Human immune system mice immunized with Plasmodium falciparum circumsporozoite protein induce protective human humoral immunity against malaria

Huang, Jing; Li, Xiangming; Coelho-dos-Reis, Jordana Grazziela Alves; Zhang, Min; Mitchell, Robert A.; Nogueira, Raquel Tayar; Tsao, Tiffany; Noe, Amy R.; Ayala, Ramses; Sahi, Vincent; Gutierrez, Gabriel M.; Nussenzweig, Victor; Wilson, James M.; Nardin, Elizabeth; Nussenzweig, Ruth S.; Tsuji, Moriya

doi:10.1016/j.jim.2015.09.005

Cited by 29 publications

(35 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The next day, mice were given human CD34 ϩ hematopoietic cells from an HLA-DR1-positive donor. AAV9-DR1/cytokine-transduced NSG mice were monitored at 6, 10, and 14 weeks after HSC engraftment by determining the percentage of human CD45 ϩ cells in the peripheral blood using flow cytometric analyses as described previously (66,69,70).…”

Section: Methodsmentioning

confidence: 99%

Capsid-CPSF6 Interaction Is Dispensable for HIV-1 Replication in Primary Cells but Is Selected during Virus Passage In Vivo

Saito

Henning

Serrao

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

Cleavage and polyadenylation specificity factor subunit 6 (CPSF6), a host factor that interacts with the HIV-1 capsid (CA) protein, is implicated in diverse functions during the early part of the HIV-1 life cycle, including uncoating, nuclear entry, and integration targeting. Preservation of CA binding to CPSF6 in vivo suggests that this interaction is fine-tuned for efficient HIV-1 replication in physiologically relevant settings. Nevertheless, this possibility has not been formally examined. To assess the requirement for optimal CPSF6-CA binding during infection of primary cells and in vivo, we utilized a novel CA mutation, A77V, that significantly reduced CA binding to CPSF6. The A77V mutation rendered HIV-1 largely independent from TNPO3, NUP358, and NUP153 for infection and altered the integration site preference of HIV-1 without any discernible effects during the late steps of the virus life cycle. Surprisingly, the A77V mutant virus maintained the ability to replicate in monocyte-derived macrophages, primary CD4 ؉ T cells, and humanized mice at a level comparable to that for the wild-type (WT) virus. Nonetheless, revertant viruses that restored the WT CA sequence and hence CA binding to CPSF6 emerged in three out of four A77V-infected animals. These results suggest that the optimal interaction of CA with CPSF6, though not absolutely essential for HIV-1 replication in physiologically relevant settings, confers a significant fitness advantage to the virus and thus is strictly conserved among naturally circulating HIV-1 strains. IMPORTANCECPSF6 interacts with the HIV-1 capsid (CA) protein and has been implicated in nuclear entry and integration targeting. Preservation of CPSF6-CA binding across various HIV-1 strains suggested that the optimal interaction between CA and CPSF6 is critical during HIV-1 replication in vivo. Here, we identified a novel HIV-1 capsid mutant that reduces binding to CPSF6, is largely independent from the known cofactors for nuclear entry, and alters integration site preference. Despite these changes, virus carrying this mutation replicated in humanized mice at levels indistinguishable from those of the wild-type virus. However, in the majority of the animals, the mutant virus reverted back to the wild-type sequence, hence restoring the wild-type level of CA-CPSF6 interactions. These results suggest that optimal binding of CA to CPSF6 is not absolutely essential for HIV-1 replication in vivo but provides a fitness advantage that leads to the widespread usage of CPSF6 by HIV-1 in vivo.T he HIV-1 capsid (CA) protein forms the protein core that envelopes viral enzymes and genetic material following fusion with the plasma membrane (1-3). Uncoating of the viral core is a fine-tuned process that regulates downstream events, including reverse transcription, nuclear entry, and integration targeting (4-9). It is likely that HIV-1 exploits multiple host factors that can directly interact with the viral CA protein for proper uncoating in virus-infected cells. These host factors likely in...

show abstract

Section: Methodsmentioning

confidence: 99%

Capsid-CPSF6 Interaction Is Dispensable for HIV-1 Replication in Primary Cells but Is Selected during Virus Passage In Vivo

Saito

Henning

Serrao

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…The protocol was approved by the Institutional Animal Care and Use Committee (IACUC) at The Rockefeller University (assurance number A3081-01). HIS mice that possess functional human CD4 ϩ T and B cells through AAV9-mediated modification with human cytokine genes were used in this study (16). To obtain HIS mice, young NSG mice (2 to 3 weeks old) were first inoculated with 1 ϫ 10 11 genomic copies (GC) of AAV9-HLA class II (DR1 or DR4) (5 ϫ 10 10 GC intrathoracically and 5 ϫ 10 10 GC intraperitoneally), together with intraperitoneal injection of 5 ϫ 10 10 GC of AAV9 -B cell-activating factor belonging to the tumor necrosis factor family (BAFF) and 5 ϫ 10 9 GC of AAV9-human cytokines (AAV9 -interleukin-3 [IL-3], AAV9 -IL-4, AAV9 -IL-7, AAV9 -IL-15, AAV9 -granulocyte macrophage colony-stimulating factor, and AAV9 -macrophage colony-stimulating factor).…”

