Immune Cell Dynamics in Rhesus Macaques Infected with a Brazilian Strain of Zika Virus

Abstract

Zika virus (ZIKV) is a mosquito-borne and sexually transmitted flavivirus, associated with fetal CNS-damaging malformations during pregnancy in humans. This study documents the viral kinetics, and immune responses in rhesus macaques infected with a clinical ZIKV Brazilian isolate. We evaluated the viral kinetics and immune responses induced after an i.v. infection with a Brazilian ZIKV clinical isolate (HS-2015-BA-01) in rhesus macaques for up to 142 days. ZIKV-specific antibody-secreting cells (ASCs), germinal center (GC) reactions as well as monocyte, DC, NK and T cell frequencies were monitored. ZIKV loads were readily detected in plasma (until day 5 or 7), semen and urine (until day 7 and 14), and saliva (until day 42), but the viremia was rapidly controlled. No detectable clinical manifestations were observed. However, lymph node (LN) hyperplasia was clearly visible post viremia, but associated with low frequencies of ZIKV-specific ASCs in LNs and bone marrow (BM), correlating with low antibody titers. CD14+/CD16- monocytes and myeloid CD11chi DCs decreased in blood, while NK and T cell numbers were only marginally altered during the course of the study. ZIKV infection caused a significant lymphoid tissue activation but limited induction of ZIKV-specific B cells, suggesting that these parameters need to be considered for ZIKV vaccine design.

Mathematical modeling of within‐host Zika virus dynamics

“…Additionally, depletion of CD8 T cells results in higher viremia in mice . However, despite this evidence of T‐cell response to ZIKV infection in mice, in rhesus macaques populations of CD8+ T cell subsets remain mostly stable during the course of infection …”

“…There has also been much effort directed toward understanding the generation and protective capacity of anti-ZIKV antibodies, as reviewed in Priyamvada et al 83 In macaque models, after a high-dose intravenous infection, total numbers of B cells increased on day 3, while antigen-specific IgG titers were not detectable until well after clearance of the plasma virus, suggesting that the antibody response was more important for long-term protection than short-term control. 84 The long-term protective role of antibodies in ZIKV infection is supported by work from a number of groups. 85,86 Aliota et al 85 found that rhesus macaques were protected from secondary homologous and heterologous challenge 70 days after primary infection.…”

“…97 However, despite this evidence of T-cell response to ZIKV infection in mice, in rhesus macaques populations of CD8+ T cell subsets remain mostly stable during the course of infection. 84 In the situation where the immune responses that should be incorporated into models are broadly unknown, each potential response can be modeled and tested via data-fitting in order to suggest areas for further experimental focus. There are a number of feasible mechanisms of immune control of viremia, each of which can be implemented in the ODE models described by Equations (1)-(6) as we discuss below.…”

Zika virus infection at mid-gestation results in fetal cerebral cortical injury and fetal death in the olive baboon

“…Non-human primates (NHPs) are the best documented animal reservoirs for ZIKV (and related flaviviruses). ZIKV infection has been achieved in male, and non-pregnant and pregnant female rhesus (Macacca mulatta) (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) cynomolgus (Macacca fascicularis) (22,32) and pigtail macaques (Macacca nemestrina) (33) following subcutaneous (SC) inoculation with French Polynesian (H/PF/2013), (20) Puerto Rican (PRVABC59, 2015) (21,22,(30)(31)(32), Brazilian (Brazil/ZKV2015; Zika virus/H.sapiens-tc/BRA/2015/Brazil_SPH2015) (26)(27)(28)(29) and Cambodian strains of ZIKV (FSS13025) (32). There are now several reports of ZIKV infection in pregnant macaques, with one study describing infection of a single pigtail macaque using an Asian strain (FSS13025 strain; Cambodia, 2010) (33), and four studies with pregnant rhesus macaques infected with either the French Polynesian or Puerto Rican strains (20,23,30,31).…”

Zika Virus, Lymph Node and Lymphoma

“…In a study on "Rhesus Macaques Infected with a Brazilian Strain of Zika Virus" Silveira by et al, "lymph node hyperplasia was clearly visible postviremia but was associated with low frequencies of ZIKV-specific Ab-secreting cells in lymph nodes and bone marrow [5]." In non-human primate, the Zika virus is proved for existence in lymph node [6].…”