Human immunodeficiency virus type 1 (HIV-1) infection of dividing and nondividing cells involves regulatory interactions with the nuclear pore complex (NPC), followed by translocation to the nucleus and preferential integration into genomic areas in proximity to the inner nuclear membrane (INM). To identify host proteins that may contribute to these processes, we performed an overexpression screen of known membrane-associated NE proteins. We found that the integral transmembrane proteins SUN1/UNC84A and SUN2/UNC84B are potent or modest inhibitors of HIV-1 infection, respectively, and that suppression corresponds to defects in the accumulation of viral cDNA in the nucleus. While laboratory strains (HIV-1_NL4.3 and HIV-1_IIIB) are sensitive to SUN1-mediated inhibition, the transmitted founder viruses RHPA and ZM247 are largely resistant. Using chimeric viruses, we identified the HIV-1 capsid (CA) protein as a major determinant of sensitivity to SUN1, and in vitro-assembled capsid-nucleocapsid (CANC) nanotubes captured SUN1 and SUN2 from cell lysates. Finally, we generated SUN1^−/− and SUN2^−/− cells by using CRISPR/Cas9 and found that the loss of SUN1 had no effect on HIV-1 infectivity, whereas the loss of SUN2 had a modest suppressive effect. Taken together, these observations suggest that SUN1 and SUN2 may function redundantly to modulate postentry, nuclear-associated steps of HIV-1 infection.

IMPORTANCE HIV-1 causes more than 1 million deaths per year. The life cycle of HIV-1 has been studied extensively, yet important steps that occur between viral capsid release into the cytoplasm and the expression of viral genes remain elusive. We propose here that the INM components SUN1 and SUN2, two members of the linker of nucleoskeleton and cytoskeleton (LINC) complex, may interact with incoming HIV-1 replication complexes and affect key steps of infection. While overexpression of these proteins reduces HIV-1 infection, disruption of the individual SUN2 and SUN1 genes leads to a mild reduction or no effect on infectivity, respectively. We speculate that SUN1/SUN2 may function redundantly in early HIV-1 infection steps and therefore influence HIV-1 replication and pathogenesis.

人类免疫缺陷病毒 1 型 (HIV-1) 感染分裂和非分裂细胞涉及与核孔复合体 (NPC) 的调节相互作用，随后易位至细胞核并优先整合到靠近内核膜 (INM) 的基因组区域. 为了识别可能有助于这些过程的宿主蛋白，我们对已知的膜相关 NE 蛋白进行了过表达筛选。我们发现完整的跨膜蛋白 SUN1/UNC84A 和 SUN2/UNC84B 分别是 HIV-1 感染的有效或适度抑制剂，并且这种抑制对应于细胞核中病毒 cDNA 积累的缺陷。而实验室毒株（HIV-1 _NL4.3和 HIV-1 _IIIB) 对 SUN1 介导的抑制敏感，传播的创始病毒 RHPA 和 ZM247 在很大程度上具有抗性。使用嵌合病毒，我们将 HIV-1 衣壳 (CA) 蛋白鉴定为对 SUN1 敏感性的主要决定因素，体外组装的衣壳-核衣壳 (CANC) 纳米管从细胞裂解物中捕获 SUN1 和 SUN2。最后，我们使用 CRISPR/Cas9 生成了 SUN1 ^-/-和SUN2 ^-/-细胞，发现 SUN1 的缺失对 HIV-1 的感染性没有影响，而 SUN2 的缺失具有适度的抑制作用。总之，这些观察结果表明 SUN1 和 SUN2 可能在调节 HIV-1 感染的进入后、核相关步骤中发挥冗余作用。

重要性HIV-1 每年导致超过 100 万人死亡。HIV-1 的生命周期已被广泛研究，但在病毒衣壳释放到细胞质和病毒基因表达之间发生的重要步骤仍然难以捉摸。我们在此提出 INM 组件 SUN1 和 SUN2 是核骨架和细胞骨架 (LINC) 复合物接头的两个成员，可能与传入的 HIV-1 复制复合物相互作用并影响感染的关键步骤。虽然这些蛋白质的过表达减少了 HIV-1 感染，但个体SUN2和SUN1的破坏基因分别导致对传染性的轻微降低或没有影响。我们推测 SUN1/SUN2 可能在早期 HIV-1 感染步骤中发挥冗余作用，因此影响 HIV-1 复制和发病机制。