Resistance to apoptosis in HIV-infected CD4+ T lymphocytes is mediated by macrophages: role for Nef and immune activation in viral persistence.
Apoptosis or programmed cell death may play a critical role in AIDS pathogenesis through depletion of both CD4(+) and CD8(+) T lymphocytes. Using a reporter virus, a recombinant HIV infectious clone expressing the green fluorescent protein (GFP), apoptosis was measured in productively infected CD4(+) T lymphocytes, in the presence and absence of autologous macrophages. The presence of macrophages in the culture increased the frequency of nonapoptotic GFP-positive productively infected CD4(+) T lymphocytes. The appearance of nonapoptotic productively infected CD4(+) T lymphocytes in the culture required intercellular contacts between macrophages and PBLs and the expression of the HIV Nef protein. The presence of macrophages did not reduce apoptosis when CD4(+) T lymphocytes were infected with a GFP-tagged virus deleted for the nef gene. TNF-alpha (TNF) expressed on the surface of macrophages prevented apoptosis in nef-expressing, productively infected CD4(+) T lymphocytes. Similarly, following TNF stimulation, apoptosis was diminished in Jurkat T cells transfected with a nef-expressing plasmid. TNF stimulation of nef-expressing Jurkat T cells resulted in NF-kappaB hyperactivation, which has been shown to deliver anti-apoptotic signals. Our results indicate that intercellular contacts with macrophages increase the rate of productively infected nonapoptotic CD4(+) T lymphocytes. The survival of productively infected CD4(+) T lymphocytes requires Nef expression as well as activation by TNF expressed on the surface of macrophages and might participate in the formation and maintenance of viral reservoirs in HIV-infected persons.
Mahlknecht
U
U
Department of Hematology/Oncology, University of Frankfurt, Frankfurt am Main, Germany.
Deng
C
C
Lu
M C
MC
Greenough
T C
TC
Sullivan
J L
JL
O'Brien
W A
WA
Herbein
G
G
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D016466:CHO Cells; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006224:Cricetinae; D015693:Gene Products, nef / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D019169:Jurkat Cells; D008164:Luminescent Proteins / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D017735:Virus Latency / Q000235:genetics / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D008164:Luminescent Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D054311:nef Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins