Background:  The naive CD4 T cell pool is maintained by thymic production of new cells, proliferation within the naive pool and cell loss through death or differentiation to memory cells. The homeostatic mechanisms operating to maintain naive and memory pools are not fully understood in healthy children; even less is known in HIV infection, particularly in resource-limited settings when ART is often initiated with advanced immunodeficiency.

Methods:  In this study, 1210 ART-naïve children meeting WHO criteria for ART in Uganda/Zimbabwe were enrolled into the ARROW trial and started combination ART; 199 children in Uganda (54% girls, aged 5 months to 18 years) underwent CD4 immunophenotyping at ART initiation using a combination of CD4, CD45RA, and CD31.

Results:  As expected, CD4 and CD4-for-age z-score varied significantly with age at ART initiation (see table), as did the percentage of CD4 cells in the ‘Recent Thymic Emigrant’ (RTE, CD45RA⁺CD31⁺), Central Naive (CN, CD45RA⁺CD31^-) and memory (M, CD45RA^-CD31^-) compartments (P =0.001, 0.01, <0.001 respectively). However, multivariable modelling showed this relationship with age was predominantly the result of the lower CD4-for-age in older children (after adjusting for CD4-for-age, P (age) =0.13, 0.40, and 0.70, respectively). Every 1 unit lower CD4-for-age was associated with 4.4% smaller RTE, 2.1% greater CN and 3.6% greater M subpopulations at ART initiation (P <0.001). There was no impact of sex on the CD4 subpopulations (P >0.5), but there was a trend towards children with lower weight-for-age having greater CN subpopulations (0.7% greater for every 1 unit lower weight-for-age, adjusted P =0.12).

Conclusions:  In all age groups, the cell proportions in these 3 CD4 compartments were lower than have been reported in healthy Caucasian children. CD4 count seems to be an important driver or consequence of lower RTE and higher central naive/memory populations, with a far stronger association than age alone. In children surviving without ART, there may be a shift to maintaining the CD4 cell pool through the relative expansion of naive and memory pools at some child-specific point, possibly representing declining capacity of the thymus to keep pace with CD4 loss. The long-term consequences of this for ART response are unclear.