as a molecule able to trigger inflammation, but also as a novel biomarker of virus-induced damage.The identification of the role of MTDs could relevant not only to identify possible new biomarkers of disease progression, but also in designing new therapeutic strategies that regard soluble mtDNA, as novel treatments could target either soluble MTDs, or the receptors they use. Thus, in HIV infection, as in other diseases characterized by excessive inflammation, interfering with MTDs could likely become a novel strategy to reduce the harmful immune activation.