HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells.
HIV infection is characterized by a brisk immune activation that plays an important role in the CD4 depletion and immune dysfunction of patients with AIDS. The mechanism underlying this activation is poorly understood. In the current study, we tested the hypothesis that this activation is the net product of two distinct pathways: the inflammatory response to HIV infection and the homeostatic response to CD4 T cell depletion. Using ex vivo BrdU incorporation of PBMCs from 284 patients with different stages of HIV infection, we found that CD4 proliferation was better predicted by the combination of CD4 depletion and HIV viral load (R(2) = 0.375, P < 0.001) than by either parameter alone (CD4 T cell counts, R(2) = 0.202, P < 0.001; HIV viremia, R(2) = 0.302, P < 0.001). Interestingly, CD8 T cell proliferation could be predicted by HIV RNA levels alone (R(2) = 0.334, P < 0.001) and this predictive value increased only slightly (R(2) = 0.346, P < 0.001) when CD4 T cell depletion was taken into account. Consistent with the hypothesis that CD4 T cell proliferation is driven by IL-7 as a homeostatic response to CD4 T cell depletion, levels of phosphorylated STAT-5 were found to be elevated in naive subsets of CD4 and CD8 T cells from patients with HIV infection and in the central memory subset of CD4 T cells. Taken together these data demonstrate that at least two different pathways lead to immune activation of T cells in patients with HIV infection and these pathways differentially influence CD4 and CD8 T cell subsets.
Catalfamo
Marta
M
Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation and Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. catalfam@niaid.nih.gov
Di Mascio
Michele
M
Hu
Zonghui
Z
Srinivasula
Sharat
S
Thaker
Vishakha
V
Adelsberger
Joseph
J
Rupert
Adam
A
Baseler
Michael
M
Tagaya
Yutaka
Y
Roby
Gregg
G
Rehm
Catherine
C
Follmann
Dean
D
Lane
H Clifford
HC
D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000378:metabolism; D019562:Viral Load
D016207:Cytokines; D050799:STAT5 Transcription Factor