SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef


HIV-1 Nef and the unrelated mouse leukaemia virus glycosylated Gag (glycoGag) strongly enhance the infectivity of HIV-1 virions produced in certain cell types in a clathrin-dependent manner. Here we show that Nef and glycoGag prevent the incorporation of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and SERINC5 into HIV-1 virions to an extent that correlates with infectivity enhancement. Silencing of both SERINC3 and SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. The infectivity of nef-deficient virions increased more than 100-fold when produced in double-knockout human CD4+ T cells that lack both SERINC3 and SERINC5, and re-expression experiments confirmed that the absence of SERINC3 and SERINC5 accounted for the infectivity enhancement. Furthermore, SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. SERINC3 and SERINC5 are highly expressed in primary human HIV-1 target cells, and inhibiting their downregulation by Nef is a potential strategy to combat HIV/AIDS.

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Figure 1: Inhibition of incorporation of SERINC proteins into HIV-1 virions by Nef correlates with infectivity enhancement.
Figure 2: Effects of exogenous SERINCs on HIV-1 infectivity.
Figure 3: Effects of depleting SERINCs in virus producer cells.
Figure 4: Effects of SERINC knockout and reconstitution on HIV-1 infectivity.
Figure 5: Nef counteracts inhibition of HIV-1 replication by SERINC3 and SERINC5.


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We thank J. Leszyk and S. Shaffer for protein microsequencing, BGI Americas for RNA-seq, R. Maehr for sgRNA and Cas9 expression plasmids, J. Sodroski for HIVec2.GFP, T. Akagi for pCXbsr, and the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH for p89.6, indinavir, maraviroc, the monoclonal antibodies 183-H12-5C and Chessie 8, and TZM-bl cells. This work was supported by NIAID/NIH grant R01AI029873 and by NIDA/NIH grant DP1DA038034.

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Y.U., Y.W. and H.G.G. designed the experiments and analysed the data. Y.U. carried out the analysis of virions and the SERINC overexpression and depletion experiments. Y.W. generated and characterized the SERINC knockout cells, carried out all experiments involving knockout cells and primary cells, and performed the qRT–PCR experiments and the BlaM-Vpr-based fusion assays. H.G.G. wrote the manuscript.

Corresponding author

Correspondence to Heinrich G. Göttlinger.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Identification of SERINC3 as a candidate target of Nef and glycoGag.

a, Anti-HIV-1 CA immunoblot of Nef+, Nef and glycoMA+ HIV-1 virions collected from the indicated fractions of OptiPrep gradients. b, Proteins identified by mass spectrometry in Nef but not in Nef+ or glycoMA+ virion lysates. The data are from two independent experiments.

Extended Data Figure 2 MLV glycoGag inhibits the incorporation of SERINC3 and SERINC5 into HIV-1 virions.

a, b, Western blots showing the effects of wild-type or mutant glycoMA on the incorporation of SERINC3–HA (a) or SERINC5–HA (b) into Nef HIV-1 virions. The NL4-3/glycoMA proviral construct expresses untagged glycoMA in cis. In all other cases, HA-tagged (a) or Flag-tagged (b) glycoMA proteins were expressed in trans. The white bands marked by asterisks are caused by co-migrating HIV-1 Pr55gag. Both experiments were performed twice.

Extended Data Figure 3 Nef and glycoGag downregulate SERINC5 from the cell surface.

a, SERINC5 re-localizes from the plasma membrane to perinuclear vesicles in the presence of glycoGag. HeLa or U2-OS cells transiently expressing SERINC5–mCherry alone or together with glycoGag were examined by live-cell fluorescence microscopy. b, Nef and glycoGag both downregulate SERINC5. JTAg cells transiently expressing SERINC5(iHA), either alone or together with NefSF2 or glycoGag, were surface-stained with anti-HA antibody and analysed by flow cytometry. Per cent fractions of cells expressing SERINC5(iHA) on the surface are indicated. This experiment was performed twice.

