Nef Obtained from Individuals with HIV-1 Vary in Their Ability to Antagonize SERINC3- and SERINC5-Mediated HIV-1 Restriction

Kruize, Zita; Nuenen, Ad C. van; Wijk, Stan W. van; Girigorie, Arginell F.; Dort, Karel A. van; Booiman, Thijs; Kootstra, Neeltje A.

doi:10.3390/v13030423

Cited by 7 publications

(4 citation statements)

References 73 publications

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“…The allelic variability of Nef observed in different isolates has proven instrumental for defining molecular determinants contributing to the ability of the viral protein to counteract SERINC5 [ 16 , 27 , 28 , 29 , 30 ]. Similarly, in this study, a nef allele derived from a subtype H isolate with defective SERINC5 downregulation activity has been used to identify an unusual polymorphism in position 150, which affects both SERINC5 counteraction and CD4 downregulation.…”

Section: Discussionmentioning

confidence: 99%

A Conserved Acidic Residue in the C-Terminal Flexible Loop of HIV-1 Nef Contributes to the Activity of SERINC5 and CD4 Downregulation

Firrito

Bertelli

Rosa

et al. 2023

Viruses

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The host transmembrane protein SERINC5 is incorporated into retrovirus particles and inhibits HIV-1 infectivity. The lentiviral Nef protein counteracts SERINC5 by downregulating it from the cell surface and preventing its incorporation into virions. The ability of Nef to antagonize the host factor varies in magnitude between different HIV-1 isolates. After having identified a subtype H nef allele unable to promote HIV-1 infectivity in the presence of SERINC5, we investigated the molecular determinants responsible for the defective counteraction of the host factor. Chimeric molecules with a subtype C Nef highly active against SERINC5 were constructed to locate Nef residues crucial for the activity against SERINC5. An Asn at the base of the C-terminal loop of the defective nef allele was found in place of a highly conserved acidic residue (D/E 150). The conversion of Asn to Asp restored the ability of the defective Nef to downregulate SERINC5 and promote HIV-1 infectivity. The substitution was also found to be crucial for the ability of Nef to downregulate CD4, but not for Nef activities that do not rely on the internalization of receptors from the cell surface, suggesting a general implication in promoting clathrin-mediated endocytosis. Accordingly, bimolecular fluorescence complementation revealed that the conserved acidic residue contributes to the recruitment of AP2 by Nef. Altogether, our results confirm that Nef downregulates SERINC5 and CD4 by engaging a similar machinery and indicates that, in addition to the di-leucine motif, other residues in the C-terminal flexible loop are important for the ability of the protein to sustain clathrin-mediated endocytosis.

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Section: Discussionmentioning

confidence: 99%

A Conserved Acidic Residue in the C-Terminal Flexible Loop of HIV-1 Nef Contributes to the Activity of SERINC5 and CD4 Downregulation

Firrito

Bertelli

Rosa

et al. 2023

Viruses

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“…The ability of Nef to counteract SER3 and SER5 varies among patients living with HIV-1. While most of the Nef proteins were capable of strongly antagonizing SER3 and SER5, some mutations were associated with a better counteraction of SER3 (N51T, H116N, and 188S) and SER5 (S163C) by increasing the HIV-1 infectivity [ 78 ]. The counteraction of SER5 by Nef was also associated with a lower viremia in HIV-1 infected patients [ 79 ].…”

Section: Nef Counteracts Serinc5mentioning

confidence: 99%

HIV-1 restriction by SERINC5

Cano-Ortiz

Luedde

Münk

2022

Med Microbiol Immunol

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Serine incorporator 5 (SERINC5 or SER5) is a multipass transmembrane protein with ill-defined cellular activities. SER5 was recently described as a human immunodeficiency virus 1 (HIV-1) restriction factor capable of inhibiting HIV-1 that does not express its accessory protein Nef (Δ Nef). SER5 incorporated into the viral membrane impairs the entry of HIV-1 by disrupting the fusion between the viral and the plasma membrane after envelope receptor interaction induced the first steps of the fusion process. The mechanisms of how SER5 prevents membrane fusion are not fully understood and viral envelope proteins were identified that escape the SER5-mediated restriction. Primate lentiviruses, such as HIV-1 and simian immunodeficiency viruses (SIVs), use their accessory protein Nef to downregulate SER5 from the plasma membrane by inducing an endocytic pathway. In addition to being directly antiviral, recent data suggest that SER5 is an important adapter protein in innate signaling pathways leading to the induction of inflammatory cytokines. This review discusses the current knowledge about HIV-1 restriction by SER5.

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“…Schoues et al further demonstrated that the variation of each residue within the range of positions 195-203 in Nef could affect anti-SERINC activity, which is driven by CD8TL (Schouest et al, 2018). Naturally occurring mutations in Nef also affect its ability to resist the inhibition of viral infection by SERINC3 and SERINC5, thus influencing the viral load in plasma (Toyoda et al, 2020;Kruize et al, 2021). Similarly, the antagonistic activity of SERINC3 and SERINC5 varies markedly among circulating Nef isolates and between viral subtypes, indicating that variation in Nef-mediated SERINC antagonism may lead to differences in pathogenesis among HIV subtypes (Jin et al, 2020).…”

Section: Serinc Proteins and Antagonistic Retroviral Factorsmentioning

confidence: 99%

The Emerging Role of the Serine Incorporator Protein Family in Regulating Viral Infection

Zheng

Pathak

et al. 2022

Front. Cell Dev. Biol.

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Serine incorporator (SERINC) proteins 1–5 (SERINC1-5) are involved in the progression of several diseases. SERINC2-4 are carrier proteins that incorporate the polar amino acid serine into membranes to facilitate the synthesis of phosphatidylserine and sphingolipids. SERINC genes are also differentially expressed in tumors. Abnormal expression of SERINC proteins occurs in human cancers of the breast, lung, colon, liver, and various glands, as well as in mouse testes. SERINC proteins also affect cleft lip and palate and nerve-related diseases, such as seizure Parkinsonism and borderline personality. Moreover, SERINC proteins have garnered significant interest as retroviral restriction factors, spurring efforts to define their function and elucidate the mechanisms through which they operate when associated with viruses. Human SERINC proteins possess antiviral potential against human immunodeficiency virus (HIV), SARS-COV-2, murine leukemia virus (MLV), equine infectious anemia virus (EIAV), and hepatitis B virus (HBV). Furthermore, the crystal structure is known, and the critical residues of SERINC5 that act against HIV have been identified. In this review, we discuss the most prevalent mechanisms by which SERINC3 and SERINC5 antagonize viruses and focus on the potential therapeutic applications of SERINC5/3 against HIV.

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Nef Obtained from Individuals with HIV-1 Vary in Their Ability to Antagonize SERINC3- and SERINC5-Mediated HIV-1 Restriction

Cited by 7 publications

References 73 publications

A Conserved Acidic Residue in the C-Terminal Flexible Loop of HIV-1 Nef Contributes to the Activity of SERINC5 and CD4 Downregulation

A Conserved Acidic Residue in the C-Terminal Flexible Loop of HIV-1 Nef Contributes to the Activity of SERINC5 and CD4 Downregulation

HIV-1 restriction by SERINC5

The Emerging Role of the Serine Incorporator Protein Family in Regulating Viral Infection

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