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MICROBIAL TRANSLOCATION, IMMUNE ACTIVATION, AND GUT DYSBIOSIS IN HIV-EXPOSED INFANTS
Charles D. Mitchell1, Sady Dominguez1, Varghese George1, Eddy Perez-Then2, Carlos V. Castillo2, Juan L. Santana-Guerrero2, Jeannette Baez3, Margaret Roach1, William Walters4, Qiaojuan Shi5, Shao-Pei Chou4, Ruth Ley4, Savita Pahwa1
1University of Miami, Miami, FL, USA,2O&M School of Medicine, Santo Domingo, Dominican Republic,3Robert Reid Children's Hospital, Santo Domingo, Dominican Republic,4Max Planck Institute for Developmental Biology, Tübingen, Germany,5Cornell University, Ithaca, NY, USA
The MITABS study (Microbial Translocation[MT], Immune Activation[IA], and Altered Bowel Flora Study[ABS]) is the first prospective, longitudinal study designed to simultaneously assess MT, IA, and alterations in the gut microbiome with clinical events in young (enrolled at < 6 months) HIV perinatally infected (HEI); and perinatally exposed, uninfected(HEU) infants in the Dominican Republic (DR) before and after starting antiretroviral therapy(ART).
Cellular immune markers of IA (HLADR+CD38+ coexpression) in CD4 and CD8 T cells were determined by flow cytometry using the method of Hanekom et al, J Immune Meth, 2004. Plasma MT and IA (LPS, sCD14 and sCD163) were determined by standard assays. Metagenomic analysis was performed on both stool and plasma. Simultaneous assessments of MT, IA, ABS, and clinical events occurred at Entry, 6 weeks, 3,6, 12, and 18 months post entry. No HEI was on ART at entry. HIV-exposed infants in the DR are formula fed
Between 6/6/13 and 3/1/17, 78 infants (31 HEI; 47 HEU) were enrolled in the DR. Median ages at entry for all 78, the 31 HEI and the 47 HEU were 106, 145, and 89 days respectively. 19/31 HEI started ART. 10/31 developed AIDS (CDC criteria); 4 of whom died. No HEU has died. At entry, compared to HEU of the same age (<6 mo, n= 44), HEI not on ART (n= 15) had higher CD8 T cell Immune activation (HLADR+CD38+, 23.6% vs 4.3%, p=0.0005),CD8 (47% vs 24%, p=0.001), lower CD4 (49% vs 71%, p= 0.002) and lower CD4/CD8 ratio (1.04 vs 2.9). HEI also had higher plasma sCD14 (2523 vs 1473ng/ml, p=0.0001), and a trend for higher sCD163 (1212 vs 932 ng/ml, p=0.06) but surprisingly, the 2 groups had similarly elevated markers of MT (LPS, HEI 250 vs HEU 249pg/ml; iFABP, HIE 3293 vs HEU 2755 pg/ml). On prospective follow-up, MT markers (LPS, sCD163) in HEU normalized by 6-9 months. T cell IA were all within the normal range in HEU over time. In HEI, although IA and MT values decreased following ART, they were higher than in HEU. HEI gut microbiome was associated with lower diversity (richness, n=13) compared to HEU (n=38), and an unknown member of the Megaspheara genus was enriched in HEI on ART compared to HEI not on ART.
HEU infants like HEI have high gut permeability during early infancy which gradually normalizes over time. Increased biomarkers of MT and IA in HEI are prevalent from early infancy and persist after starting ART. HEI have a less diverse microbiome than HEU, with enrichment of the genus Megaspheara in HEI on ART