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A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

During its most recent outbreak across the Americas, Zika virus (ZIKV) was surprisingly shown to cause fetal loss and congenital malformations in acutely and chronically infected pregnant women. However, understanding the underlying pathogenesis of ZIKV congenital disease has been hampered by a lack of relevant in vivo experimental models. Here we present a candidate New World monkey model of ZIKV infection in pregnant marmosets that faithfully recapitulates human disease. ZIKV inoculation at the human-equivalent of early gestation caused an asymptomatic seroconversion, induction of type I/II interferon-associated genes and proinflammatory cytokines, and persistent viremia and viruria. Spontaneous pregnancy loss was observed 16-18 days post-infection, with extensive active placental viral replication and fetal neurocellular disorganization similar to that seen in humans. These findings underscore the key role of the placenta as a conduit for fetal infection, and demonstrate the utility of marmosets as a highly relevant model for studying congenital ZIKV disease and pregnancy loss.

A monkey model of Zika virus (ZIKV) infection is urgently needed to better understand transmission and pathogenesis, given its proven association with fetal brain defects in pregnant women and acute neurological illness. Here we experimentally infected 4 male marmosets with ZIKV (prototype 1947 African strain) and monitored them clinically with sampling of various body fluids and tissues for nearly 3 months. We show that the course of acute infection with ZIKV in these New World monkeys resembles the human illness in many respects, including (1) lack of apparent clinical symptoms in most cases, (2) persistence of the virus in body fluids such as semen and saliva for longer periods of time than in serum, and (3) generation of neutralizing antibodies as well as an antiviral immunological host response. Importantly, ZIKV-infected saliva samples (in addition to serum) were found to be infectious, suggesting potential capacity for viral transmission by the oral route. Re-challenge of a previously infected marmoset with a contemporary outbreak strain SPH2015 from Brazil resulted in continued protection against infection, no viral shedding, and boosting of the immune response. Given the key similarities to human infection, a marmoset model of ZIKV infection may be useful for testing of new drugs and vaccines.

Vaccines based on live attenuated viruses are highly effective immunogens in the simian immunodeficiency virus (SIV)/rhesus macaque animal model and offer the possibility of studying correlates of protection against infection with virulent virus. We utilized a tether system for studying, in naive macaques and animals vaccinated with a live-attenuated vaccine, the acute events after challenge with pathogenic SIV. This approach allowed for the frequent sampling of small blood volumes without sedation or restraining of the animals, thus reducing the confounding effect of sampling stress. Before challenge, vaccinated animals presented significantly higher levels of proliferating and activated B cells than naive macaques, which were manifested by high expression of CD8 on B cells. After SIV challenge, the only changes observed in protected vaccinated macaques were significant increases in expression of the NK marker NKG2C on CD4 and CD8 T cells. We also identified that infection of naive macaques with SIV resulted in a transient peak of expression of CD20 on CD8 T cells and a constant rise in the number of B cells expressing CD8. Finally, analysis of a larger cohort of vaccinated animals identified that, even when circulating levels of vaccine virus are below the limit of detection, live attenuated vaccines induce systemic increases of IP-10 and perforin. These studies indicate that components of both the innate and adaptive immune systems of animals inoculated with a live-attenuated SIV vaccine respond to and control infection with virulent virus. Persistence of the vaccine virus in tissues may explain the elevated cytokine and B-cell activation levels. In addition, our report underpins the utility of the tether system for the intensive study of acute immune responses to viral infections. [ABSTRACT FROM AUTHOR]

Background γδ T cells are effector cells that eliminate cancer and virus-infected cells. Chimpanzees are an endangered species that can naturally and experimentally be infected with SIV and HIV, respectively, but no information about the functionality of γδ T cells during chronic lentiviral infection is currently available. Methods Healthy and HIV-infected chimpanzee γδ T cells were characterized by flow cytometry. γδ T subsets were studied after stimulation with T-cell activators, and the release of cytokines was analyzed by Luminex assay. Results γδ T-cell subsets, Vδ1 and Vδ2 Vγ9, showed different patterns in the expression of CD4, CD195, CD159a, and CD159c. Stimulation of γδ T cells resulted in increased levels of CD4 and HLA- DR, which is more pronounced in Vδ1 T cells. Distinct cytokine patterns were found between healthy and HIV-infected chimpanzees. Conclusions Analyses of major chimpanzee γδ T subsets show similarities to human γδ T cells and suggest different functionality and roles in their immune response against HIV infection. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus infection is characterized by dysregulation of antigen-presenting cell function and defects in cell-mediated immunity. Recent evidence suggests that impaired ability of CD4+ T cells to upregulate the costimulatory molecule CD154 is at the core of this dysregulation. To test the hypothesis that increased expression of CD154 on infected CD4+ T cells could modulate immune function, we constructed a replication-competent simian immunodeficiency virus (SIV) vector that expressed CD154. We found that this recombinant vector directed the expression of CD154 on the surface of infected CD4+ T cells and that expression of CD154 resulted in activation of B cells present in the same cultures. Experimental infection of rhesus macaques resulted in very low viral loads for the CD154-expressing virus and the control virus, indicating that expression of CD154 did not result in increased viral replication. Analyses of the anti-SIV immune responses and the phenotype of lymphocytes in blood and lymphoid tissues showed changes that occurred during the acute phase of infection only in animals infected with the CD154-expressing SIV, but that became indistinguishable from those seen in animals infected with the control virus at later time points. We conclude that the level of expression of CD154 in itself is not responsible for affecting the immune response to an attenuated virus. Considering that the CD154-expressing SIV vector and the virus control did not carry an active nef gene, our results suggest that, in CD4+ T cells infected with wild-type virus, Nef is the viral factor that interferes with the immune mechanisms that regulate expression of CD154. [ABSTRACT FROM AUTHOR]

