Abstract
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.
Highlights
Necrosis used to be viewed as an accidental and unregulated process for cell death
Apoptosis is characterized by annexin V-positive and 7-AAD-negative staining, while necrosis is characterized by annexin V-negative and 7-AAD-positive staining
We found that Nec-1 suppressed necrosis over 50% in Human immunodeficiency virus type 1 (HIV-1)-infected CD4+ T cells, illustrating that the necrostic cell death was largely due to necroptosis (Fig. 1A)
Summary
Necrosis used to be viewed as an accidental and unregulated process for cell death. accumulating evidence has suggested that necrosis, like apoptosis, can occur in a coordinated and regulated manner, aptly termed ‘necroptosis’ [1,2,3]. Similar to the process of apoptosis activation, necroptosis is triggered by tumor necrosis factor alpha (TNF-a), but leads to cell death independently of caspase-8 [4,5]. It has been reported that the initiation of necroptosis by death receptors, such as tumor necrosis factor receptor 1 (TNFR1), requires the kinase activities of both receptor interacting protein 1 (RIP1) and 3 (RIP3) [6,7]. Recent reports provided evidence that mixed lineage kinase domain like (MLKL) and phosphoglycerate mutase 5 (PGAM5) are integral parts of the necroptotic signaling machinery downstream of RIP1 and RIP3 activation and are the substrates of RIP3 [7,13,14,15]. In order to identify putative RIP3 substrates, they screened a chemical library and identified a small molecule named necrosulfonamide (NSA), which inhibited necroptosis by covalently modifying MLKL [13,15,16]
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