Necroptosis takes place in human immunodeficiency virus type-1 (HIV-1)-infected CD4+ T lymphocytes.
Human immunodeficiency virus type 1 (HIV-1) infection is characterized by progressive depletion of CD4+ T lymphocytes and dysfunction of the immune system. The numbers of CD4+ T lymphocytes in the human body are maintained constantly by homeostatic mechanisms that failed during HIV-1 infection, resulting in progressive loss of CD4+ T cells mainly via apoptosis. Recently, a non-apoptotic form of necrotic programmed cell death, named necroptosis, has been investigated in many biological and pathological processes. We then determine whether HIV-1-infected cells also undergo necroptosis. In this report, we demonstrate that HIV-1 not only induces apoptosis, but also mediates necroptosis in the infected primary CD4+ T lymphocytes and CD4+ T-cell lines. Necroptosis-dependent cytopathic effects are significantly increased in HIV-1-infected Jurkat cells that is lack of Fas-associated protein-containing death domain (FADD), indicating that necroptosis occurs as an alternative cell death mechanism in the absence of apoptosis. Unlike apoptosis, necroptosis mainly occurs in HIV-infected cells and spares bystander damage. Treatment with necrostatin-1(Nec-1), a RIP1 inhibitor that specifically blocks the necroptosis pathway, potently restrains HIV-1-induced cytopathic effect and interestingly, inhibits the formation of HIV-induced syncytia in CD4+ T-cell lines. This suggests that syncytia formation is mediated, at least partially, by necroptosis-related processes. Furthermore, we also found that the HIV-1 infection-augmented tumor necrosis factor-alpha (TNF-α) plays a key role in inducing necroptosis and HIV-1 Envelope and Tat proteins function as its co-factors. Taken together,necroptosis can function as an alternative cell death pathway in lieu of apoptosis during HIV-1 infection, thereby also contributing to HIV-1-induced cytopathic effects. Our results reveal that in addition to apoptosis, necroptosis also plays an important role in HIV-1-induced pathogenesis.
Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.
Ting
T
Pan
Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.
Shuangxin
S
Wu
Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.
Xin
X
He
Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.
Haihua
H
Luo
Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.
Yijun
Y
Zhang
Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.
Miaomiao
M
Fan
Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.
Guannan
G
Geng
Division of Infectious Diseases, Department of Medicine, Center for Human Virology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Vivian Clarke
VC
Ruiz
Division of Infectious Diseases, Department of Medicine, Center for Human Virology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Jim
J
Zhang
Division of Infectious Diseases, Department of Medicine, Center for Human Virology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Lisa
L
Mills
Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.
Chuan
C
Bai
Institute of Human Virology, Sun Yatsen University, Guangzhou, China; Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yatsen University, Guangzhou, China.
Hui
H
Zhang
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology* / Q000821:virology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology*; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000276:immunology
D007093:Imidazoles; D007211:Indoles; C507699:necrostatin-1