The establishment of human immunodeficiency virus type 1 (HIV-1) and HIV-2 infections in humans is the consequence of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) from chimpanzees (SIVcpz) and sooty mangabeys (SIVsmm), respectively. While over 40 African nonhuman primate (NHP) species carry their unique strain of SIV, many of which resulted from simian-to-simian transmissions, these natural SIV infections are chronic and productive but not associated with immunodeficiency. Baboons (Papio hamadryas ssp.), one of the most widely distributed African NHP species, do not seem to be naturally infected with SIV, even though their home ranges overlap those of many SIV-infected NHP species. Despite some serological evidence for SIV infection in very few wild-living baboons, isolation of a replicating virus from these animals has not been reported. The reasons for this apparent natural resistance to SIV infection are not known. Baboons have been shown to be susceptible to experimental infections with some HIV-1, HIV-2 or SHIVs strains. Further, in our hands, baboon lymphocytes support productive infection with SIVmac and SIVagm, indicating that intracellular antiviral factors like APOBEC3 proteins, Trim-5α, and Tetherin probably do not contribute to this resistance. Our long-term goal is to identify the factors responsible for natural resistance to SIV infection in baboons. We hypothesized that cytokines and cytotoxic factors from cells from the innate immune system are involved in this natural resistance. As a first step towards testing this hypothesis, we performed in vitro infections with SIV of lymphocytes from baboons and Indian rhesus macaques. We determined kinetics of viral replication, and measured cytokine production and cell activation in order to identify differences between these NHP species. While all the rhesus PBMC preparations supported SIV replication, there were PBMC from some baboons that were refractory to SIV infection; this difference was more pronounced for infections with SIVagm than with SIVmac. We also observed that in vitro stimulation of rhesus cells resulted in higher levels of CD4 T cell activation in comparison to stimulated cells from baboons; however, the concentration of cytokines that compete with SIV for binding to CCR5 (such as RANTES, MIP-1α, and MIP-1β) was higher for stimulated baboon cells than for macaque cells. Taken together, these differences in T cell activation status and cytokine levels could explain the natural immunity of baboons to SIV infection. Further work is underway to identify genes associated with this natural immunity. Identification of these genes ultimately may help inform the development of new therapeutic or preventive approaches to AIDS. [ABSTRACT FROM AUTHOR]

Vaccines based on live attenuated viruses are highly effective immunogens in the simian immunodeficiency virus (SIV)/rhesus macaque animal model and offer the possibility of studying correlates of protection against infection with virulent virus. We utilized a tether system for studying, in naive macaques and animals vaccinated with a live-attenuated vaccine, the acute events after challenge with pathogenic SIV. This approach allowed for the frequent sampling of small blood volumes without sedation or restraining of the animals, thus reducing the confounding effect of sampling stress. Before challenge, vaccinated animals presented significantly higher levels of proliferating and activated B cells than naive macaques, which were manifested by high expression of CD8 on B cells. After SIV challenge, the only changes observed in protected vaccinated macaques were significant increases in expression of the NK marker NKG2C on CD4 and CD8 T cells. We also identified that infection of naive macaques with SIV resulted in a transient peak of expression of CD20 on CD8 T cells and a constant rise in the number of B cells expressing CD8. Finally, analysis of a larger cohort of vaccinated animals identified that, even when circulating levels of vaccine virus are below the limit of detection, live attenuated vaccines induce systemic increases of IP-10 and perforin. These studies indicate that components of both the innate and adaptive immune systems of animals inoculated with a live-attenuated SIV vaccine respond to and control infection with virulent virus. Persistence of the vaccine virus in tissues may explain the elevated cytokine and B-cell activation levels. In addition, our report underpins the utility of the tether system for the intensive study of acute immune responses to viral infections., Competing Interests: Author Disclosure Statement No competing financial interests exist.