Exploiting a rodent cell block for intrinsic resistance to HIV-1 gene expression in human T cells

Unlike humans, mice are unable to support HIV-1 infection. This is due, in part, to a constellation of defined minor, species-specific differences in conserved host proteins needed for viral gene expression. Here, we used precision CRISPR/Cas9 gene editing to engineer a "mousified" version...

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Published in:mBio 2023-10, Vol.14 (5), p.e0042023
Main Authors: Behrens, Ryan T, Rajashekar, Jyothi Krishnaswamy, Bruce, James W, Evans, 3rd, Edward L, Hansen, Amelia M, Salazar-Quiroz, Natalia, Simons, Lacy M, Ahlquist, Paul, Hultquist, Judd F, Kumar, Priti, Sherer, Nathan M
Format: Article
Language:English
Subjects:
CCNT1
Cyclin T1
human immunodeficiency virus
lentiviruses
nuclear export
Research Article
transcription
Virology
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Summary:Unlike humans, mice are unable to support HIV-1 infection. This is due, in part, to a constellation of defined minor, species-specific differences in conserved host proteins needed for viral gene expression. Here, we used precision CRISPR/Cas9 gene editing to engineer a "mousified" version of one such host protein, cyclin T1 (CCNT1), in human T cells. CCNT1 is essential for efficient HIV-1 transcription, making it an intriguing target for gene-based inactivation of virus replication. We show that isogenic cell lines engineered to encode CCNT1 bearing a single mouse-informed amino acid change (tyrosine in place of cysteine at position 261) exhibit potent, durable, and broad-spectrum resistance to HIV-1 and other pathogenic lentiviruses, and with no discernible impact on host cell biology. These results provide proof of concept for targeting in the context of one or more functional HIV-1 cure strategies.
ISSN:2150-7511
2150-7511
DOI:10.1128/mbio.00420-23