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 - 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.
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U2 - 10.1172/jci.insight.153046
DO - 10.1172/jci.insight.153046
M3 - Article
C2 - 35104248
AN - SCOPUS:85125888191
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 5
M1 - e153046
ER -