Antibody-mediated depletion of viral reservoirs is limited in SIV-infected macaques treated early with antiretroviral therapy

Swanstrom, Adrienne E.; Immonen, Taina T.; Oswald, Kelli; Pyle, Cathi; Thomas, James A.; Bosche, William J.; Silipino, Lorna; Hull, Michael; Newman, Laura P.; Coalter, Vicky; Wiles, Adam; Wiles, Rodney; Kiser, Jacob; Morcock, David R.; Shoemaker, Rebecca; Fast, Randy; Breed, Matthew W.; Kramer, Joshua; Donohue, Duncan; Malys, Tyler; Fennessey, Christine M.; Trubey, Charles M.; Deléage, Claire; Estes, Jacob D.; Lifson, Jeffrey D.; Keele, Brandon F.; Prete, Gregory Q. Del

doi:10.1172/jci142421

Cited by 16 publications

(35 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Blood was collected in EDTA tubes and plasma was separated by density gradient centrifugation and used for the determination of plasma VLs by SIVgag RT-qPCR at NIRC or at Leidos (Quantitative Molecular Diagnostics Core, AIDS and Cancer Virus Program, Frederick National Laboratory). Tissue VLs from snap-frozen colorectal bx and LN FNAs were performed at Leidos (A14X004, A14X005, and A14X013) as described ( 78 ) or, for the remaining macaques and from PBMCs of all macaques, they were performed as described ( 77 ).…”

Section: Methodsmentioning

confidence: 99%

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo

Samer¹,

Thomas²,

Araínga³

et al. 2022

JCI Insight

View full text Add to dashboard Cite

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 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 (TGFBR1) inhibitor, galunisertib. We tested the effect of galunisertib in SIV-infected, ART-treated macaques by monitoring SIV-env expression via PET/CT using the Cu 64 -anti-gp120 Fab(7D3) probe, along with plasma and tissue viral loads (VL). Exogenous TGF-β reduced HIV-1 reactivation in U1 and ACH2 models.Galunisertib increased HIV-1 latency reversal ex vivo and in PBMC from HIV-1 infected, ART-treated aviremic donors. In vivo, oral galunisertib promoted increased total standardized uptake values (SUVtot) 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 pVL. 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.

show abstract

Section: Methodsmentioning

confidence: 99%

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo

Samer¹,

Thomas²,

Araínga³

et al. 2022

JCI Insight

View full text Add to dashboard Cite

show abstract

“…Blood was collected in EDTA tubes and plasma was separated by density gradient centrifugation and used for the determination of plasma VL by SIVgag qRT-PCR at NIRC or at Leidos (Quantitative Molecular Diagnostics Core, AIDS and Cancer Virus Program Frederick National Laboratory). Tissue VL from snap frozen colorectal biopsies and LN FNA were performed at Leidos (A14X004, A14X005 and A14X013) as described in( 100 ) or, for the remaining macaques and from PBMC of all macaques they were performed as described in ( 99 ).…”

Section: Methodsmentioning

confidence: 99%

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responsesin vivo

Samer

Thomas

Araínga

et al. 2022

Preprint

View full text Add to dashboard Cite

Elevated levels of TGF-β, a potent immunosuppressive factor, are present in HIV-1 infected individuals even after years of antiretroviral therapy (ART). 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 one of the main cellular reservoirs after long term ART and the low inducibility of the latent provirus constitutes one of the major obstacles to “kick and kill” cure strategies. We hypothesized that releasing cells from TGF-β-driven signaling would promote latency reversal. To test our hypothesis, we compared ex vivo models of HIV-1 latency reactivation with and without TGF-β and a TGF-β type 1 receptor (TGFBR1) inhibitor, galunisertib. We also tested the effect of galunisertib in SIV infected, ART treated macaques by monitoring SIV envelope (env) protein expression via PET/CT using the Cu64-anti gp120 Fab (7D3) probe, along with plasma and tissue viral loads (VL). Exogenous TGF-1β reduced HIV-1 reactivation in U1 and ACH2 latency models. Galunisertib increased HIV-1 latency reversal both in ex vivo models and in PBMC from HIV-1 infected, cART treated aviremic donors. In vivo, oral galunisertib promoted increased SIV env protein total standardized uptake values (SUVtot) in PET/CT images of tissues (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 gut tissue. Two out of 7 animals also exhibited increases in plasma viral load. Higher anti-SIV T cell responses and anti-SIV env antibody titers were detected after galunisertib treatment in most animals. In summary, our data suggest that blocking TGF-β signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.

show abstract

“…Importantly, we have previously shown that the barcode remains intact during several months of replication and have not found any indication that different variants, which are isogenic except for the barcode sequences, differ in their replicative capacity [ 26 ]. The ability to quantify the replication of thousands of individual clonal variants greatly increases analytic resolution into the structure of the virus population, allowing detection of nuanced changes to its composition [ 34 ], and provides a way to directly estimate the rate of reactivation from latency for individual animals [ 26 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Transient viral replication during analytical treatment interruptions in SIV infected macaques can alter the rebound-competent viral reservoir

et al. 2021

Self Cite

View full text Add to dashboard Cite

Analytical treatment interruptions (ATIs) of antiretroviral therapy (ART) play a central role in evaluating the efficacy of HIV-1 treatment strategies targeting virus that persists despite ART. However, it remains unclear if ATIs alter the rebound-competent viral reservoir (RCVR), the virus population that persists during ART and from which viral recrudescence originates after ART discontinuation. To assess the impact of ATIs on the RCVR, we used a barcode sequence tagged SIV to track individual viral lineages through a series of ATIs in Rhesus macaques. We demonstrate that transient replication of individual rebounding lineages during an ATI can lead to their enrichment in the RCVR, increasing their probability of reactivating again after treatment discontinuation. These data establish that the RCVR can be altered by uncontrolled replication during ATI.

show abstract

Antibody-mediated depletion of viral reservoirs is limited in SIV-infected macaques treated early with antiretroviral therapy

Cited by 16 publications

References 64 publications

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responsesin vivo

Transient viral replication during analytical treatment interruptions in SIV infected macaques can alter the rebound-competent viral reservoir

Contact Info

Product

Resources

About