Abstract
TGF-β plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent the main cellular reservoir after long-term antiretroviral therapy (ART). We hypothesized that releasing cells from TGF-β–driven signaling would promote latency reversal. To test our hypothesis, we compared HIV-1 latency models with and without TGF-β and a TGF-β type 1 receptor inhibitor, galunisertib. We tested the effect of galunisertib in SIV-infected, ART-treated macaques by monitoring SIV-env expression via PET/CT using the 64Cu-DOTA-F(ab′)2 p7D3 probe, along with plasma and tissue viral loads (VLs). Exogenous TGF-β reduced HIV-1 reactivation in U1 and ACH-2 models. Galunisertib increased HIV-1 latency reversal ex vivo and in PBMCs from HIV-1–infected, ART-treated, aviremic donors. In vivo, oral galunisertib promoted increased total standardized uptake values in PET/CT images in gut and lymph nodes of 5 out of 7 aviremic, long-term ART-treated, SIV-infected macaques. This increase correlated with an increase in SIV RNA in the gut. Two of the 7 animals also exhibited increases in plasma VLs. Higher anti-SIV T cell responses and antibody titers were detected after galunisertib treatment. In summary, our data suggest that blocking TGF-β signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.
| Original language | English (US) |
|---|---|
| Article number | e162290 |
| Journal | JCI Insight |
| Volume | 7 |
| Issue number | 21 |
| DOIs | |
| State | Published - Nov 8 2022 |
Funding
This research was funded by grants NIH R01AI139288 and R01AI111907 to FV and PJS, NIH R240D010947 to FV, R56AI157822 to EM, and P01AI131346 and P30AI117943 to TJH. The work of IS, JA, and C Cicala was supported by NIAID/NIH intramural program. The Clinical Pharmacology Core at Northwestern University (IMSERC) received support from NIH (1S10OD012016-01/1S10RR019071-01A1), Soft and Hybrid Nanotechnology Experimental Resource (NSF ECCS-1542205), the State of Illinois, and International Institute for Nanotechnology. We are grateful to J Lifson, W Boshe, R Shoemaker, and the team of the AIDS and Cancer Virus Program (Leidos Biomedical Research, Inc.) for supporting this work with timely plasma and tissue VL measurements. We thank the RADAR study team for providing samples. We acknowledge the outstanding help and assistance of the professional staff and technicians of the NIRC and the staff of the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core Facility of Northwestern University for their assistance with flow cytometry analysis. We thank Richard D’Aquila, Professor of Medicine at Northwestern University, for editing the manuscript. This research was funded by grants NIH R01AI139288 and R01AI111907 to FV and PJS, NIH R240D010947 to FV, R56AI157822 to EM, and P01AI131346 and P30AI117943 to TJH. The work of IS, JA, and C Cicala was supported by NIAID/NIH intramural program. The Clinical Pharmacology Core at Northwestern University (IMSERC) received support from NIH (1S10OD012016-01/1S10RR019071-01A1), Soft and Hybrid Nanotechnology Experimental Resource (NSF ECCS-1542205), the State of Illinois, and International Institute for Nanotechnology.
ASJC Scopus subject areas
- General Medicine
