The interaction between HIV-1 Nef and adaptor protein-2 reduces Nef-mediated CD4+ T cell apoptosis

Jacob, Rajesh; Johnson, Aaron L.; Pawlak, Emily N.; Dirk, Brennan S.; Nynatten, Logan R. Van; Haeryfar, S. M. Mansour; Dikeakos, Jimmy D.

doi:10.1016/j.virol.2017.05.018

Cited by 17 publications

(22 citation statements)

References 58 publications

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“…Nef also binds and activates the serine/threonine kinase p21 activated kinase 2 (PAK2), which induces T cell activation [ 57 ]. Nef thus alters the activation status of cells, perhaps inducing the correct balance between activating and inhibitory signaling, thereby enabling optimal viral replication without inducing anergy or activation induced cell death [ 75 ]. However, when compared to Nef, little is known regarding how Vpu alters T cell activation.…”

Section: Discussionmentioning

confidence: 99%

The HIV-1 accessory proteins Nef and Vpu downregulate total and cell surface CD28 in CD4+ T cells

et al. 2018

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BackgroundThe HIV-1 accessory proteins Nef and Vpu alter cell surface levels of multiple host proteins to modify the immune response and increase viral persistence. Nef and Vpu can downregulate cell surface levels of the co-stimulatory molecule CD28, however the mechanism of this function has not been completely elucidated.ResultsHere, we provide evidence that Nef and Vpu decrease cell surface and total cellular levels of CD28. Moreover, using inhibitors we implicate the cellular degradation machinery in the downregulation of CD28. We shed light on the mechanisms of CD28 downregulation by implicating the Nef LL165 and DD175 motifs in decreasing cell surface CD28 and Nef DD175 in decreasing total cellular CD28. Moreover, the Vpu LV64 and S52/56 motifs were required for cell surface CD28 downregulation, while, unlike for CD4 downregulation, Vpu W22 was dispensable. The Vpu S52/56 motif was also critical for Vpu-mediated decreases in total CD28 protein level. Finally, the ability of Vpu to downregulate CD28 is conserved between multiple group M Vpu proteins and infection with viruses encoding or lacking Nef and Vpu have differential effects on activation upon stimulation.ConclusionsWe report that Nef and Vpu downregulate cell surface and total cellular CD28 levels. We identified inhibitors and mutations within Nef and Vpu that disrupt downregulation, shedding light on the mechanisms utilized to downregulate CD28. The conservation and redundancy between the abilities of two HIV-1 proteins to downregulate CD28 highlight the importance of this function, which may contribute to the development of latently infected cells.Electronic supplementary materialThe online version of this article (10.1186/s12977-018-0388-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The HIV-1 accessory proteins Nef and Vpu downregulate total and cell surface CD28 in CD4+ T cells

et al. 2018

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“…Interaction between adipocyte and immune cells The consequences of a lipid-rich environment Mazzon and Mercer, 2014 Oxidative stress Malmberg et al, 2001;Ivanov et al, 2016 Hypoxia in adipose tissue Tao et al, 2015 Insulin sensitivity Tsai et al, 2018 Viral and pharmacological parameters HIV viral proteins Boya et al, 2004;Debaisieux et al, 2012;Clark et al, 2017;Jacob et al, 2017 Adipose tissue remodeling and fibrosis Sun et al, 2013;Vila et al, 2014;Marcelin et al, 2017 Antiretroviral diffusion (ARV) Dupin et al, 2002; impact on the persistence of HIV-infected CD4 T cells, and might also interfere with the effective differentiation of memory cells. Indeed, CD4 T cell help is a crucial factor in the differentiation and maintenance of CD8 T cells.…”

Section: Limited Efficiency Of Ag Presenting Cellsmentioning

confidence: 99%

“…It has been shown that the HIV proteins Tat, Nef, gp120, and Vpr can modulate immune cells, notably by inducing the apoptosis of non-infected CD4 T cells as a bystander effect (Boya et al, 2004). Nef binds to CXCR4 and modulates T cell activation (Jacob et al, 2017), and so may also be involved in HIV persistence. Tat induces apoptosis in non-infected CD8 and CD4 T cells, and alters the metabolic, morphologic, and biochemical properties of CD4 T cells (Debaisieux et al, 2012;Faller et al, 2014;Clark et al, 2017).…”

