TY - JOUR
T1 - IFN-α blockade during ART-treated SIV infection lowers tissue vDNA, rescues immune function, and improves overall health
AU - Swainson, Louise A.
AU - Sharma, Ashish Arunkumar
AU - Ghneim, Khader
AU - Ribeiro, Susan Pereira
AU - Wilkinson, Peter
AU - Dunham, Richard M.
AU - Albright, Rebecca G.
AU - Wong, Samson
AU - Estes, Jacob D.
AU - Piatak, Michael
AU - Deeks, Steven G.
AU - Hunt, Peter W.
AU - Sekaly, Rafick Pierre
AU - McCune, Joseph M.
N1 - Funding Information:
Funding was provided by the DARE (Delaney AIDS Research Enterprise to Defeat HIV) grant U19AI096109 and by the Bill & Melinda Gates Foundation (grant OPP1112415). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Bill & Melinda Gates Foundation. We thank the Applied Functional Genomics Core and Case Western Genomics core for RNA extraction and sequencing of whole blood and rectal biopsies. We thank Argos Therapeutics for providing the anti–IFN-α antibody AGS-009 and Keith Reimann for the provision of the control IgG antibody. We are grateful to Gilead Sciences for providing tenofovir and emtricitabine, to Merck for the provision of raltegravir, and to Tibotec for the provision of darunavir for ART treatment.
Publisher Copyright:
© 2022, Swainson et al.
PY - 2022/3/8
Y1 - 2022/3/8
N2 - Type I IFNs (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of HIV infection treated with antiretroviral therapy (ART) also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8+ T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TIIFN- inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate proinflammatory plasma cytokines, expression of monocyte activation genes, IL-12-induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-β levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates treated with anti-IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrated that IFN-α blockade during ART-treated SIV infection was safe and associated with the induction of immune/ erythroid pathways that reduced viral persistence during ART while mitigating the weight loss and anemia that typically ensue after ART interruption.
AB - Type I IFNs (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of HIV infection treated with antiretroviral therapy (ART) also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8+ T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TIIFN- inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate proinflammatory plasma cytokines, expression of monocyte activation genes, IL-12-induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-β levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates treated with anti-IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrated that IFN-α blockade during ART-treated SIV infection was safe and associated with the induction of immune/ erythroid pathways that reduced viral persistence during ART while mitigating the weight loss and anemia that typically ensue after ART interruption.
UR - http://www.scopus.com/inward/record.url?scp=85125888191&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125888191&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.153046
DO - 10.1172/jci.insight.153046
M3 - Article
C2 - 35104248
AN - SCOPUS:85125888191
VL - 7
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 5
M1 - e153046
ER -