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

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

doi:10.3390/v13030423

Zita Kruize, Karel A Van Dort + Show 5 more

Open Access

https://doi.org/10.3390/v13030423

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Abstract

Nef is a multifunctional viral protein that has the ability to downregulate cell surface molecules, including CD4 and major histocompatibility complex class I (MHC-I) and, as recently shown, also members of the serine incorporator family (SERINC). Here, we analyzed the impact of naturally occurring mutations in HIV-1 Nef on its ability to counteract SERINC restriction and the clinical course of infection. HIV-1 Nef sequences were obtained from 123 participants of the Amsterdam Cohort Studies and showed multiple amino acid variations and mutations. Most of the primary Nef proteins showed increased activity to counteract SERINC3 and SERINC5 as compared to NL4-3 Nef. Several mutations in Nef were associated with either an increased or decreased infectivity of Bal26-pseudotyped HIV-1 produced in the presence of SERINC3 or SERINC5. The 8R, 157N and R178G Nef mutations were shown to have an effect on disease progression. Survival analysis showed an accelerated disease progression of individuals infected with HIV-1 carrying arginine or asparagine at position 8 or 157 in Nef, respectively, or the R178G Nef mutation. Here, we observed that naturally occurring mutations in Nef affect the ability of Nef to counteract SERINC3- and SERINC5-mediated inhibition of viral infectivity. The majority of these Nef mutations had no significant effect on HIV-1 pathogenesis and only the 8R, 157N and R178G mutations were associated with disease course.

Highlights

Nef is a 27–32-kilodalton accessory protein encoded by HIV-1 and other primate lentiviruses
Recent reports demonstrated that three specific sites in Nef, the amino acids 12 to
We analyzed primary Nef proteins obtained from 123 individuals with HIV-1 participating in the Amsterdam Cohort Studies for amino acid changes at the previously described positions and regions as compared to consensus B (Supplementary Table S1)

Summary

Introduction

Nef is a 27–32-kilodalton (kDa) accessory protein encoded by HIV-1 and other primate lentiviruses. Nef is a multifunctional viral protein that has the ability to downregulate cell surface molecules, including CD4, major histocompatibility complex class I (MHC-I) and Tcell receptor, via clathrin-dependent endocytosis and subsequent lysosomal degradation [1]. Nef’s ability to internalize CD4 and MHC-I from an infected cell surface allows HIV-1 to evade antibody-dependent cellular cytotoxicity (ADCC) and cytotoxic T lymphocytes (CTLs) [2,3,4,5]. Nef-mediated enhancement of viral infectivity was recently shown to be due, in part, to its ability to counteract members of the serine incorporator family (SERINC). SERINC5 can be incorporated in the membrane of progeny virions, which subsequently inhibits infection of new target cells at the level of membrane fusion [11]. HIV-1 Nef has been shown to prevent SERINC5 incorporation into the virion and counteracts the SERINC5-mediated restriction.

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