Massive loss of lamina propria CD4(+) T cells, changes in the lymphatic architecture, and altered intestinal epithelial barrier leading to microbial translocation are the common features of HIV-1 infection and are not fully restored under combined antiretroviral therapy (cART). To better understand determinants of gut mucosal restoration, we have performed phenotypic and gene expression analyses of the gut from HIV-infected patients, naive or treated with cART initiated either at the early phase of the primary infection or later during the chronic phase. We found a depletion of T helper type 22 (Th22) and interleukin-17-producing cells in naive patients. These populations, except Th22 cells, were not restored under cART. Regulatory T cells/Th17 ratio was significantly increased in HIV-infected patients and was inversely correlated to the restoration of CD4(+) T cells but not to gut HIV DNA levels. Gene profile analysis of gut mucosal distinguished two groups of patients, which fitted with the timing of cART initiation. In their majority early, but not later treated patients, exhibited conserved intestinal lymphoid structure, epithelial barrier integrity and dendritic cell maturation pathways. Our data demonstrate that early initiation of cART helps to preserve and/or restore lymphoid gut mucosal homeostasis and provide a rationale for initiating cART during the acute phase of HIV infection.

Summary Mucosal immune responses to HIV-1 involve the recognition of the viral envelope glycoprotein (gp)160 by tissue-resident B cells and subsequent secretion of antibodies. To characterize the B cells “sensing” HIV-1 in the gut of infected individuals, we probed monoclonal antibodies produced from single intestinal B cells binding to recombinant gp140 trimers. A large fraction of mucosal B cell antibodies were polyreactive and showed only low affinity to HIV-1 envelope glycoproteins, particularly the gp41 moiety. A few high-affinity gp140 antibodies were isolated but lacked neutralizing, potent ADCC, and transcytosis-blocking capacities. Instead, they displayed cross-reactivity with defined self-antigens. Specifically, intestinal HIV-1 gp41 antibodies targeting the heptad repeat 2 region (HR2) cluster II cross-reacted with the p38α mitogen-activated protein kinase 14 (MAPK14). Hence, physiologic polyreactivity of intestinal B cells and molecular mimicry-based self-reactivity of HIV-1 antibodies are two independent phenomena, possibly diverting and/or impairing mucosal humoral immunity to HIV-1.

This study shows that 16% of Caucasian patients with ICP bear ABCB4 gene mutations, and confirms the significant involvement of this gene in the pathogenesis of this complex disorder.

Objective: Narrow-Band Imaging (NBI) is as sensitive as Lugol chromoendoscopy to detect oesophageal squamous cell carcinoma (SCC) but its specificity, which appears higher than than that of Lugol chromoendoscopy in expert centres, remains to be established in current practice. This study aimed to prove the superiority of NBI specificity over Lugol chromoendoscopy in the detection of oesophageal SCC and high-grade dysplasia (HGD) in current practice (including tertiary care centres, local hospitals, and private clinics). Trial Design: Prospective randomised multicentre trial including consecutive patients with previous or current SCC of the upper aerodigestive tract addressed for gastroscopy. Patients included were randomly allocated to either the Lugol or NBI group. In the Lugol group, examination with white light and Lugol chromoendoscopy were successively performed. In the NBI group, NBI exam was performed after white light endoscopy. We compared the diagnostic characteristics of NBI and Lugol chromoendoscopy in a per-patient analysis. Results: 334 patients with previous history of SCC were included and analysed in intention-to-tret from 15 French institutions between March 2011 and December 2015. In a per-patient analysis, sensitivity, specificity, positive and negative likelihood values were respectively 100%, 66.0%, 21.2%, and 100% for Lugol chromoendoscopy vs. 100%, 79.9%, 37.5%, and 100% for NBI. NBI specificity was greater than Lugol chromoendoscopy (p=0.0023). Conclusions: As previously demonstrated in expert centres, NBI is more specific than Lugol in current gastroenterology practice for the detection of early SCC but combined approaches with both NBI and lugol could improve the detection of squamous neoplasia.

HIV-1 infection is associated with B cell dysregulation and dysfunction. In HIV-1-infected patients, we previously reported preservation of intestinal lymphoid structures and dendritic cell maturation pathways after early combination antiretroviral therapy (e-ART), started during the acute phase of the infection, compared with late combination antiretroviral therapy started during the chronic phase. In this study, we investigated whether the timing of combination antiretroviral therapy initiation was associated with the development of the HIV-1-specific humoral response in the gut. The results showed that e-ART was associated with higher frequencies of functional resting memory B cells in the gut. These frequencies correlated strongly with those of follicular Th cells in the gut. Importantly, frequencies of HIV-1 Env gp140-reactive B cells were higher in patients given e-ART, in whom gp140-reactive IgG production by mucosal B cells increased after stimulation. Moreover, IL-21 release by PBMCs stimulated with HIV-1 peptide pools was greater with e-ART than with late combination antiretroviral therapy. Thus, early treatment initiation helps to maintain HIV-1-reactive memory B cells in the gut as well as follicular Th cells, whose role is crucial in the development of potent affinity-matured and broadly neutralizing Abs.