Natural HIV-1 Nef Polymorphisms Impair SERINC5 Downregulation Activity

Jin, Steven; Alsahafi, Nirmin; Kuang, Xiangyu; Swann, Shayda A.; Toyoda, Mako; Göttlinger, Heinrich G.; Walker, Bruce D.; Ueno, Takamasa; Finzi, Andrés; Brumme, Zabrina L.; Brockman, Mark A.

doi:10.1016/j.celrep.2019.10.007

Cited by 21 publications

(49 citation statements)

References 53 publications

(78 reference statements)

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“…In contrast, Nef-mediated HLA downregulation ranged from 0 to 99.8% between clones while SERINC5 downregulation ranged from 22.8 to 104.5%. Strong conservation of Nef-mediated CD4 downregulation, yet wider ranges for other functions mirrors observations from cross-sectional, population-based studies [37,44,46] and suggests that the latter type of study may benefit from isolating multiple Nef clones per participant for better representation. Thirdly, despite substantial within-host nef evolution, Nef-mediated CD4, HLA and SERINC5 downregulation functions and steady-state Nef protein expression levels were, on the whole, remarkably conserved, suggesting that a certain amount of selective pressure to preserve these Nef properties is maintained throughout infection [58,59].…”

Section: Discussionmentioning

confidence: 57%

“…To assess Nef-mediated internalization of SERINC5 from the cell surface, 1 × 10 6 CEM-A*02 T cells were co-transfected with 1 μg of pSELECT-GFPzeo encoding nef and 5 μg of pSELECT-SERINC5-internal HA tag (iHA)-∆GFP by electroporation in 150 μL OPTI-mem medium (Thermo Fisher), as described in [37]. The pSELECT-SERINC5-iHA-∆GFP was sub-cloned from the pBJ5-SERINC5(iHA) described in [32].…”

Section: Nef-mediated Cd4 Hla and Serinc5 Downregulation Assaysmentioning

confidence: 99%

“…More recently, Nef has been found to internalize the transmembrane host restriction factor Serine incorporator 5 (SERINC5), thereby preventing its inclusion into budding HIV virions and enhancing viral infectivity [31,32]. We and others have observed that all three of these functions are attenuated in Nef clones isolated from HIV elite controllers who spontaneously suppress plasma viremia to < 50 RNA copies/mL in the absence of therapy [33][34][35][36][37], suggesting that variation in Nef activity contributes to biologic outcomes.…”

Section: Introductionmentioning

confidence: 98%

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Longitudinal within-host evolution of HIV Nef-mediated CD4, HLA and SERINC5 downregulation activity: a case study

et al. 2020

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The HIV accessory protein Nef downregulates the viral entry receptor CD4, the Human Leukocyte Antigen (HLA)-A and-B molecules, the Serine incorporator 5 (SERINC5) protein and other molecules from the infected cell surface, thereby promoting viral infectivity, replication and immune evasion. The nef locus also represents one of the most genetically variable regions in the HIV genome, and nef sequences undergo substantial evolution within a single individual over the course of infection. Few studies however have simultaneously characterized the impact of withinhost nef sequence evolution on Nef protein function over prolonged timescales. Here, we isolated 50 unique Nef clones by single-genome amplification over an 11-year period from the plasma of an individual who was largely naïve to antiretroviral treatment during this time. Together, these clones harbored nonsynonymous substitutions at 13% of nef's codons. We assessed their ability to downregulate cell-surface CD4, HLA and SERINC5 and observed that all three Nef functions declined modestly over time, where the reductions in CD4 and HLA downregulation (an average of 0.6% and 2.0% per year, respectively) achieved statistical significance. The results from this case study support all three Nef activities as being important to maintain throughout untreated HIV infection, but nevertheless suggest that, despite nef's mutational plasticity, within-host viral evolution can compromise Nef function, albeit modestly, over prolonged periods.

