Background:  Despite suppression of viral replication by highly active antiretroviral therapy (HAART), the CD4 cell recovery is impeded in some HIV-infected patients. We hypothesized that immune activation would be increased in these discordant responders.

Methods: In the Danish HIV Cohort Study, we identified HIV-1-infected patients initiating HAART with a CD4 cell count <100 cells/μL, followed by HIV-RNA<50 copies/mL for 3 years. After the 3 years, 21 patients had a CD4 count <200 cells/μL and were identified as possible cases; 42 patients with a CD4 count >200 cells/μL were randomly selected as controls. Subsequently, patients were included at routine visits (case group:  n = 18; control group: n = 33). Whole blood samples were subjected to six-color flow cytometry. Plasma cytokine levels and cytokine production from whole blood stimulated with LPS or PHA were assessed.

Results:  At inclusion, the mean CD4 count was 214 and 637 cells/μL in the case and control groups, respectively. Cases were older than controls (median:  54 versus 44 years, p <0.01). The proportion of naïve (CD45RA⁺CD62L⁺) cells in the CD4 and CD8 subsets were lower in the case group in unadjusted analysis (CD4: unadjusted/age and sex adjusted:  p <0.01/p = 0.06; CD8: p <0.01/p = 0.05). The proportion of CD28⁺ cells was lower among cases in the CD4 subset (p <0.01/p <0.01) and in the naïve CD4 subset (p <0.01/p <0.01). Similarly, CD28 expression was decreased on naïve CD8 cells (p <0.0001/p <0.001). The expression of HLA-DR was lower in the case group on phenotypically naïve CD4 cells (p <0.001/p <0.01), CD8 cells (p <0.01/p <0.05), and in unadjusted analysis on memory (CD45RA^–CD45RO⁺) CD4 cells (p <0.01/p = 0.06). The production of IL-10 to PHA (p <0.0001/p <0.001), IL-10 to LPS (p <0.05/p <0.05), and IL-2 to PHA (p <0.01/p <0.05) was decreased in cases. Plasma IL-10 was lower in cases (p <0.05/p <0.05) with no difference in TNF-α.

Conclusions:  Not only were the CD4 cell counts lower in cases but the proportions of naïve cells among CD4 and CD8 cells were lower as well. We previously reported that low expression of CD28 and impaired production of cytokines were linked to immune activation and poor prognosis among untreated patients. Immune activation with decreased CD28 and increased HLA-DR expression on T cell subsets were key findings among cases in this study. Moreover, this study supports an impaired production of the anti-inflammatory IL-10 as a cofactor in immune activation and attenuated CD4 recovery during HAART.