CD4+ T cells from CD4C/HIVNef transgenic mice show enhanced activation in vivo with impaired proliferation in vitro but are dispensable for the development of a severe AIDS-like organ disease.
The cellular and molecular mechanisms of dysfunction and depletion of CD4+ T lymphocytes over the course of human immunodeficiency virus type 1 (HIV-1) infection are still incompletely understood, but chronic immune activation is thought to play an important role in disease progression. We studied CD4+ T-cell biology in CD4C/HIV transgenic (Tg) mice, in which Nef expression is sufficient to induce a severe AIDS-like disease including a preferential decrease of CD4+ T cells. We show here that Nef-expressing Tg CD4+ T cells exhibit an activated/memory-like phenotype which appears to be independent of antigenic stimulation, as documented in experiments involving breeding with AD10 TcR Tg mice. In addition, in vivo bromodeoxyuridine incorporation showed that a larger proportion of Tg than non-Tg CD4+ T cells entered the S phase. However, in vitro, Tg CD4+ T cells were found to have a very limited capacity to divide in response to stimulation with anti-CD3 and anti-CD28 or in allogeneic mixed leukocyte reactions. Interestingly, despite these observations, the deletion of Tg CD4+ T cells had little impact on the development of other AIDS-like organ phenotypes. Thus, the Nef-induced chronic activation of CD4+ T cells may exhaust the T-cell pool and may contribute to the thymic atrophy and the low number of CD4+ T cells observed in these Tg mice.
Weng
Xiaoduan
X
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada.
Priceputu
Elena
E
Chrobak
Pavel
P
Poudrier
Johanne
J
Kay
Denis G
DG
Hanna
Zaher
Z
Mak
Tak W
TW
Jolicoeur
Paul
P
D000163:Acquired Immunodeficiency Syndrome / Q000209:etiology*; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015693:Gene Products, nef / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology*; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D054311:nef Gene Products, Human Immunodeficiency Virus; D001973:Bromodeoxyuridine