Antiretroviral therapy reveals triphasic decay of intact SIV genomes and persistence of ancestral variants

Fray, Emily J.; Wu, Fengting; Simonetti, Francesco R.; Zitzmann, Carolin; Sambaturu, Narmada; Molina-Parı́s, Carmen; Bender, Alexandra M.; Liu, Po-Ting; Ventura, John D.; Wiseman, Roger W.; O’Connor, David H.; Geleziunas, Romas; Leitner, Thomas; Ribeiro, Ruy M.; Perelson, Alan S.; Barouch, Dan H.; Siliciano, Janet D.; Siliciano, Robert F.

doi:10.1016/j.chom.2023.01.016

Cited by 16 publications

(68 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, although we did not have a concurrent control group, this decrease was not present in similar studies conducted in SIVmac239M2 infected macaques on the same ART regimen, but not treated with galunisertib. Considering studies by other groups with different models (SIVmac251), they report 2 nd phase decay of SIV intact provirus (weeks ∼32 to ∼100pi, Fig 2B in( 68 )) with a t 1/2 of >8 months( 68 ). In contrast, in our study, the intact provirus decreased by 3 folds (median) in a little over 3 months (from week 35pi, BC1 to week 49pi, AC4).…”

Section: Discussionmentioning

confidence: 95%

TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirsin vivo

Kim,

Bose,

Araínga

et al. 2023

Preprint

View full text Add to dashboard Cite

HIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous infection and therapeutic dosing of the anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirmed the latency reversal properties of in vivo TGF-β blockade, decreased viral reservoirs and stimulated immune responses. Eight SIV-infected macaques on suppressive ART were treated with 4 2-week cycles of galunisertib. ART was discontinued 3 weeks after the last dose, and macaques euthanized 6 weeks after ART-interruption(ATI). One macaque did not rebound, while the remaining rebounded between week 2 and 6 post-ATI. Galunisertib led to viral reactivation as indicated by plasma viral load and immunoPET/CT with the 64Cu-DOTA-F(ab')2-p7D3-probe. Half to 1 Log decrease in cell-associated (CA-)SIV DNA was detected in lymph nodes, gut and PBMC, while intact pro-virus in PBMC decreased by 3-fold. No systemic increase in inflammatory cytokines was observed. High-dimensions cytometry, bulk and single-cell RNAseq revealed a shift toward an effector phenotype in T and NK cells. In summary, we demonstrated that galunisertib, a clinical stage TGFβ inhibitor, reverses SIV latency and decreases SIV reservoirs by driving T cells toward an effector phenotype, enhancing immune responses in vivo in absence of toxicity.

show abstract

Section: Discussionmentioning

confidence: 95%

TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirsin vivo

Kim,

Bose,

Araínga

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Ten Indian-origin rhesus macaques were infected with simian immunodeficiency virus (SIVmac251 stock) and initiated ART at ≈ 48 weeks post-infection. Intact proviruses in CD4 + T cells were quantified using the intact proviral DNA assay (IPDA) (33, 34) periodically from the day ART was initiated ( t = 0 weeks), for about four years ( t = 216 weeks). Envelope gene ( env ) sequences in SIV DNA in circulating CD4 + T cells were then obtained using single genome sequencing, and filtered to remove any sequences with defects (deletions, premature stop codons, hypermutations, etc.)…”

Section: Resultsmentioning

confidence: 99%

“…resulting in non-defective proviral env sequences; see Methods and Fray et al . (33) for details. In this work, we analyze the data for the first ≈ 3 years ( t = 146 weeks).…”

Section: Resultsmentioning

confidence: 99%

“…We determined the divergence of the non-defective proviral env sequences from the consensus sequence of the infecting virus stock. Based on the prior knowledge that at least two T cell subsets with different half-lives exist (32, 33), we tested whether the divergence decayed with time on ART, and if so, whether the decay was monophasic or biphasic. We found the decay to be biphasic with an approximately 500 times faster first phase decline than second phase decline when considering non-defective proviral DNA sequences obtained at all time points (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, Fray et al . (33) found that intact simian immunodeficiency virus (SIV) genomes decay with triphasic kinetics, and archival SIV variants persist, upon treatment with ART.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Last in first out: SIV proviruses seeded later in infection are harbored in short-lived CD4⁺T cells

Sambaturu,

Fray,

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

HIV can persist in a latent form as integrated DNA (provirus) in resting CD4+T cells of infected individuals and as such is unaffected by antiretroviral therapy (ART). Despite being a major obstacle for eradication efforts, the genetic variation and timing of formation of this latent reservoir remains poorly understood. Previous studies on when virus is deposited in the latent reservoir have come to contradictory conclusions. To reexamine the genetic variation of HIV in CD4+T cells during ART, we determined the divergence in envelope sequences collected from 10 SIV infected rhesus macaques. We found that the macaques displayed a biphasic decline of the viral divergence over time, where the first phase lasted for an average of 11.6 weeks (range 4-28 weeks). Motivated by recent observations that the HIV-infected CD4+T cell population is composed of short- and long-lived subsets, we developed a model to study the divergence dynamics. We found that SIV in short-lived cells was on average more diverged, while long-lived cells harbored less diverged virus. This suggests that the long-lived cells harbor virus deposited starting earlier in infection and continuing throughout infection, while short-lived cells predominantly harbor more recent virus. As these cell populations decayed, the overall proviral divergence decline matched that observed in the empirical data. This model explains previous seemingly contradictory results on the timing of virus deposition into the latent reservoir, and should provide guidance for future eradication efforts.Significance statementHIV can persist in a latent reservoir unaffected by antiretroviral drugs. The genetic variation of this latent virus population is a major obstacle for eradication efforts, but also a clue to when HIV variants are deposited in the reservoirs. Unfortunately, previous studies assessing when the virus was deposited in latent reservoirs have come to contradictory conclusions. Here, we propose SIV proviral DNA exists in both short- and long-lived CD4+T cells, and that these two cell subsets harbor different genetically diverged virus populations. Our model explains the contradictory findings and shows that when CD4+T cells decay under effective drug treatment, which prevents virus replication, the resulting virus divergence decreases and recapitulates observed data. This knowledge should help in improving future eradication efforts.

show abstract

Antigen specificities of HIV-infected cells: A role in infection and persistence?

Faua,

Fafi-Kremer,

Gantner

2023

Journal of Virus Eradication

View full text Add to dashboard Cite

Antiretroviral therapy reveals triphasic decay of intact SIV genomes and persistence of ancestral variants

Cited by 16 publications

References 98 publications

TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirsin vivo

TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirsin vivo

Last in first out: SIV proviruses seeded later in infection are harbored in short-lived CD4⁺T cells

Antigen specificities of HIV-infected cells: A role in infection and persistence?

Contact Info

Product

Resources

About

Antiretroviral therapy reveals triphasic decay of intact SIV genomes and persistence of ancestral variants

Cited by 16 publications

References 98 publications

TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirsin vivo

TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirsin vivo

Last in first out: SIV proviruses seeded later in infection are harbored in short-lived CD4+T cells

Antigen specificities of HIV-infected cells: A role in infection and persistence?

Contact Info

Product

Resources

About

Last in first out: SIV proviruses seeded later in infection are harbored in short-lived CD4⁺T cells