Lymphopenia-induced proliferation of CD4 T-cells is associated with CD4 T-lymphocyte exhaustion in treated HIV-infected patients

BACKGROUND & OBJECTIVES: Under the lymphopenic condition, T-cells divide to maintain their peripheral pool size. Profound chronic lymphopenia in some treated HIV-infected patients, characterized by poor T-cell recovery, might result in intensive homeostatic proliferation and can cause T-cell exhaustion and/or senescence. The present study was undertaken to evaluate the homeostatic proliferation of CD4(+) T-cells in treated HIV-infected individuals, and to determine the amount of phenotypically exhausted and senescent CD4 T-lymphocytes. METHODS: Thirty seven treated HIV-infected patients with suppressed HIV viral load (<50 copies/ml) were studied. Patients were divided into two groups: immunological non-responders (INRs) with CD4(+) T-cells <350/μl (n=16) and immunological responders (IRs) with CD4(+) T-cells >350/μl (n=21). T-cell subsets [naïve, central memory (CM), and effector memory (EM)] and proportions of cycling (Ki-67(+)), senescent (CD57(+)) and exhausted (PD-1(+)) T-lymphocytes were assessed using flow cytometry. RESULTS: CD4(+) T-cell cycling rate was higher in INRs than in IRs due to more extensive proliferation of CM, 4.7 vs 2.7 per cent (P <0.01) and EM, 4.8 vs 3.2 per cent (P <0.05). The percentages of CD4(+) Ki-67(+) CM and EM T-lymphocytes were inversely related to the CD4(+) T-cell counts in the appropriate subset, r=–0.584 (P <0.001) and r=–0.556, (P <0.001), respectively. Exhaustion [24.2 vs 16.7% (P <0.01)], but not senescence [7.1 vs 10.8% (P>0.05)] was more pronounced in the INR group than in the IR group. The frequency of CD4(+) Ki-67(+) CM T-cells was related to the proportion of CD4(+) PD-1(+) cells of the same subset, r=0.789 (P <0.001). The numbers of CD4(+) Ki-67(+) PD-1(+) CM and EM T-cells were substantially higher in INRs than in IRs. INTERPRETATION & CONCLUSIONS: The present data indicated that intensive homeostatic proliferation contributed to the T-cell exhaustion in HIV-infection.