In vivo plasma LPS levels in HIV negative subjects alter T cell proliferative responses, stimulate cytokine release and induce TLR cross tolerance in monocytes ex vivo

Abstract Multiple studies have shown correlates of immune activation with microbial translocation and plasma lipopolysaccharide (LPS) levels during HIV-1 infection. It is unclear whether this activation is solely due to LPS, residual viral replication, or both. LPS and other pathogen-associated molecular patterns (PAMPs) are recognized by Toll-like receptors (TLRs). Binding of PAMPs to TLRs can alter subsequent responses by inducing self/cross-tolerance or priming. These effects of can alter immune functions in the context of chronic LPS exposure. Few studies have addressed the effects of chronic in vivo levels of LPS on specific immune functions in humans in the absence of chronic viral infection. We previously reported on a cohort of HIV negative high-risk men who have sex with men with elevated plasma LPS levels. This cohort allowed us to assess cellular immune functions in the context of plasma LPS levels ex vivo without confounding viral effects. Using 2 time points with different plasma LPS levels, we now show that in vivo plasma LPS levels altered ex vivo cytokine expression by monocytes, without stimulation and in response to several TLR ligands. We further showed that high levels of plasma LPS in vivo delayed early T cell proliferative responses in vitro, whereas intermediate plasma LPS levels enhanced T cell proliferation. These data suggest that increased levels of plasma endotoxemia can have profound effects on immune function.