Biology subjects

De Paris, K.

Publications and source records attributed to De Paris, K..

3 recordsLinked to original sources

bioRxiv2019

Signatures of divergent antimalarial treatment responses in peripheral blood from infants and adults in Malawi

BackgroundHeterogeneity in the immune response to parasite infection is mediated in part by differences in host genetics, sex, and age group. In neonates and infants, ongoing immunological maturation often results in increased susceptibility to infection and variable responses to drug treatment, increasing the risk of complications. Even though significant age-specific effects on host cytokine responses to Plasmodium falciparum infection have been identified, age effects on uncomplicated malaria infection and antimalarial treatment remain poorly understood. MethodsIn samples of whole blood from a cohort of naturally infected malaria-positive individuals in Malawi (n=63 total; 34 infants <2 years old, 29 adults >18 years old), we assessed blood cytokine levels and characterized monocyte and dendritic cell frequencies at two timepoints: acute infection, and four weeks post antimalarial treatment. We modeled the effects of age group, sex, and timepoint, and evaluated the role of these factors on infection and treatment outcomes. ResultsRegardless of treatment timepoint, in our population age was significantly associated with overall blood hemoglobin, which was higher in adults, and plasma nitric oxide, IL-10, and TNF- levels, which were higher in infants. We found a significant effect of age on the hemoglobin treatment response, whereby after treatment, levels increased in infants and decreased in adults. Furthermore, we observed significant age-specific effects on treatment response for overall parasite load, IFN-{gamma} and IL-12(p40), and these effects were sex-dependent. We uncovered significant age effects on the overall levels and treatment response of myeloid dendritic cell frequencies. In addition, within each age group, we found continuous age effects on gametocyte levels (Pfs16), TNF-, and nitric oxide. ConclusionsIn a clinical study of infants and adults experiencing natural malaria infection and receiving antimalarial treatment, we identified age-specific signatures of infection and treatment responses in peripheral blood. We describe host markers that may indicate, and potentially mediate, differential post-treatment outcomes for malaria in infants versus adults.

immunology↗

bioRxiv2019

Oral clade C SHIV challenge models to study pediatric HIV-1 infection by breastmilk transmission

Nonhuman primate (NHP) models are invaluable for HIV pathogenesis, intervention and cure studies. To enhance the translational potential of NHP HIV vaccine studies, clinically relevant R5-tropic, tier 2 neutralization sensitive, and mucosally transmissible simian-human immunodeficiency viruses (SHIVs) have been designed. Towards our goal of developing vaccines to prevent breastmilk transmission of HIV, we evaluated virological outcomes of three distinct SHIVs in repeated weekly oral exposure regimens in infant rhesus macaques. The selected strains SHIV-1157ipd3N4, SHIV-1157(QNE)Y173H, and SHIV CH505 375H.dCT express a clade C HIV Env, the clade most prevalent in regions with high pediatric HIV infections. All three SHIVs were orally transmissible. However, compared to the pediatric SIVmac251 model, SHIV replication was more attenuated. Some animals exposed to weekly low-dose (20 TCID50) SHIV-1157ipd3N4 had transient viremia blips associated with lack or delayed seroconversion. Animals with acute viremia [≥]10,000 viral RNA copies/ml seroconverted. This finding was reminiscent of an earlier study suggesting to continue challenges until a threshold of [≥]10,000 viral RNA copies/ml is surpassed to achieve seroconversion, one criterion of HIV diagnosis. All animals exposed weekly with higher doses (>104 TCID50) of SHIV-1157(QNE)Y173H or SHIV CH505 375h.dCT developed persistent infection with high peak viremia and seroconverted. Chronic viremia varied widely in all three SHIV infection models. Thus, although R5 clade C SHIVs are excellent tools to study prevention of virus acquisition, secondary virological outcomes of vaccine efficacy (e.g. risk of infection per exposure, modulation of peak viremia, viral set point) will require careful consideration and validation in SHIV challenge models. IMPORTANCEThe development of an effective HIV vaccine remains a top priority towards the goal of reducing the number of new HIV infections. Studies in nonhuman primate models of HIV infection have been instrumental in the preclinical evaluation of candidate vaccines. To assess the role of HIV Env-specific antibodies with broadly neutralizing or Fc-mediated effector function in these NHP models, the development and optimization of novel SHIV challenge models is required. We evaluate three different clade C HIV Env SHIVs for infectivity of infant macaques by the oral route. Our results demonstrate that SHIV-1157ipd3N4, SHIV-1157(QNE)Y173H, and SHIV CH505 375H.dCT can be orally transmitted and establish persistent infection in infant rhesus macaques, but chronic viremia levels vary widely. Therefore, SHIV infection models are most pertinent when prevention of systemic infection is the primary readout of vaccine efficacy, but secondary outcome measures of vaccine efficacy will require stringent criteria and extensive validation.

microbiology↗

bioRxiv2019

SHIV.CH505-infected infant and adult rhesus macaques exhibit similar HIV Env-specific antibody kinetics, despite distinct T-follicular helper (Tfh) and germinal center B cell landscapes

Pediatric HIV infection remains a large global health concern despite the widespread use of antiretroviral therapy (ART). Thus, global elimination of pediatric HIV infections will require the development of novel immune-based approaches, and understanding infant immunity to HIV is critical to guide the rational design of these intervention strategies. Despite their immunological immaturity, HIV-infected children develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults do. Furthermore, T-follicular helper (Tfh) cells have been associated with bnAb development in HIV-infected children and adults. To further our understanding of age-related differences in the development of HIV-specific immunity, we evaluated the generation of virus-specific humoral immune responses in infant (n=6) and adult (n=12) rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human immunodeficiency virus (SHIV.C.CH505). The plasma HIV envelope-specific IgG antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant differences in the magnitude or breadth of these responses. Interestingly, autologous tier 2 virus neutralization responses also developed with similar frequency and kinetics in infant and adult RMs, despite infants exhibiting significantly higher Tfh and germinal center B cell frequencies compared to adults. Our results indicate that the humoral immune response to SHIV infection develops with similar kinetics among infant and adult RMs, suggesting that the early life immune system is equipped to respond to HIV-1 and promote the production of neutralizing HIV antibodies. ImportanceThere is a lack of understanding on how the maturation of the infant immune system influences immunity to HIV infection, or how these responses differ from those of adults. Improving our knowledge of infant HIV immunity will help guide antiviral intervention strategies that take advantage of the unique infant immune environment to successfully elicit protective immune responses. We utilized a rhesus macaque model of SHIV infection as a tool to distinguish the differences in HIV humoral immunity in infants versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral immune response to HIV are highly comparable to that of adults during the early phase of infection, despite distinct differences in their Tfh responses, indicating that slightly different mechanisms may drive infant and adult humoral immunity.

immunology↗