Background:  Our objective was to analyze whether undetectable plasma viremia in elite controllers protects against CD4⁺ T cell loss.

Methods:  Subjects were selected from the IPM Study Center / ICH cohort into 3 groups:  elite controllers (n = 8, 3 female, 5 male; plasma viral load <50 copies/mL), medium controllers (n = 13, 5 female, 8 male, plasma viral load 50 to 5000 copies/mL), and HAART-treated controls (n = 20, 3 female, 17 male, stable suppression of plasma viral load to <50 copies/mL) (values included starting at year 3 of HAART). Minimum follow-up required was 1 year; at least 3 CD4⁺ counts had to be available. Observations were censored when plasma viral load increased to >50 copies/mL (group 1), >5000 copies/mL (group 2), or when antiretroviral or hepatitis C virus (HCV) treatment, cytotoxic therapy, or interleukin (IL) -2 were given. Individual slopes of CD4⁺ and CD8⁺ T cells were determined assuming a linear fit, based on a mean of 13 (3 to 34) values (mean 3.3 per year). Individual CD4⁺ and CD8⁺ cell changes per year were calculated based on slopes. Samples from 120 blood donors were used to establish age and gender-adjusted normal CD4⁺ cell ranges.

Results:   Inclusion CD4⁺ counts were not significantly different between the groups:  7 of 8 elite, as well as 9 of 13 medium controllers exhibited decreasing CD4⁺ T cells over a median of 5.2 (2.8 to 16.7) and 3.0 (1.1 to 6.6) years, respectively. Calculated median annual CD4⁺ changes were –42 cells/µL in the elite and –15 in the medium controllers. In contrast, HAART-treated controls had an annual change of +30 cells/µL (p = 0.0008, Kruskal-Wallis ANOVA). In pairwise comparisons, both controller groups were significantly different from the controls (Mann-Whitney U test), but not from each other. Fewer elite controllers had normal CD4⁺ values (within the 95% confidence interval of age and gender-adjusted normal values) at the end of the observation interval than at inclusion. In contrast, more controls on HAART had normal CD4⁺ counts than at baseline. CD8⁺ T cell changes were not significantly different between the groups. A repeat analysis excluding time-points without plasma viral load values left the results unchanged.

Conclusions:  Despite limitations due to small case numbers, especially with regard to the magnitude of changes, these results suggest that even in elite controllers of HIV replication, CD4⁺ T cell counts may decrease with long-term follow-up. Stable or increasing CD4⁺ cells in the controls on HAART support the view that this decrease is directly or indirectly related to HIV replication. There could indeed be no “harmless” level of HIV replication.