AbstractHuman immunodeficiency virus type 1 (HIV-1) infection involves a selection bottleneck that leads to transmission of one or a few variants. C–C motif chemokine receptor 5 (CCR5) or C–X–C motif chemokine receptor 4 (CXCR4) can act as coreceptors for HIV-1 viral entry. However, initial infection mostly occurs via CCR5, despite abundant expression of CXCR4 on target cells.

摘要人类免疫缺陷病毒1型（HIV-1）感染涉及一个选择瓶颈，导致一种或几种变体的传播。C–C基序趋化因子受体5（CCR5）或C–X–C基序趋化因子受体4（CXCR4）可以作为HIV-1病毒进入的辅助受体。然而，尽管CXCR4在靶细胞上大量表达，但最初的感染主要通过CCR5发生。

The host factors that influence HIV-1 susceptibility and selection during transmission are unclear. Here we conduct CRISPR–Cas9 screens and identify SLC35A2 (a transporter of UDP–galactose expressed in target cells in blood and mucosa) as a potent and specific CXCR4-tropic restriction factor in primary target CD4+ T cells.

在传播过程中影响HIV-1易感性和选择的宿主因素尚不清楚。在这里，我们进行CRISPR-Cas9筛选，并将SLC35A2（血液和粘膜中靶细胞中表达的UDP-半乳糖的转运蛋白）鉴定为主要靶CD4+T细胞中有效且特异的CXCR4嗜性限制因子。

SLC35A2 inactivation, which resulted in truncated glycans, not only increased CXCR4-tropic infection levels but also decreased those of CCR5-tropic strains consistently. Single-cycle infections demonstrated that the effect is cell-intrinsic. These data support a role for a host protein that influences glycan structure in regulating HIV-1 infection.

导致截短聚糖的SLC35A2失活不仅增加了CXCR4热带感染水平，而且持续降低了CCR5热带菌株的感染水平。。这些数据支持宿主蛋白在调节HIV-1感染中影响聚糖结构的作用。

Host cell glycosylation may, therefore, affect HIV-1 selection during transmission in vivo..

因此，宿主细胞糖基化可能会在体内传播过程中影响HIV-1的选择。。

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Fig. 1: SLC35A2 is an X4-specific hit in a CRISPR-KO screen for HIV-1 restriction factors in primary CD4+ T cells.Fig. 2: SLC35A2 KO differentially impacts X4 and CCR5-tropic HIV-1.Fig. 3: SLC35A2 inactivation causes truncated glycans on host cells and impacts HIV-1 entry in a cell-intrinsic manner.Fig.

图1:SLC35A2是CRISPR-KO筛选原代CD4+T细胞中HIV-1限制因子的X4特异性命中。图2:SLC35A2 KO差异影响X4和CCR5热带HIV-1。图3:SLC35A2失活导致宿主细胞上截短的聚糖，并以细胞内在方式影响HIV-1进入。图。

4: SLC35A2 does not impact HIV-1 receptor or coreceptor expression.Fig. 5: Working model of the impact of CD4+ T cell glycosylation on HIV-1 infection..

4： SLC35A2不影响HIV-1受体或辅助受体的表达。图5:CD4+T细胞糖基化对HIV-1感染影响的工作模型。。

Data availability

数据可用性

Illumina sequencing reads from HIV-CRISPR screens can be accessed via the NCBI Sequence Read Archive (SRA BioProject ID PRJNA1111960). Data for all figures are provided as source data. Source data are provided with this paper.

可以通过NCBI序列读取档案（SRA BioProject ID PRJNA111960）访问来自HIV-CRISPR筛选的Illumina测序读数。所有数字的数据均作为源数据提供。本文提供了源数据。

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Download referencesAcknowledgementsWe thank the Fred Hutch Shared Resources Genomics and Bioinformatics Cores, particularly A. Dawson and E. Jensen for performing Illumina and Sanger sequencing, respectively; the Fred Hutch Center for Data Visualization, especially M. Zager, N. Thorpe and S.

下载参考文献致谢我们感谢Fred Hutch共享资源基因组学和生物信息学核心，特别是A.Dawson和E.Jensen分别进行了Illumina和Sanger测序；弗雷德·哈奇数据可视化中心，特别是M.Zager、N.Thorpe和S。

Minot, for their support with MAGeCK analysis; M. Emerman, M. Ohainle, C. Stoddard and A. Willcox for helpful discussions and technical assistance. We also thank M. Emerman (Division of Human Biology, Fred Hutchinson Cancer Center) for sharing LAI and VSV-G envelope plasmids with us. Figures 1a, 3a and 5 were generated with BioRender.

Minot，感谢他们对MAGeCK分析的支持；M、 Emerman，M.Ohainel，C.Stoddard和A.Willcox感谢他们的有益讨论和技术援助。我们还感谢M.Emerman（弗雷德·哈钦森癌症中心人类生物学系）与我们共享LAI和VSV-G包膜质粒。图1a，3a和5是用BioRender生成的。

This work was supported by the following NIH grants: NICHD R01 HD103571 to J.O. and NIGMS T32 GM007270 and NIAID F31 AI165168 to H.L.I. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.Author informationAuthor notesDaryl HumesPresent address: Tr1X Inc, La Jolla, CA, USAAuthors and AffiliationsMolecular and Cellular Biology PhD Program, University of Washington, Seattle, WA, USAHannah L.

