Microbial Translocation Does Not Drive Immune Activation in Ugandan Children Infected With HIV
Authors: Fitzgerald Felicity C , Lhomme Edouard , Harris Kathryn , Kenny Julia , Doyle Ronan , Kityo Cissy , Shaw Liam P , Abongomera George , Musiime Victor , Cook Adrian , Brown Julianne R , Brooks Anthony , Owen-Powell Ellen , Gibb Diana M , Prendergast Andrew J , Sarah Walker A , Thiebaut Rodolphe , Klein Nigel ,   The CHAPAS-3 Trial Team, Chintu Chifumbe , Mulenga Veronica , Kabamba Desiree , Kavindele Dorothy , Chabala Chishala , Mwenechanya Musaku , Kapasa Monica , Zulu Caroline C , Kalumbi Mox , Chambula Elias , Lungu Joyce , Liusha Marjory N , Zangata Dorothy , Masuka Dorica , Chambula Elias , Chanshi Shadreck , Chipoya Terence , Zulu Semy , Chola Daniel , Chanda Betty , Malama Steven , Chama Chama , Mulambo Sylvia , Mwanza Mpala , Asiimwe R Alice , Tukei J Vicent , Korutaro Violet , Komunyena Justine , Sebuliba Isaac , Kisekka Muzamil , Nansubuga Carolyn , Mpanga N Justine , Matovu Moses , Okello Charles , Kesande Sharon , Namutebi Gladys , Tumuheirirwe E Glorius , Nagawa Immaculate , Nakimera Sarah , Onen Geoffrey , Kabasita Fatuma , Sunday Fred , Isabirye Dick , Kityo Cissy , Musiime Victor , Mirembe Grace , Kaudha Elizabeth , Drasiku Amos , Bainomuhwezi Bernard , Wavamunno Priscilla , Odongo Florence , Lukowe Constance , Namala Winnie , Sseremba Daniel , Balaba Alison , Kwaga Alice , Kayiwa Joshua , Odera Matthew , Oronon Paul , Bagurukira Edith , Mwesigwa Phyllis , Apugulu Philip , Mugarura Lincoln , David Williams Eram , Odoch Denis , Nankya Immaculate , Ndashimyeeva Emmanuel , Nabulime Eva , Abach James , Agings Odong Willy , Arach Beatrice , Claren Aciro Irene , Omongin Joseph , Amone Geoffrey , Okello Peter , Aleti Philliam , Otim Edward , Kidega Patrick , Achol Emmanuel , Mwape Innocent , Zulu Joshua , Chipili Gabriel , Chibesa Linda , Gibb Diana M , Walker A Sarah , Thomason Margaret J , Cook Adrian , Owen-Powell Ellen , Ferrier Alex , Baptiste David , Male Charlotte , Murphy Brendan , Spyer Moira , Kenny Julia , Klein Nigel , Burger David , Fillekes Quirine , Colbers Angela , McIlleron Helen , Chomba Elwyn , Ramos Jose , Akol Zainab , Elyanu Peter , Nakimuli Harriet , Kenny Julia , Gibb Diana M 
Published: August 2018

Abstract

Objective
Immune activation is associated with morbidity and mortality during human immunodeficiency virus (HIV) infection, despite receipt of antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children.

Methods
Nineteen markers of immune activation and inflammation were measured over 96 weeks in HIV-infected Ugandan children in the CHAPAS-3 Trial and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques, including next-generation sequencing.

Results
Of 249 children included, 142 were infected with HIV; of these, 120 were ART naive, with a median age of 2.8 years (interquartile range [IQR], 1.7–4.0 years) and a median baseline CD4+ T-cell percentage of 20% (IQR, 14%–24%), and 22 were ART experienced, with a median age of 6.5 years (IQR, 5.9–9.2 years) and a median baseline CD4+ T-cell percentage of 35% (IQR, 31%–39%). The control group comprised 107 children without HIV infection. The median increase in the CD4+ T-cell percentage was 17 percentage points (IQR, 12–22 percentage points) at week 96 among ART-naive children, and the viral load was &lt;100 copies/mL in 76% of ART-naive children and 91% of ART-experienced children. Immune activation decreased with ART use. Children could be divided on the basis of immune activation markers into the following 3 clusters: in cluster 1, the majority of children were HIV uninfected; cluster 2 comprised a mix of HIV-uninfected children and HIV-infected ART-naive or ART-experienced children; and in cluster 3, the majority were ART naive. Immune activation was low in cluster 1, decreased in cluster 3, and persisted in cluster 2. Blood microbial DNA levels were negative or very low across groups, with no difference between clusters except for Enterobacteriaceae organisms (the level was higher in cluster 1; P &lt; .0001).

Conclusion
Immune activation decreased with ART use, with marker clustering indicating different activation patterns according to HIV and ART status. Levels of bacterial DNA in blood were low regardless of HIV status, ART status, and immune activation status. Microbial translocation did not drive immune activation in this setting.

Clinical Trials Registration
ISRCTN69078957.