Extended Data Figure 4 SERINC mRNA expression levels.

a, Expression of SERINC family members in uninfected and HIV-infected Jurkat E6.1 cells. RNA was extracted at the peak of infection with wild-type (Nef+) or Nef HIV-1NL43, and gene expression was quantified by RNA-seq as reads per kilobase of coding sequence per million reads (RPKM) (n = 1). The HIV-1 budding factor TSG101 and the housekeeping gene HPRT1 are included for comparison. b, Levels of SERINC3 and SERINC5 mRNA (arbitrary units) in cell lines and primary cells, as measured by qRT–PCR (n = 3). PBMC were left unstimulated or stimulated with 0.5 μg ml−1 phytohemagglutinin (PHA) and 20 U ml−1 IL-2 for 2 days. c, SERINC5 mRNA expression is not induced by INF-α. PBMC were left untreated or treated with 1,000 U ml−1 human INF-α 2a (PBL Assay Science) for 14 h (n = 2). Data are mean and s.d. NS, not significant (P > 0.05) two-tailed unpaired t-test.

Extended Data Figure 5 Exogenous SERINC5 inhibits the fusion of progeny virions with target cells.

TZM-bl or A549/CD4/CXCR4 cells were exposed to equal amounts of virus containing BlaM-Vpr, and fusion was analysed by measuring the Env-dependent increase in blue fluorescence using multiparameter flow cytometry. Virions were produced in 293T cells transfected with an Env HIV-1 provirus, a vector expressing EnvHXB2 (Env+) or a frameshift mutant (Env), a vector expressing BlaM-Vpr, and a vector expressing SERINC5 (1 μg or 100 ng) or an equimolar amount of the empty vector (0.7 μg or 70 ng). The percentage of cells displaying increased blue fluorescence is indicated.

Extended Data Figure 6 Exogenous SERINC5 reduces the infectivity of Nef HIV-1 progeny virions for primary target cells.

In two independent experiments, PHA-stimulated PBMC from different donors were infected with equal amounts of single-cycle GFP–HIV-1 virions produced in 293T cells in the absence or presence of exogenous SERINC5. Per cent fractions of infected (GFP-positive) cells are indicated.

Extended Data Figure 7 SERINC5 incorporation into HIV-1 virions that differ in Nef responsiveness.

Recombinant virions were produced in 293T cells co-transfected with the HXB/Env/Nef provirus and vectors expressing the poorly Nef-responsive EnvJRFL or the highly Nef-responsive JR(SF V1/V2) Env chimaera, along with a vector expressing SERINC5–HA. Empty pBJ5 vector or a version expressing HA-tagged Nef97ZA012 was also co-transfected. SERINC5–HA in purified virions was detected by western blotting. This experiment was performed twice.

Extended Data Figure 8 Characterization of JTAg knockout cells.

a, Mutant SERINC3 alleles identified in SERINC3 knockout clones. b, Mutant SERINC5 alleles identified in SERINC5 knockout and SERINC3/5 double-knockout clones. The single-guide RNA (sgRNA) target sites are highlighted, and the predicted Cas9 target sites are indicated by arrowheads. Inserted nucleotides are in red. One of the two mutated SERINC5 alleles in JTAg S3−/− S5−/− (1) cells has an inversion between sgRNA target sites A and B. JTAg S5−/− (2) cells contain three mutated SERINC5 alleles. All mutations cause frameshifts and/or large deletions of coding sequence. No wild-type alleles were detected in any of the knockout clones.

Extended Data Figure 9 SERINC3 and SERINC5 expression levels in reconstituted double-knockout cells

a, SERINC3 protein levels in parental, double-knockout, and reconstituted double-knockout JTAg cells were compared by western blotting. SERINC3 migrated close to a prominent background band that was also recognized by the anti-SERINC3 antibody. b, SERINC5 mRNA levels in parental and reconstituted double-knockout JTAg cells were compared by qRT–PCR (n = 3).

Extended Data Figure 10 Effects of SERINC knockout and reconstitution on HIV-1 replication.

Parental, double-knockout and SERINC3+SERINC5-reconstituted double-knockout CD4high JTAg cells were analysed by immunoblotting with anti-HIV CA at days 9 and 11 after infection with equal amounts (2 ng ml−1p24) of HIV-1NL43 encoding either wild-type or disrupted versions of NefNL43 or Nef97ZA012.

Supplementary information

Supplementary Figure 1

The file contains the full scans of Western blot data with molecular weight markers for Figures 1a, 1b, 2b, 2e, 3a, 3f, 5a, 5b and Extended Data Figures 1a, 2a, 2b, 7, 9a and 10. (PDF 1387 kb)

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Usami, Y., Wu, Y. & Göttlinger, H. SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef. Nature 526, 218–223 (2015).

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