Maternal HIV-1 Env Vaccination for Systemic and Breast Milk Immunity To Prevent Oral SHIV Acquisition in Infant Macaques

Eudailey, Joshua; Dennis, Maria; Parker, Morgan; Phillips, Bonnie; Huffman, Tori; Bay, Camden; Hudgens, Michael G.; Wiseman, Roger W.; Pollara, Justin; Fouda, Genevieve G.; Ferrari, Guido; Pickup, David J.; Kozlowski, Pamela A.; Rompay, Koen K. A. Van; Paris, Kristina De; Permar, Sallie R.

doi:10.1128/msphere.00505-17

Cited by 20 publications

(34 citation statements)

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“…Based on this initial virus titration, we proceeded with a weekly oral exposure regimen of 20 TCID 50 in 7 infant macaques starting at week 6 of age (50). Five of 7 SHIV-1157ipd3N4 infected infant macaques developed high peak viremia (>10 6 viral RNA copies/ ml) that subsequently declined at variable levels (Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

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

Hudgens

et al. 2019

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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.

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Section: Resultsmentioning

confidence: 99%

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

Hudgens

et al. 2019

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“…We defined time to viral rebound as a plasma VL >10 times LOD (150 copies/mL) post-ART discontinuation. Plasma VL pre-ART, ADCC antibodies, CD4+ CD69+ T cells and autologous virus neutralizing antibodies were pre-selected as primary parameters based on their previously published associations with rate of HIV acquisition (29, 30) and disease progression (31, 32). Of these parameters, higher levels of plasma VL pre-ART and ADCC antibody titers on ART demonstrated associations with increased risk of viral rebound (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…The plasma concentrations of HIV Env-specific antibodies were estimated by ELISA, as previously described (29). Human CH22 monoclonal antibody was used as standard and the concentration of HIV Env-specific IgG antibody was calculated relative to the standard using a 5-parameter fit curve (SoftMax Pro 7).…”

Section: Methodsmentioning

confidence: 99%

“…HIV antigens were covalently conjugated to polystyrene beads (Bio-Rad), and binding of IgG to the bead-conjugated HIV-1 antigens was measured in RM plasma samples (29). The antigens used for the assay have been described in (26).…”

Section: Methodsmentioning

confidence: 99%

“…Neutralization of MW965.LucR.T2A.ecto/293T IMC (clade C, tier 1) and the autologous CH505.TF (clade C, tier 2) HIV-1 pseudovirus by plasma antibodies was measured in TZM-bl cells as previously described (29, 52, 53). The ID 50 was calculated as described in (26).…”

Section: Methodsmentioning

confidence: 99%

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Analytical treatment interruption after short-term anti-retroviral therapy in a postnatally SHIV infected infant rhesus macaque model

Goswami

Nelson

et al. 2019

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word count: 235 34 Text word count: 5631 35 36 37 38 39 40 41 42 43 44 45 3 ABSTRACT. 46 47 To achieve long-term viral remission in HIV-infected children, novel strategies beyond 48 early anti-retroviral therapy (ART) will be necessary. Identifying clinical predictors of 49 time to viral rebound upon ART interruption will streamline the development of novel 50 therapeutic strategies and accelerate their evaluation in clinical trials. However, 51 identification of these biomarkers is logistically challenging in infants, due to sampling 52 limitations and potential risks of treatment interruption. To facilitate identification of 53 biomarkers predicting viral rebound, we have developed an infant rhesus macaque 54 (RM) model of oral SHIV.CH505.375H.dCT challenge and analytical treatment 55 interruption (ATI) after short-term ART. We used this model to characterize SHIV 56 replication kinetics and virus-specific immune responses during short-term ART or post-57 ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a 58 decline in humoral immune responses and partial dampening of systemic immune 59 activation upon initiation of ART in these infants. Furthermore, we documented that 60 infant and adult macaques have similar SHIV replication and rebound kinetics and 61 equally potent virus-specific humoral immune responses. Finally, we validated our 62 models by confirming a well-established correlate of time to viral rebound, namely pre-63 ART plasma viral load, as well as identified additional potential humoral immune 64 correlates. Thus, this model of infant ART and viral rebound can be used and further 65 optimized to define biomarkers of viral rebound following long-term ART as well as to 66 pre-clinically assess novel therapies to achieve a pediatric HIV functional cure.67 68 4 IMPORTANCE. 69 70 Novel interventions that do not rely on daily adherence to ART are needed to achieve 71 sustained viral remission for perinatally infected children who currently rely on lifelong 72 ART. Considering the risks and expense associated with ART-interruption trials, 73 identification of biomarkers of viral rebound will prioritize promising therapeutic 74 intervention strategies, including anti-HIV Env protein therapeutics. However, 75 comprehensive studies to identify those biomarkers are logistically challenging in 76 human infants, demanding the need for relevant non-human primate models of HIV 77 rebound. In this study, we developed an infant RM model of oral Simian/Human 78 Immunodeficiency virus infection expressing clade C HIV Env, and short-term ART 79 followed by ATI, longitudinally characterizing immune responses to viral infection during 80 ART and post-ATI. Additionally, we compared this infant RM model to an analogous 81 adult RM rebound model and identified virologic and immunologic correlates of time to 82 viral rebound post-ATI. 83 84 Word limit: 150 85 Word count: 141 86 87 88 89 90 91 5 INTRODUCTION. 92 93Despite the widespread availability and effectiveness of antiretroviral therapy...

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Easy pan-detection of human IgA immunoglobulins

Planchais

Mouquet

2020

Journal of Immunological Methods

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Maternal HIV-1 Env Vaccination for Systemic and Breast Milk Immunity To Prevent Oral SHIV Acquisition in Infant Macaques

Cited by 20 publications

References 81 publications

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

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

Analytical treatment interruption after short-term anti-retroviral therapy in a postnatally SHIV infected infant rhesus macaque model

Easy pan-detection of human IgA immunoglobulins

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