Early treatment with reverse transcriptase inhibitors significantly suppresses peak plasma IFNα in vivo during acute simian immunodeficiency virus infection.
Innate interferons (IFN) are comprised of multiple Type I and III subtypes. The in vivo kinetics of subtype responses during human immunodeficiency virus (HIV) infection is not well defined. Using the acute simian immunodeficiency virus (SIV) infection model, we show that plasma IFNα levels peak at day 10 post-infection (pi) after which they rapidly declined. The mRNA expression of Type I and III IFN subtypes were significantly elevated in the lymph nodes (LN) at day 10 pi. Though the expression levels of all subtypes declined by day 14-31 pi, numerous subtypes remained elevated suggesting that ongoing viral replication in LN continues to drive induction of these subtypes. Interestingly, treatment with reverse transcriptase (RT) inhibitors at day 7 pi significantly suppressed plasma IFNα responses by day 10 pi that significantly correlated with cell-associated SIV DNA loads suggesting that RT byproducts such as viral DNA likely plays a role in driving IFN responses during acute SIV infection. Quantification of Type I and III subtype transcripts in sorted subsets of LN CD4+ and CD8+ T cells, CD14+/CD14- monocytes/macrophages, and total CD11c/CD123+ dendritic cells (DC) at day 10 pi showed that DC expressed ∼3-4 log more subtype transcripts as compared to the other subsets. Taken together, our results provide new insights into the kinetics of innate interferon responses during early stages of infection, and provide evidence that DC's are a major in vivo source of innate IFN during acute SIV infection.
Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Jeffy
J
George
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
Lynnsey
L
Renn
Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
Daniela
D
Verthelyi
Vaccine Research Center, National Institutes of Health, Bethesda, MD, United States.
Mario
M
Roederer
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
Ronald L
RL
Rabin
Uniformed Services University of the Health Sciences, Bethesda, MD, United States. Electronic address: joseph.mattapallil@usuhs.edu.
Joseph J
JJ
Mattapallil
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000628:therapy*; D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D004279:DNA, Viral / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007165:Immunosuppression Therapy; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000097:blood; D008198:Lymph Nodes / Q000276:immunology* / Q000821:virology; D008253:Macaca mulatta; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*
D004279:DNA, Viral; D016898:Interferon-alpha; D018894:Reverse Transcriptase Inhibitors
Dendritic cells; HIV; IFNα; IFNβ; Mucosa; SIV; Subtypes