Association of persistent wild-type measles virus RNA with long-term humoral immunity in rhesus macaques.

Ashley N Nelson,Wen-Hsuan W Lin,Nicole E Putnam,Lisa Mangus,Diane E Griffin,Rupak Shivakoti,Debra Hauer,Robert J Adams,Victoria K Baxter

doi:10.1172/jci.insight.134992

Ashley N Nelson, Wen-Hsuan W Lin + Show 7 more

Open Access

https://doi.org/10.1172/jci.insight.134992

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Journal: JCI insight	Publication Date: Feb 13, 2020
Citations: 23	License type: cc-by

Affiliation: Johns Hopkins University, Johns Hopkins Medicine

Abstract

Recovery from measles results in life-long protective immunity. To understand induction of long-term immunity, rhesus macaques were studied for 6 months after infection with wild-type measles virus (MeV). Infection caused viremia and rash, with clearance of infectious virus by day 14. MeV RNA persisted in PBMCs for 30-90 days and in lymphoid tissue for 6 months most often in B cells but was rarely detected in BM. Antibody with neutralizing activity and binding specificity for MeV nucleocapsid (N), hemagglutinin (H), and fusion proteins appeared with the rash and avidity matured over 3-4 months. Lymph nodes had increasing numbers of MeV-specific antibody-secreting cells (ASCs) and germinal centers with late hyalinization. ASCs appeared in circulation with the rash and continued to appear along with peripheral T follicular helper cells for the study duration. ASCs in lymph nodes and PBMCs produced antibody against both H and N, with more H-specific ASCs in BM. During days 14-21, 20- to 100-fold more total ASCs than MeV-specific ASCs appeared in circulation, suggesting mobilization of preexisting ASCs. Therefore, persistence of MeV RNA in lymphoid tissue was accompanied by continued germinal center formation, ASC production, avidity maturation, and accumulation of H-specific ASCs in BM to sustain neutralizing antibody and protective immunity.

Highlights

Despite the availability of safe and highly effective live attenuated measles virus (MeV) vaccines, measles continues to be a significant, and recently increasing, cause of morbidity and mortality, with more than 100,000 deaths each year [1, 2]
We have identified ongoing changes in lymphoid tissue architecture, T follicular helper (Tfh) cells in circulation, and the frequencies of MeV-specific antibody-secreting cells (ASCs) in lymphoid tissue, PBMCs, and BM associated with persistence of MeV RNA
Infectious virus was cleared by day 14, with persistent MeV RNA in PBMCs that gradually decreased to undetectable levels 30–90 days after infection (Figure 1 and refs. 8, 11)

Summary

Introduction

Despite the availability of safe and highly effective live attenuated measles virus (MeV) vaccines, measles continues to be a significant, and recently increasing, cause of morbidity and mortality, with more than 100,000 deaths each year [1, 2]. MeV is a highly infectious, negative-strand RNA virus transmitted by aerosol or respiratory droplets that causes a systemic rash disease in both humans and nonhuman primates [3, 4]. The rash appears 10–14 days after infection and coincides with the appearance of the adaptive immune response, clearance of infectious virus, and clinical recovery [8]. Despite the elimination of infectious virus, MeV RNA persists in PBMCs, urine, and nasopharyngeal secretions of children with measles for at least 3–4 months [9, 10]. After clearance from PBMCs, viral RNA is still detected in lymphoid tissues [8]

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