Cytopathic killing of peripheral blood CD4(+) T lymphocytes by human immunodeficiency virus type 1 appears necrotic rather than apoptotic and does not require env.
An important unresolved issue of AIDS pathogenesis is the mechanism of human immunodeficiency virus (HIV)-induced CD4(+) T-lymphocyte destruction. We show here that HIV type 1 (HIV-1) exerts a profound cytopathic effect upon peripheral blood CD4(+) T lymphocytes that resembles necrosis rather than apoptosis. Necrotic cytopathology was found with both laboratory-adapted strains and primary isolates of HIV-1. We carefully investigated the role of env, which has been previously implicated in HIV cytopathicity. HIV-1 stocks with equivalent infectivity were prepared from constructs with either an intact or mutated env coding region and pseudotyped with the glycoprotein of vesicular stomatitis virus (VSV-G) so that the HIV envelope was not rate-limiting for infection. Infected Jurkat T cells died whether or not env was intact; however, the expression of env accelerated death significantly. The accelerated death was blocked by protease inhibitors, indicating that it was due to reinfection by newly produced virus in env(+) cultures. Accordingly, we found no disparity in kinetics in CD4(lo) Jurkat cells. In highly infected peripheral blood T cells, profound necrosis occurred equivalently with both env(+) and env(-) stocks of HIV-1. We also found that HIV-1 cytopathicity was undiminished by the absence of nef. However, viral stocks made by complementation or packaging of HIV-1 genomes with the natural protein-coding sequences replaced by the green fluorescent protein were highly infectious but not cytopathic. Thus, env can accelerate cell death chiefly as an entry function, but one or more viral functions other than env or nef is essential for necrosis of CD4(+) T cells induced by HIV-1.
Lenardo
Michael J
MJ
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892, USA. Lenardo@nih.gov
Angleman
Sara B
SB
Bounkeua
Viengngeun
V
Dimas
Joseph
J
Duvall
Melody G
MG
Graubard
Moses B
MB
Hornung
Felicita
F
Selkirk
Marianne C
MC
Speirs
Christina K
CK
Trageser
Carol
C
Orenstein
Jan O
JO
Bolton
Diane L
DL
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000821:virology*; D003588:Cytopathogenic Effect, Viral; D015686:Gene Products, env / Q000235:genetics / Q000502:physiology*; D015693:Gene Products, nef / Q000502:physiology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins; D009154:Mutation; D009336:Necrosis; D011995:Recombination, Genetic; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus
C028391:G protein, vesicular stomatitis virus; D015686:Gene Products, env; D015693:Gene Products, nef; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus