CROI 2016 Abstract eBook
founder variants that were inferred to arise fromminority viral populations in the source, identified as a distinct clade most closely related to the inferred founder variant. These variant lineages were representative of 1.0 to 5.4% of the sampled source population. Conclusions: Incorporating sequence data from the source increased the ability to determine the multiplicity of founder variants, reduced misclassification, and allowed us to infer the transmission of minority variants. 233 Gut Integrity, CD4 T Follicular Helper Cells, and IgA+ B Cells in GALT Following ART John J. Zaunders 1 ; Gerald Mak 2 ; Michelle Bailey 2 ; Nabila Seddiki 3 ;Yin Xu 2 ; David Cooper 4 ; Mark Boyd 5 ; Anthony Kelleher 2 ; Mark Danta 6 ; Kersten K. Koelsch 5 1 St Vincent’s Hosp, Darlinghurst, Australia; 2 Univ of New South Wales, Sydney, Australia; 3 Univ Paris Est Creteil, Creteil, France; 4 Kirby Inst, Sydney, Australia; 5 Kirby Inst, Univ of New South Wales, Sydney, Australia; 6 St Vincent’s Clinical Sch, Univ of New South Wales, Sydney, Australia Background: Disruption of the gastrointestinal tract (GIT) epithelial and immune barriers is believed to contribute to microbial translocation, systemic inflammation and progression of HIV-1 infection. ART may lead to improved reconstitution of gastrointestinal-associated lymphoid tissue (GALT), but its impact on the integrity of the GIT epithelial barrier is unclear. We hypothesized that incomplete reconstitution of CD4 T cells in the GALT following ART commenced in chronic HIV-1 infection, compared with commencing in primary HIV-1 infection, may be associated with reduced numbers of CD4+ T follicular helper cells (Tfh). This in turn may result in lower levels of locally resident B cells switched to IgA production, loss of first line defense against luminal microbial products, and reduced GIT epithelial integrity. Methods: Fifty-two subjects were recruited into three groups: healthy adult controls (HC) undergoing routine endoscopy and colonoscopy (n=23); HIV+ subjects commencing ART in either primary HIV-1 infection (PHI; n=8); or in chronic infection; CHI; n=21). Confocal endomicroscopy was used to assess gut integrity in vivo in 5 subjects from each group. Gut biopsies were assessed by histology, and flow cytometry of single cell suspensions from biopsies from left colon (LC) and terminal ileum (TI) were used to accurately count T and B cell subsets, as well as EpCAM+ epithelial cells. Results: Confocal endomicroscopy found no difference in fluorescein cell leakage or tight junction enhancement between the 3 groups. The TI CD4+ T cell counts in gut biopsies were 2 fold lower in all HIV+ versus HC (106,000 v 228,000 cells; p=0.01) and there were similarly less CD4+ T cells relative to epithelial cells in both TI (1/55 v 1/22; p=0.02) and LC (1/115 v 1/62; p=0.05). However, we found no significant differences in Tfh or IgA+ B cell counts at either site between all HIV+ and HC. Further analysis showed no difference in CD4, Tfh or IgA+ B cells between subjects who started ART in PHI compared to CHI. Conclusions: In contrast to the current paradigm, confocal endomicroscopy did not find disrupted GIT integrity in treated HIV-1 infection. We found lower absolute and relative CD4 counts in the TI in HIV+ subjects on ART, but they were not associated with significantly reduced Tfh cell counts or IgA+ B cells, compared with healthy controls, or whether the ART was commenced in PHI or CHI.
234 Microbial Translocation and Inflammation Responses to Lubiprostone in HIV Infection Gregory D. Huhn 1 ; Anna L. Hotton 2 ; Andrew G. Sigman 1 ; Sheila M. Keating 3 1 Ruth M. Rothstein CORE Cntr, Chicago, IL, USA; 2 John H. Stroger Jr Hosp of Cook County, Chicago, IL, USA; 3 Blood Systems Rsr Inst, San Francisco, CA, USA
Background: Microbial translocation (MT) may play a role in delayed CD4 recovery in HIV infection after initiating antiretroviral therapy (ART). Lubiprostone (LPT), a bicyclic fatty acid with no drug-drug interactions that specifically activates ClC-2, a selective chloride channel constituent of the apical membrane of the human intestine, is indicated for treatment of chronic idiopathic constipation. Luminal action is exerted within 4 weeks of therapy. In animal models LPT stimulates recovery of mucosal barrier function via restoration of tight junction protein complexes through intracellular trafficking of occludins. An intervention that aims to decrease the level of MT using modulators that act at the mucosal tight junction barrier has not been studied in HIV .
Methods: In the 2-arm, open-label LAMBCHOP (Lubiprostone Activity among the MicroBiota of the Colon in HIV in Opposing Permeability) study (NCT01839734), HIV-1 infected adults aged >18 years from The Ruth M. Rothstein CORE Center with CD4 <350 cells/ul after >72 weeks of continuous ART and >48 weeks of virologic suppression up to baseline (N=20) were randomized 4:1 to 4 weeks of once-daily LPT (24 µg) vs no drug. Baseline demographics were recorded, serum and plasma specimens were collected, and CD4, HIV RNA, MT biomarkers (intestinal fatty acid binding protein [iFAPB], zonulin, sCD14, sCD163) and inflammation markers (IL-6, hsCRP) were measured at baseline and 4 weeks. P-values with α<0.05 by Exact Wilcoxon test were calculated for comparisons of median change from baseline to week 4. Results: Baseline demographics were similar between arms. Median age was 49 years (49.5 in the LPT arm vs 49 in controls;p=0.77), male gender was 81.3% in the LPT arm and 50% in controls (p=0.29), and Black race was 37.5% in the LPT arm and 100% in controls (p=0.13). Change in CD4, MT, and inflammation markers are listed in Table 1. The most commonly reported side effect was soft stools, and there were no LPT discontinuations or HIV RNA virologic rebound events. Conclusions: In this pilot trial, there was no change in MT and inflammation markers in HIV-infected persons with delayed CD4 recovery on suppressive ART following 4 weeks of LPT, a duration of therapy that produces appropriate responses in CIC-2 activation for its indicated use in humans. LPT was well- tolerated with once-daily dosing. Further investigation with LPT is ongoing to characterize possible alterations of gut microbiota in stools samples to evaluate potential mechanisms of MT in HIV infection.
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