CD4 T cell depletion, and not age, drives reconstitution within CD4 cell compartments in HIV-infected children initiating ART in Uganda
Background: The naïve CD4 T cell pool is maintained by new thymic emigrants, proliferation within the naïve pool and cell loss through death or differentiation to memory cells. Drivers influencing these homeostatic mechanisms in HIV-infected children are not fully understood, particularly in resource-limited settings.
Methods: 199 ART-naive Ugandan children (54% girls, 5m-18yrs) in the ARROW trial underwent CD4 immunophenotyping at ART initiation, and 4,12,24,36 and 48 weeks later. CD4 subsets were identified by expression of CD45RA, CD31, HLA-DR and Ki67 by flow cytometry. We estimated trends over time using linear mixed models for log cell %.
Results Over 48 weeks on ART there was a marked shift from memory to naive phenotypes (Table), most substantial in those initiating ART with lowest CD4% (p less than 0.001). Adjusting for pre-ART CD4%, there was no independent effect of age on changes in Recent Thymic Emigrants (RTE, CD45RA+CD31+) (p=0.27), Central Naïve (CD45RA+CD31-) (p=0.45) or Memory (M, CD45RA-CD31-) (p=0.72) compartments. At ART initiation, HLA-DR and Ki67 expression were lowest in RTEs, intermediate in CN, and highest in M compartments (all pairwise p less than 0.02). Over 48 weeks on ART,
Ki67+CD4+ T cells declined profoundly in all compartments and across
all pre-ART CD4%. In contrast, declines in HLA-DR% were smaller and had mostly occurred by week 4, thereafter remaining similar.
Conclusions: HIV-infected children with most profound immunosuppression had highest pre-ART proliferation and activation and greatest shift from memory to naïve phenotypes after ART. ART had a sustained and dramatic effect on CD4 proliferation but only a modest impact on activation, occurring shortly after ART initiation, suggesting that non-viral drivers sustain ongoing immune activation despite ART.
Prendergast, A.; Walker, A.S.; Musiime, V.; Ntege, P.N.; Kekitiinwa, A.; Spyer, M.; Keishanyu, R.; M Kihembo, M.; Nakiire, L.; Klein, N. CD4 T cell depletion, and not age, drives reconstitution within CD4 cell compartments in HIV-infected children initiating ART in Uganda. Presented at 18th Conference on retroviruses and opportunistic infections, 27 February – 2 March 2011, Boston, Massachusetts. (2011) 1 pp.