Abstract
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.
Highlights
The Human Immunodeficiency Virus Type 1 (HIV-1) accessory proteins Nef and Vpu alter cell surface levels of multiple host proteins to modify the immune response and increase viral persistence
The HIV‐1 accessory proteins Nef and Vpu downregulate cell surface and total CD28 protein levels The co-stimulatory molecule CD28 is essential for immune cell activation and proliferation of naïve and memory T cells [2]
To investigate the effects of the HIV-1 accessory proteins Nef and Vpu on endogenous CD28 levels, CD4+ Sup-T1 T cells were infected with Gag-Pol truncated, VSV-G pseudotyped and eGFP expressing HIV-1 NL4.3 viruses encoding both Nef and Vpu (NL4.3), Vpu alone, Nef alone, or neither accessory protein
Summary
The 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, the mechanism of this function has not been completely elucidated. Viruses inhibit signaling downstream of co-stimulatory receptors, or alter the levels of cell surface co-stimulatory or inhibitory molecules [13,14,15,16]. The importance of viral alterations to immune cell activation are evidenced by the specific HIV-1 proteins that play key roles in T cell activation
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.