Interleukin-7 signalling defects in naive CD4+ T cells of HIV patients with CD4+ T-cell deficiency on antiretroviral therapy are associated with T-cell activation and senescence.
OBJECTIVE
To examine the relationship of defects in interleukin (IL)-7-induced naive CD4 T-cell homeostasis with residual immune activation and CD4 T-cell senescence in HIV patients receiving antiretroviral therapy (ART) who exhibit persistent CD4 T-cell deficiency.


METHODS
IL-7 induced proliferation of, and IL-7 receptor signalling in, total and naive CD4 T cells of HIV patients who had low (<350 cells/μl) or normal (>500 cells/μl) CD4 T-cell counts on ART was examined and related to markers of CD4 T-cell activation and senescence and innate immune activation.


METHODS
Total, naive (CD45RA CD27) and CD31 naive CD4 T cells from aviremic HIV patients (n=39) with nadir CD4 T-cell counts less than 100 cells/μl, who had received ART for a median time of 7 (range 1-11) years, were assessed for CD127 expression, proliferation (Ki67), signal transducer and activator of transcription 5 phosphorylation (pSTAT5) and CD127 modulation following IL-7 stimulation. Changes were related to proportions of CD4 T cells expressing HLA-DR or CD57 and plasma levels of sCD14, CXCL9 and CXCL10.


RESULTS
Patients with CD4 T-cell deficiency exhibited lower expression of CD127 on total, naive and CD31 naive CD4 T cells. Downregulation of CD127 after culture with IL-7 correlated inversely with CD4 T-cell counts and directly with Ki67 expression. Induction of pSTAT5 in CD4 T-cell subsets was greater in patients with normal CD4 T-cell counts. CD127 expression correlated inversely with proportions of CD4CD57 T cells, and pSTAT5 induction correlated inversely with CD4 T-cell expression of HLA-DR and CD57.


CONCLUSIONS
Defects of IL-7 signalling in HIV patients with persistent CD4 T-cell deficiency receiving ART are associated with CD4 T-cell activation and senescence.
aSchool of Pathology and Laboratory Medicine, University of Western Australia bDepartment of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Western Australia, Australia.
Sara
S
Tanaskovic
Sonia
S
Fernandez
Patricia
P
Price
Martyn A
MA
French
D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000276:immunology*; D019394:Ki-67 Antigen / Q000032:analysis; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D050799:STAT5 Transcription Factor / Q000032:analysis; D015398:Signal Transduction
D044966:Anti-Retroviral Agents; D015703:Antigens, CD; C508605:IL7 protein, human; D015851:Interleukin-7; D019394:Ki-67 Antigen; D050799:STAT5 Transcription Factor