High viral burden and rapid CD4+ cell depletion in human immunodeficiency virus type 1-infected SCID-hu mice suggest direct viral killing of thymocytes in vivo.
The mechanism of CD4+ cell loss in lymphoid organs is unknown. In this study, human immunodeficiency virus (HIV) infection of human fetal thymus/liver implants in severe combined immunodeficient mice was used to investigate the mechanism of HIV-induced depletion of CD4-bearing cells in vivo. The implants were assessed for depletion of CD4+ thymocytes, apoptosis, and viral burden. We detected two phases of CD4 cell depletion, an initial rapid phase and a more gradual later phase. Compared to mock-infected implants, HIV-infected implants did not demonstrate detectable increases in the levels of apoptosis while severe depletion of CD4-bearing cells was ongoing. During peak loss of CD4+ cells, high viral burden was observed, suggesting that loss of CD4+ cells in this in vivo system is due to direct killing of infected thymocytes. Increased levels of apoptosis were observed during the later phase of thymocyte depletion; however, these apoptotic cells lacked CD4. This finding suggests that a second indirect mechanism may be responsible for the destruction of CD4- CD8+ thymocytes in vivo. Taken together, these results suggest that CD4+ and CD4- cells may die by different mechanism(s).
Jamieson
B D
BD
Department of Medicine, UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California 90095-1678, USA.
Uittenbogaart
C H
CH
Schmid
I
I
Zack
J A
JA
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D005434:Flow Cytometry; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D008212:Lymphocyte Depletion; D051379:Mice; D016513:Mice, SCID; D016133:Polymerase Chain Reaction / Q000379:methods; D013950:Thymus Gland / Q000166:cytology / Q000821:virology*; D013997:Time Factors