Simian immunodeficiency virus Vpr/Vpx proteins kill bystander noninfected CD4+ T-lymphocytes by induction of apoptosis.
The depletion of CD4+ T-lymphocytes central to the immunodeficiency in acquired immunodeficiency syndrome (AIDS) is largely mediated by apoptosis of both infected and uninfected cells, but the mechanisms involved and the viral proteins responsible are still poorly characterized. It has recently been suggested that, in human and simian immunodeficiency virus (HIV) and SIV, Vpr is a major modulator of apoptosis in infected cells. Recently, we have reported on a chimera of caprine arthritis-encephalitis virus (CAEV) carrying vpr/vpx genes from SIVmac239, which is replication competent in goat macrophages but not in lymphocytes or human cells. Despite infection being restricted to macrophages, inoculation of primary goat peripheral blood mononuclear cells (PBMCs) with this chimera induced apoptosis in the lymphocyte population. In addition, when infected goat synovial membrane (GSM) cells were co-cultured with human CD4+ T lymphocyte SupT1 cell line, these CD4+ T cells showed increased apoptosis. The parental CAEV induced no significant apoptosis in goat PBMC cultures or in co-cultures with human SupT1 lymphocytes. This indicates that SIV Vpr/Vpx proteins indeed mediate apoptosis of T-lymphocytes and, moreover, do so without the need for active infection of these cells. Moreover, this apoptosis was observed when SupT1s were cocultured in direct contact, but not in absence of contact with CAEV-pBSCAvpxvpr-infected GSM cells. In view of these data, we propose that SIV Vpx/Vpr activate cell-to-cell contact-dependent extracellular signaling pathways to promote apoptotic death of uninfected bystander T-lymphocytes. Understanding this mechanism might bring insight for intervening in the loss of CD4+ T lymphocytes in the SIV infection model and in human AIDS.
Bouzar
Amel Baya
AB
UMR 754 INRA/ENVL/UCBL Rétrovirus et Pathologie Comparée Virologie Cellulaire, Moléculaire et Maladies Emergentes, IFR-128 Université Claude Bernard Lyon-1, 69366, Lyon Cedex 07, France.
Villet
Stephanie
S
Morin
Thierry
T
Rea
Angela
A
Genestier
Laurent
L
Guiguen
François
F
Garnier
Céline
C
Mornex
Jean Francois
JF
Narayan
Opendra
O
Chebloune
Yahia
Y
D000818:Animals; D017209:Apoptosis; D016088:Arthritis-Encephalitis Virus, Caprine / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016336:Gene Products, vpr / Q000235:genetics / Q000276:immunology*; D006041:Goats; D006801:Humans; D008212:Lymphocyte Depletion; D011994:Recombinant Proteins / Q000276:immunology; D012191:Retroviridae Proteins / Q000235:genetics / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D013583:Synovial Membrane; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology*
D016336:Gene Products, vpr; D011994:Recombinant Proteins; D012191:Retroviridae Proteins; C074286:VPX protein, Human immunodeficiency virus 2; C513059:VPX protein, Simian immunodeficiency virus; D054334:Viral Regulatory and Accessory Proteins