The majority of HIV infections are established through the genital or rectal mucosa. Fibroblasts are abundant in these tissues, and although not susceptible to infection, can potently enhance HIV infection of CD4+ T cells. Hyaluronic acid (HA) is a major component of the extracellular matrix of fibroblasts, and its levels are influenced by the inflammatory state of the tissue. Since inflammation is known to facilitate HIV sexual transmission, we investigated the role of HA in genital mucosal fibroblast-mediated enhancement of HIV infection. Depletion of HA by CRISPR-Cas9 in primary foreskin fibroblasts augmented the ability of the fibroblasts to increase HIV infection of CD4+ T cells. This amplified enhancement required direct contact between the fibroblasts and CD4+ T cells, and could be attributed to both increased rates of trans-infection and the increased ability of HA-deficient fibroblasts to push CD4+ T cells into a state of higher permissivity to infection. This HIV-permissive state was characterized by differential expression of genes associated with regulation of cell metabolism and death. Our results suggest that conditions resulting in diminished cell-surface HA on fibroblasts, such as genital inflammation, can promote HIV transmission by conditioning CD4+ T cells toward a state more vulnerable to infection by HIV.

大多数 HIV 感染是通过生殖器或直肠粘膜建立的。这些组织中有丰富的成纤维细胞，虽然不易感染，但可以有效增强 CD4+ T 细胞的 HIV 感染。透明质酸 (HA) 是成纤维细胞细胞外基质的主要成分，其水平受组织炎症状态的影响。由于已知炎症会促进 HIV 性传播，我们研究了 HA 在生殖器粘膜成纤维细胞介导的 HIV 感染增强中的作用。CRISPR-Cas9 在原代包皮成纤维细胞中消耗 HA 增强了成纤维细胞增加 CD4+ T 细胞的 HIV 感染的能力。这种放大的增强需要成纤维细胞和 CD4+ T 细胞之间的直接接触，并且可以归因于反式感染和缺乏 HA 的成纤维细胞将 CD4+ T 细胞推入更高感染允许状态的能力增强。这种 HIV 允许状态的特点是与细胞代谢和死亡调节相关的基因表达差异。我们的研究结果表明，导致成纤维细胞表面 HA 减少的情况（例如生殖器炎症）可以通过将 CD4+ T 细胞调节到更容易被 HIV 感染的状态来促进 HIV 传播。