Evidence for increased T cell turnover and decreased thymic output in HIV infection.
The effects of HIV infection upon the thymus and peripheral T cell turnover have been implicated in the pathogenesis of AIDS. In this study, we investigated whether decreased thymic output, increased T cell proliferation, or both can occur in HIV infection. We measured peripheral blood levels of TCR rearrangement excision circles (TREC) and parameters of cell proliferation, including Ki67 expression and ex vivo bromodeoxyuridine incorporation in 22 individuals with early untreated HIV disease and in 15 HIV-infected individuals undergoing temporary interruption of therapy. We found an inverse association between increased T cell proliferation with rapid viral recrudescence and a decrease in TREC levels. However, during early HIV infection, we found that CD45RO-CD27high (naive) CD4+ T cell proliferation did not increase, despite a loss of TREC within naive CD4+ T cells. A possible explanation for this is that decreased thymic output occurs in HIV-infected humans. This suggests that the loss of TREC during HIV infection can arise from a combination of increased T cell proliferation and decreased thymic output, and that both mechanisms can contribute to the perturbations in T cell homeostasis that underlie the pathogenesis of AIDS.
Douek
D C
DC
Vaccine Research Center, Clinical and Molecular Retrovirology Section, National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Betts
M R
MR
Hill
B J
BJ
Little
S J
SJ
Lempicki
R
R
Metcalf
J A
JA
Casazza
J
J
Yoder
C
C
Adelsberger
J W
JW
Stevens
R A
RA
Baseler
M W
MW
Keiser
P
P
Richman
D D
DD
Davey
R T
RT
Koup
R A
RA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023241:Antiretroviral Therapy, Highly Active; D001973:Bromodeoxyuridine / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D015329:Gene Rearrangement, T-Lymphocyte; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007156:Immunologic Memory; D007399:Interphase / Q000276:immunology; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
D019394:Ki-67 Antigen; D001973:Bromodeoxyuridine