In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: why are CD4+ but not CD8+ T cells depleted?
Deuterated glucose labeling was used to measure the in vivo turnover of T lymphocytes. A realistic T cell kinetic model, with populations of resting and activated T cells, was fitted to d-glucose labeling data from healthy and HIV-1-infected individuals before and after antiretroviral treatment. Our analysis highlights why HIV-1 infection, which increases the fraction of both CD4(+) and CD8(+) T lymphocytes that are proliferating (Ki67(+)), leads to CD4 but not CD8 depletion. We find that HIV-1 infection tends to increase the rates of death and proliferation of activated CD4(+) T cells, and to increase the rate at which resting CD4 T cells become activated, but does not increase the fraction of activated CD4(+) T cells, consistent with their preferential loss in HIV-1-infected individuals. In contrast, HIV-1 infection does not lead to an increase in proliferation or death rates of activated CD8(+) T cells, but did increase the fraction of activated CD8(+) T cells, consistent with these cells remaining in an activated state longer and undergoing more rounds of proliferation than CD4(+) T cells. Our results also explain why telomeres shorten in CD8(+) cells, but not in CD4(+) cells of HIV-1-infected patients, compared with age-matched controls.
Ribeiro
Ruy M
RM
Theoretical Division, Los Alamos National Laboratory, NM 87545, USA. ruy@lanl.gov
Mohri
Hiroshi
H
Ho
David D
DD
Perelson
Alan S
AS
D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016923:Cell Death; D002455:Cell Division; D005947:Glucose / Q000032:analysis; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008954:Models, Biological; D016615:Telomere / Q000648:ultrastructure
D019394:Ki-67 Antigen; D005947:Glucose