T cell activation is insufficient to drive SIV disease progression

Apetrei, Cristian; Gaufin, Thaidra; Brocca-Cofano, Egidio; Sivanandham, Ranjit; Sette, Paola; He, Tianyu; Sivanandham, Sindhuja; Martinez Sosa, Natalie; Martin, Kathryn J.; Raehtz, Kevin D.; Kleinman, Adam J.; Valentine, Audrey; Krampe, Noah; Gautam, Rajeev; Lackner, Andrew A.; Landay, Alan L.; Ribeiro, Ruy M.; Pandrea, Ivona

doi:10.1172/jci.insight.161111

T cell activation is insufficient to drive SIV disease progression

Journal Article · Mon Jul 24 00:00:00 EDT 2023 · JCI Insight

DOI:https://doi.org/10.1172/jci.insight.161111· OSTI ID:2222627

Apetrei, Cristian ^[1]; Gaufin, Thaidra ^[2]; Brocca-Cofano, Egidio ^[3]; ^[3]; Sette, Paola ^[3]; ^[3]; ^[3]; Martinez Sosa, Natalie ^[3]; Martin, Kathryn J. ^[3]; ^[3]; ^[3]; Valentine, Audrey ^[3]; ^[3]; Gautam, Rajeev ^[2]; Lackner, Andrew A. ^[2]; Landay, Alan L. ^[4]; ^[5]; Pandrea, Ivona ^[1]

Univ. of Pittsburgh, PA (United States); Tulane Univ., Covington, LA (United States)
Tulane Univ., Covington, LA (United States)
Univ. of Pittsburgh, PA (United States)
Rush University Medical Center, Chicago, IL (United States)
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Resolution of T cell activation and inflammation is a key determinant of the lack of SIV disease progression in African green monkeys (AGMs). Although frequently considered together, T cell activation occurs in response to viral stimulation of acquired immunity, while inflammation reflects innate immune responses to mucosal injury. We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs. This intervention abolished control of T cell immune activation beyond the transition from acute to chronic infection. Ontak had no effect on gut barrier integrity, microbial translocation, inflammation, and hypercoagulation, despite increasing T cell activation. Ontak administration increased macrophage counts yet decreased their activation. Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4⁺ T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 2222627

Report Number(s):: LA-UR--23-24126

Journal Information:: JCI Insight, Journal Name: JCI Insight Journal Issue: 14 Vol. 8; ISSN 2379-3708

Publisher:: American Society for Clinical InvestigationCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
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inflammation
ontak

T cell activation is insufficient to drive SIV disease progression

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