Background: CD4 lymphopenia is the cardinal manifestation of HIV infection. The impact of increased turnover in CD4 loss and in HIV pathogenesis remains controversial. An evaluation of T-cell turnover before and after HAART was performed in order to study turnover changes induced by HAART as well as correlations of T-cell turnover with viral load and with T-cell activation.

Methods: PBMCs from 18 ARV-naïve HIV-infected patients (randomly selected from a larger cohort) were collected at weeks 0, 24, and 52 of HAART (AZT, 3TC, IND, and NVP) for immunophenotypic analyses with markers of activation (HLA-DR and CD38) and recent proliferation/turnover (intracellular Ki67). Nonparametric tests (paired signed rank test and Spearman rank correlation) were used for analysis.

Results: At week 52, CD4 counts increased from a median of 386 cells/μL at baseline to 640 cells/μL, CD8 counts decreased from 838 cells/μL at baseline to 727 cells/μL, and viral load decreased from 56,635 copies/ml at baseline to <500 copies/mL. The percentage of CD4 cells expressing Ki-67 decreased from 9.8% at baseline to 4.9% (p<0.001) at week 52 (13 healthy controls: 2.6%), and the percentage of CD8 cells expressing Ki-67 decreased from 12.1% at baseline to 5% (p<0.001) at week 52 (13 healthy controls: 2.7%). The percentage of Ki-67+ cells correlated with the viral load in CD4 and CD8 subsets (R=0.59, p<0.001 for both). The percent of Ki-67+ cells also correlated strongly with the co-expression of HLA-DR and CD38 in both CD4 (R=0.82, p<0.001) and CD8 (R=0.76, p<0.001) subsets. A correlation between the percent of Ki67+ cells and the absolute cell count was seen exclusively in the CD4 subset (R= -0.5, p<0.001).

Conclusion: Turnover of both CD4 and CD8 T cells, as measured indirectly by intracellular Ki-67, is increased in HIV infection and decreases significantly after initiation of HAART, but does not normalize despite suppression of viral load to <50. Turnover of both CD4 and CD8 subsets is strongly associated with viral load and with the activation status of these T cells, as measured by the co-expression of HLA-DR and CD38.  These data suggest that immune activation in HIV infection is central in the observed increased CD4 turnover and CD4 lymphopenia.