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Section: Discussionmentioning

confidence: 57%

Section: Nef-mediated Cd4 Hla and Serinc5 Downregulation Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Longitudinal within-host evolution of HIV Nef-mediated CD4, HLA and SERINC5 downregulation activity: a case study

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“…We determine the frequency of genetic polymorphisms in accessory (Vif, Vpr, Nef) and regulatory (Rev) HIV-1 proteins of B PANDEMIC and FL/expanded B CAR datasets that were previously associated with slow HIV-1 disease progression and differential function [39][40][41][42][43][44][45][46][47][48][49][50]. The Geno2Pheno algorithm was used to predict the chemokine receptor tropism of the B PANDEMIC and expanded B CAR env dataset sequences based on their V3 region [51].…”

Section: Phenotypic Predictionmentioning

confidence: 99%

“…The sole exception was position 23, located in Tat cysteine-rich domain (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37), and reported as one of the three major sites of p53-derived restriction of Tat mediated by PKR phosphorylation [67]. We also evaluate the frequency of several polymorphisms in Vif, Vpr, Nef and Rev previously associated with long-term non-progressors (LTNPs) HIV-1 infected subjects and differential protein function in vitro and ex vivo [39][40][41][42][43][44][45][46][47][48][49][50] (Table 4). Analysis of amino acid composition at those positions failed to detect significant differences between B CAR and B PANDEMIC datasets, except for position 77 in Vpr that showed a significantly higher prevalence of the R77Q mutation in B CAR (83%) in comparison with B PANDEMIC (48%) sequences [45].…”

Section: Predicted Phenotypic Characteristics Of B Car and B Pandemicmentioning

confidence: 99%

Few amino acid signatures distinguish HIV-1 subtype B pandemic and non-pandemic strains

et al. 2020

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The Human Immunodeficiency Virus Type I (HIV-1) subtype B comprises approximately 10% of all HIV infections in the world. The HIV-1 subtype B epidemic comprehends a pandemic variant (named B PANDEMIC) disseminated worldwide and non-pandemic variants (named B CAR) that are mostly restricted to the Caribbean. The goal of this work was the identification of amino acid signatures (AAs) characteristic to the B CAR and B PANDEMIC variants. To this end, we analyzed HIV-1 subtype B full-length (n = 486) and partial (n = 814) genomic sequences from the Americas classified within the B CAR and B PANDEMIC clades and reconstructed the sequences of their most recent common ancestors (MRCA). Analysis of contemporary HIV-1 sequences revealed 13 AAs between B CAR and B PANDEMIC variants (four on Gag, three on Pol, three on Rev, and one in Vif, Vpu, and Tat) of which only two (one on Gag and one on Pol) were traced to the MRCA. All AAs correspond to polymorphic sites located outside essential functional proteins domains, except the AAs in Tat. The absence of stringent AAs inherited from their ancestors between modern B CAR and B PANDEMIC variants support that ecological factors, rather than viral determinants, were the main driving force behind the successful spread of the B PANDEMIC strain.

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Consequences of HLA‐associated mutations in HIV‐1 subtype C Nef on HLA‐I downregulation ability

Mann

Rajkoomar

Jin

et al. 2020

Journal of Medical Virology

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Identification of CD8+ T lymphocyte (CTL) escape mutations that compromise the pathogenic functions of the Nef protein may be relevant for an HIV-1 attenuation-based vaccine. Previously, HLA-associated mutations 102H, 105R, 108D, and 199Y were individually statistically associated with decreased Nef-mediated HLA-I downregulation ability in a cohort of 298 HIV-1 subtype C infected individuals. In the present study, these mutations were introduced by site-directed mutagenesis into different patient-derived Nef sequence backgrounds of high similarity to the consensus C Nef sequence, and their ability to downregulate HLA-I was measured by flow cytometry in a CEM-derived T cell line. A substantial negative effect of 199Y on HLA-I downregulation and Nef expression was observed, while 102H and 105R displayed negative effects on HLA-I downregulation ability and Nef expression to a lesser extent. The total magnitude of CTL responses in individuals harboring the 199Y mutation was lower than those without the mutation, although this was not statistically significant. Overall, a modest positive relationship between Nef-mediated HLA-I downregulation ability and total magnitude of CTL responses was observed, suggesting that there is a higher requirement for HLA-I downregulation with increased CTL pressure. These results highlight a region of Nef that could be targeted by vaccine-induced CTL to reduce HLA-I downregulation and maximize CTL efficacy.

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Natural HIV-1 Nef Polymorphisms Impair SERINC5 Downregulation Activity

Cited by 21 publications

References 53 publications

Longitudinal within-host evolution of HIV Nef-mediated CD4, HLA and SERINC5 downregulation activity: a case study

Longitudinal within-host evolution of HIV Nef-mediated CD4, HLA and SERINC5 downregulation activity: a case study

Few amino acid signatures distinguish HIV-1 subtype B pandemic and non-pandemic strains

Consequences of HLA‐associated mutations in HIV‐1 subtype C Nef on HLA‐I downregulation ability

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