这项工作得到了以下NIH资助的支持：NICHD R01 HD103571授予J.O.，NIGMS T32 GM007270和NIAID F31 AI165168授予H.L.I。资助者在研究设计，数据收集和分析，决定出版或准备手稿方面没有任何作用。作者信息作者注释Daryl HumesPresent地址：Tr1X Inc，美国加利福尼亚州拉霍亚作者和附属机构华盛顿大学分子与细胞生物学博士项目，华盛顿州西雅图，USAHannah L。

ItellDivision of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USAHannah L. Itell, Jamie Guenthoer, Daryl Humes, Nell E. Baumgarten & Julie OverbaughAuthorsHannah L. ItellView author publicationsYou can also search for this author in.

华盛顿州西雅图弗雷德·哈钦森癌症中心人类生物学系，USAHannah L.Itell，杰米·根索，达里尔·休姆斯，内尔·E·鲍姆加滕和朱莉·奥弗鲍豪索申纳L.ItellView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarJamie GuenthoerView author publicationsYou can also search for this author in

PubMed谷歌学者Jamie GuenthoerView作者出版物您也可以在

PubMed Google ScholarDaryl HumesView author publicationsYou can also search for this author in

PubMed Google ScholarDaryl HumesView作者出版物您也可以在

PubMed Google ScholarNell E. BaumgartenView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsJ.O. conceived the project and J.O., H.L.I., J.G. and D.H. designed the methodology of the study. H.L.I., J.G., D.H. and N.E.B. performed experiments. H.L.I., J.G. and D.H. conducted the data analysis, with the supervision of J.O. H.L.I. generated data visualizations.

PubMed谷歌学术贡献。O、 构思了该项目，J.O.，H.L.I.，J.G.和D.H.设计了研究方法。H、 L.I.，J.G.，D.H.和N.E.B.进行了实验。H、 在J.O.H.L.I.生成的数据可视化的监督下，L.I.，J.G.和D.H.进行了数据分析。

J.O. and H.L.I. wrote the paper with input from J.G., D.H. and N.E.B.Corresponding authorCorrespondence to.

J、 O.和H.L.I.根据J.G.，D.H.和N.E.B.的输入撰写了这篇论文。相应的作者回复。

Julie Overbaugh.Ethics declarations

Julie Overbaugh。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Peer review

同行评审

Peer review information

同行评审信息

Nature Microbiology thanks Nuria Izquierdo-Useros and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Nature Microbiology感谢Nuria Izquierdo Useros和其他匿名审稿人对这项工作的同行评审做出的贡献。同行评审报告可用。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 SLC35A2 KO has opposite effects on two HIV-1 strains that utilize different coreceptors, related to Figures 2b, 2c, and 3e.a.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据扩展数据图1 SLC35A2 KO对利用不同辅助受体的两种HIV-1菌株具有相反的作用，与图2b，2c和3e.a相关。

Independent experimental replicates for data depicted in Fig. 2b. Reverse transcriptase (RT) activity, relative (rel) to CD19 KO for each independent primary CD4+ T cell experiment, at 2 dpi (MOI=0.02). Knockouts were performed in five donors across independent knockout and infection experiments as indicated.

图2b所示数据的独立实验重复。对于每个独立的原代CD4+T细胞实验，逆转录酶（RT）活性相对于CD19 KO，在2 dpi（MOI=0.02）。如所示，在独立的敲除和感染实验中，在五个供体中进行了敲除。

b. Independent experimental replicates for data depicted in Fig. 2c. Percentage of CD4+ T cells staining positive for HIV-Gag at 3 dpi (MOI=1). Donor letters correspond with those in Panel A. c. Independent experimental replicates for data depicted in Fig. 3e. Percentage of GFP+ CD4+ T cells, relative to CD19 KO, after 2 days of infection with GFP-expressing HIV-1 pseudoviruses (MOI=1).

b、 图2c所示数据的独立实验重复。在3 dpi（MOI=1）时，HIV Gag染色阳性的CD4+T细胞百分比。供体字母与A.c组中的字母相对应。图3e所示数据的独立实验重复。在用表达GFP的HIV-1假病毒（MOI=1）感染2天后，相对于CD19 KO，GFP+CD4+T细胞的百分比。

Infection data from all panels are shown as the mean of 2-3 technical replicates, as indicated by individual data points.Source dataExtended Data Fig. 2 SLC35A2 KO differentially impacts CXCR4-tropic and CCR5-tropic HIV-1, related to Figure 2e.a. Percentage of CD4+ T cells staining positive for HIV-Gag, relative (rel) to CD19 KO, at 6 dpi (MOI=0.02, same infections as depicted in Fig.

如各个数据点所示，来自所有小组的感染数据显示为2-3个技术重复的平均值。来源数据扩展数据图2 SLC35A2 KO差异性地影响CXCR4热带和CCR5热带HIV-1，与图2e相关。a.在6 dpi（MOI=0.02，与图1所示相同的感染）时，HIV Gag染色阳性的CD4+T细胞相对于CD19 KO的百分比。

2e, different measurement of HIV-1 infection). b. RT activity over time from spreading infections (MOI=0.02) in primary CD4+ T cells from two donors to determine coreceptor tropism. Results are separated by expected coreceptor tropism. Donor numbering is consistent within this figure and with Fig. 2e.

2e，HIV-1感染的不同测量）。b、 随着时间的推移，RT活性从两个供体的原代CD4+T细胞中传播感染（MOI=0.02），以确定共受体的趋向性。结果由预期的共受体趋向性分开。供体编号在该图和图2e中是一致的。

Additional information on the strains used for infections is presented in Extended Data Tab.

扩展数据选项卡中提供了有关用于感染的菌株的其他信息。

Nat Microbiol (2024). https://doi.org/10.1038/s41564-024-01806-7Download citationReceived: 21 October 2023Accepted: 06 August 2024Published: 03 October 2024DOI: https://doi.org/10.1038/s41564-024-01806-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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