Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques

• Type of Material: Article
• Authors: Matthew P Wood, Seattle Children’s Research Institute; Chloe I Jones, Seattle Children’s Research Institute; Adriana Lippy, Seattle Children’s Research Institute; Brian G Oliver, Seattle Children’s Research Institute; Brynn Walund, Seattle Children’s Research Institute; Katherine A Fancher, Seattle Children’s Research Institute; Bridget S Fisher, Seattle Children’s Research Institute; Piper J Wright, Seattle Children’s Research Institute; James T Fuller, University of Washington; Patience Murapa, University of Washington; Jakob Habib, Emory University; Maud Mavigner, Emory University; Ann Chahroudi, Emory University; Noah D Sather, Seattle Children’s Research Institute; Deborah H Fuller, University of Washington; Donald L Sodora, Seattle Children’s Research Institute
• Language: English
• Date: 2021-05-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Wood et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1009575
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 17
• Issue: 5
• Start Page: e1009575
• End Page: e1009575
• Grant/Funding Information: The data generated in this manuscript was supported by grants from: National Institute of Dental and Craniofacial Research DE023047 to DLS, DE026336 to DLS and DNS, National Institute of Allergy and Infectious Diseases AI133706 to AC, University of Washington Department of Global Health (US) A1750915 to MPW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: SIMIAN IMMUNODEFICIENCY VIRUS; PEDIATRIC HIV-INFECTION; Science & Technology; Virology; Microbiology; Parasitology; GERMINAL CENTER; MEMORY B-CELLS; Life Sciences & Biomedicine; INTERFERON-ALPHA; PLASMACYTOID DENDRITIC CELLS; EXPRESSION; ANTIBODY-RESPONSES; DEPLETION; IMMUNE ACTIVATION

Abstract

HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were divided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody and viral load, with RP infants having low SIV-specific antibodies and high viral loads. Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype. Interestingly, TypP had lower levels of total CD4 T cells, similar reductions in CD4/CD8 ratios and elevated activation of CD8 T cells, as measured by the levels of HLA-DR, compared to RP. Differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope diversity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques.