Immune activation is present in HIV-1 Exposed Seronegative Individuals (HESN) and is indipendent from microbial translocation

Background: Analyses on the presence of immune activation in HIV-exposed seronegative individuals (HESN) yielded discrepant results. To clarify this issue we performed an extensive investigation of immune parameters in HESN and, in particular, we analyzed the possible presence in these individuals of microbial translocation, the most widely accepted reason driving immune activation in HIV-infected patients (HIV+). Methods: Twenty HESN, 20 HIV-unexposed healthy controls (HC) and 20 HIV+ individuals were enrolled to evaluate: 1) T lymphocytes activation markers, maturation pathways and TLR4+CD14+ expression; 2) TLR transduction pathway in response to LPS stimulation; 3) production of proinflammatory cytokines by LPS- stimulated PBMC; and 4) LPS and sCD14 plasma levels. Results: Results showed that in HESN and HIV+ compared to HC; 1) CD4+CD25+, CD8+CD38+, and memory T lymphocytes were increased whereas naïve T cells were reduced 2) PBMC were more responsive to LPS stimulation and were characterized by increased mRNA levels of effector mediators; and 3) IL6, TNF and IFNproduction was augmented. In contrast with these results, LPS and sCD14 levels were significantly reduced in HESN and HC compared to HIV+; these discrepancies were not secondary to differences in TLR4 expression. Conclusion: Immune activation and increased responsiveness to LPS characterize the HESN phenotype; this is not driven by alterations of the gastrointestinal barrier and microbial translocation. The activation state seen in HESN may influence the induction of stronger adaptive antiviral immune responses and may represent a virus exposure-induced innate immune protective phenotype against HIV.