Polyclonal proliferation and apoptosis of CCR5+ T lymphocytes during primary human immunodeficiency virus type 1 infection: regulation by interleukin (IL)-2, IL-15, and Bcl-2.
We measured apoptosis of subsets of T lymphocytes by single-cell analysis of caspase activation, to confirm high turnover of chemokine receptor CCR5(+) T cells in subjects with acute, primary human immunodeficiency virus type 1 (HIV-1) infection (PHI). High levels of spontaneous apoptosis, consisting mainly of CD8(+) T lymphocytes, were closely associated with increases in the activation markers Ki-67, CD38, and the HIV coreceptor CCR5 and with decreases in Bcl-2 and the interleukin (IL)-7 receptor at the single-cell level. Increased expression of Ki-67 and CCR5 ex vivo, as well as increased apoptosis, was seen in all T cell receptor beta-chain variable region (TCRBV) subfamilies studied. The addition of IL-2 or IL-15, but not IL-7, significantly inhibited caspase activation, increased Bcl-2 expression, and rapidly initiated proliferation in vitro of CD8(+) T cells expressing CCR5 and multiple TCRBV subfamilies. Furthermore, IL-15 receptor alpha-chain messenger RNA levels were increased in peripheral blood mononuclear cells during PHI. These results suggest that CCR5(+)Ki-67(+)Bcl-2(dim) activated T cells generated during PHI traffic via blood to tissue sites, where the cells may survive and/or further proliferate under the local influence of IL-2 or IL-15. Understanding cytokine effects on CCR5(+) T cells will be important in understanding chronic HIV-1 replication and pathogenesis.
Centre for Immunology, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
John J
JJ
Zaunders
Laure
L
Moutouh-de Parseval
Shinichi
S
Kitada
John C
JC
Reed
Steffney
S
Rought
Davide
D
Genini
Lorenzo
L
Leoni
Anthony
A
Kelleher
David A
DA
Cooper
Don E
DE
Smith
Pat
P
Grey
Jérôme
J
Estaquier
Susan
S
Little
Douglas D
DD
Richman
Jacques
J
Corbeil
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology*; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000276:immunology*; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*
C508024:IL15RA protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D019713:Receptors, CCR5; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D012313:RNA; D020169:Caspases