HIVが体内の炎症経路を引き起こしてT細胞を死滅させることを発見(HIV triggers body’s own inflammatory pathways to kill T cells)

2024-05-07

2024-05-03 ワシントン大学セントルイス校

セントルイスにあるワシントン大学医学部の研究者たちは、HIVに対する体の免疫応答がこのウイルス感染で特徴的なT細胞の死を引き起こす原因であることを特定しました。この研究は、HIV治療の新たな戦略に光を当てる可能性があります。HIV感染は体内のCARD8インフラマソームと呼ばれる炎症分子を活性化し、T細胞を徐々に枯渇させます。CARD8インフラマソームを不活性化することで、HIV感染中のT細胞の死を防ぐことができることが分かりました。この発見は、「Cell」誌に掲載されています。

<関連情報>

HIV/SIVの病態と病勢進行を規定するCARD8インフラマソーム The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression

Qiankun Wang,Kolin M. Clark,Ritudhwaj Tiwari,…,Tricia H. Burdo,Guido Silvestri,Liang Shan
Cell Published:February 29, 2024
DOI:https://doi.org/10.1016/j.cell.2024.01.048

Highlights

HIV induces rapid CD4⁺ T cell loss by activating the CARD8 inflammasome
HIV protease encapsulated in viral particles is detected by CARD8 during viral entry
CARD8 activation contributes to the progression of disease in HIV infection
The “natural” hosts of SIV have acquired loss-of-function mutations in CARD8

Summary

While CD4⁺ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of “natural” hosts such as sooty mangabeys does not cause CD4⁺ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4⁺ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from “natural hosts,” which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4⁺ T cell depletion during pathogenic HIV/SIV infections.