Section: Hiv Viral Proteins Affecting Immune Cellsmentioning

confidence: 99%

Specific Biological Features of Adipose Tissue, and Their Impact on HIV Persistence

et al. 2019

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Although white AT can contribute to anti-infectious immune responses, it can also be targeted and perturbed by pathogens. The AT's immune involvement is primarily due to strong pro-inflammatory responses (with both local and paracrine effects), and the large number of fat-resident macrophages. Adipocytes also exert direct antimicrobial responses. In recent years, it has been found that memory T cells accumulate in AT, where they provide efficient secondary responses against viral pathogens. These observations have prompted researchers to re-evaluate the links between obesity and susceptibility to infections. In contrast, AT serves as a reservoir for several persistence pathogens, such as human adenovirus Ad-36, Trypanosoma gondii, Mycobacterium tuberculosis, influenza A virus, and cytomegalovirus (CMV). The presence and persistence of bacterial DNA in AT has led to the concept of a tissuespecific microbiota. The unexpected coexistence of immune cells and pathogens within the specific AT environment is intriguing, and its impact on anti-infectious immune responses requires further evaluation. AT has been recently identified as a site of HIV persistence. In the context of HIV infection, AT is targeted by both the virus and the antiretroviral drugs. AT's intrinsic metabolic features, large overall mass, and wide distribution make it a major tissue reservoir, and one that may contribute to the pathophysiology of chronic HIV infections. Here, we review the immune, metabolic, viral, and pharmacological aspects that contribute to HIV persistence in AT. We also evaluate the respective impacts of both intrinsic and HIV-induced factors on AT's involvement as a viral reservoir. Lastly, we examine the potential consequences of HIV persistence on the metabolic and immune activities of AT.

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“…The AP-2 complex is involved in a variety of biological processes. 10,29 However, no studies have been conducted on the roles of AccAP2m in response to adverse stress conditions in A. cerana cerana. Adult worker bees are responsible for pollen collection, pollination, and other works; because of high levels of contact with the external environment, these bees are easily affected by the F I G U R E 3 AccAP2m transcription expression level under environmental stress factors.…”

Section: Discussionmentioning

confidence: 99%

Identification of an adaptor protein‐2 mu gene (AccAP2m) in Apis cerana cerana and its role in oxidative stress responses

Wang

Chao

Wang

et al. 2019

J of Cellular Biochemistry

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The adaptor protein‐2 (AP‐2) complex refers to a class of proteins that play an important role in cargo recognition and are involved in clathrin‐mediated endocytosis of cargo proteins from the plasma membrane in animal cells. However, there have been few studies of AP‐2 in insects. Here, we isolated an AP‐2 gene from Apis cerana cerana (A. cerana cerana) and explored the function of this gene, named AccAP2m. The obtained amino acid sequence of AccAP2m is highly conserved across species and contains conserved features of the AP‐2 family. Quantitative real‐time PCR analysis showed that AccAP2m mRNA levels were high in newly emerged workers, and the expression levels were higher in muscle than in other tissues. The expression of AccAP2m was altered in response to various environmental stress factors. Moreover, overexpression of recombinant AccAP2m protein enhanced the resistance of the bacteria to HgCl2, CdCl2, and cumyl hydroperoxide. In addition, after knockdown of AccAP2m in A. cerana cerana by RNA interference (RNAi), the transcription of some antioxidant genes was downregulated, and the activities of some antioxidant enzymes decreased. Taken together, these results indicate that AccAP2m may play an indispensable role in response to oxidative stresses.

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The interaction between HIV-1 Nef and adaptor protein-2 reduces Nef-mediated CD4+ T cell apoptosis

Cited by 17 publications

References 58 publications

The HIV-1 accessory proteins Nef and Vpu downregulate total and cell surface CD28 in CD4+ T cells

The HIV-1 accessory proteins Nef and Vpu downregulate total and cell surface CD28 in CD4+ T cells

Specific Biological Features of Adipose Tissue, and Their Impact on HIV Persistence

Identification of an adaptor protein‐2 mu gene (AccAP2m) in Apis cerana cerana and its role in oxidative stress responses

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