Section: Rsvmentioning

confidence: 99%

“…We recently established HIS mice that possess functional human CD8 ϩ or CD4 ϩ T and B cells. These mice were generated by the introduction of an adeno-associated virus serotype 9 (AAV9) vector carrying human cytokine genes into highly immunodeficient NOD scid gamma (NSG) mice followed by engraftment of human hematopoietic stem cells (15,16). In this study, we investigated the use of HIS mice with human CD4 ϩ T cells and B cells as a model for human RSV disease with the following two objectives: (i) to assess if this model leads to features of human RSV lung disease, even those that are not primarily thought to be associated with immune cell function, such as mucus cell hyperplasia, and (ii) to evaluate if this model can be used to generate human neutralizing antibodies, one of the major immune correlates for protection.…”

mentioning

confidence: 99%

Respiratory Syncytial Virus (RSV) Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology

Sharma

Sung

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease, which causes high rates of morbidity and mortality in infants and the elderly. Models of human RSV pulmonary disease are needed to better understand RSV pathogenesis and to assess the efficacy of RSV vaccines. We assessed the RSV-specific human innate, humoral, and cellular immune responses in humanized mice (mice with a human immune system [HIS mice]) with functional human CD4 ؉ T and B cells. These mice were generated by introduction of HLA class II genes, various human cytokines, and human B cell activation factor into immunodeficient NOD scid gamma (NSG) mice by the use of an adeno-associated virus vector, followed by engraftment of human hematopoietic stem cells. During the first 3 days of infection, HIS mice lost more weight and cleared RSV faster than NSG mice. Human chemokine (C-C motif) ligand 3 (CCL3) and human interleukin-1␤ (IL-1␤) expression was detected in the RSV-infected HIS mice. The pathological features induced by RSV infection in HIS mice included peribronchiolar inflammation, neutrophil predominance in the bronchioalveolar lavage fluid, and enhanced airway mucus production. Human anti-RSV IgG and RSVneutralizing antibodies were detected in serum and human anti-RSV mucosal IgA was detected in bronchioalveolar lavage fluid for up to 6 weeks. RSV infection induced an RSV-specific human gamma interferon response in HIS mouse splenocytes. These results indicate that human immune cells can induce features of RSV lung disease, including mucus hyperplasia, in murine lungs and that HIS mice can be used to elicit human anti-RSV humoral and cellular immunity. Infection of the lower respiratory tract with respiratory syncytial virus (RSV) is the most common cause for hospitalization of infants and children (1) and globally causes up to 200,000 deaths in children under the age of 5 years (2). Premature infants, especially those with chronic lung disease or congenital heart disease (3), and the elderly (4) are the most susceptible to the development of severe disease. Early RSV infections are also associated with the later development of asthma (5). No efficient therapeutics or vaccines active against RSV are available. Only immunoprophylaxis with palivizumab, a monoclonal anti-RSV F antibody, provides some protection for infants at risk (6). Several animal models have been developed to model human RSV disease (7). As mouse models have limitations in mimicking human RSV disease, better models would be useful for the preclinical assessment of novel anti-RSV therapies and vaccines. Humoral immunity is essential in the prevention of RSV infections. Higher levels of maternally derived antibodies (8) and prophylactic administration of intravenous immunoglobulin enriched for high levels of RSV-neutralizing antibodies (9) or humanized monoclonal antibody against RSV (10) are associated with a reduction of disease severity in RSV-infected infants. Therefore, a humanized mouse model with functional human CD4 ϩ T and B...

show abstract

“…This type of strategy is already beginning to be used and will also form a bridge between conventional mouse studies and human clinical studies [90]. An ideal malaria vaccine candidate would target multiple lifecycle stages of the parasite, with some combination of protection against sporozoites, liver stages, blood stages or transmission to the mosquito vector.…”

Section: Future Perspectivementioning

confidence: 99%

“…However, even if this type of model is achievable, significant hurdles remain such as the need for HLA matching of the solid tissue and the immune compartment, as well as overcoming the complexity of producing human immune cells that are educated in the periphery by mouse thymic cells. These hurdles are however being tackled, for instance with dual-chimeric mice and the expression of human MHC in the periphery [90,91]. While such a highly advanced humanized mouse model can and should be pursued, existing tools can already be used in iterative cycles of identifying vaccine targets through basic parasitology conducted in rodent models and in vitro models of P. falciparum, testing of vaccine candidates in human CHMI clinical trials and testing of the resulting samples in human liver-chimeric mice.…”

Section: Future Perspectivementioning

confidence: 99%

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

2016

View full text Add to dashboard Cite

Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts. Malaria continues to cause significant morbidity and mortality despite renewed and concerted efforts to eliminate the causative agents, parasites of the genus Plasmodium. These efforts have largely focused on control of the Anopheles mosquito vectors, and antimalarial drug treatment of symptomatic infected individuals. The 214 million new malaria infections and 438,000 deaths due to malaria in 2015 were disproportionately borne by low income countries where malaria is endemic, and declines in malaria infections since 2000 have been slowest in countries with low resource availability and high malaria burden [1]. In the fight against malaria, effective vaccines preventing both disease and transmission will be important tools to achieve WHO goals of a 90% reduction in disease burden by 2030 [1,2]. In humans, malaria is caused predominantly by the parasite species Plasmodium falciparum and Plasmodium vivax, with the remainder of infections caused by three additional parasite species, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi [1].Malaria parasite transmission occurs when a Plasmodium-infected Anopheles mosquito bites and by probing the skin for a blood meal, deposits motile sporozoite stages into the host. Sporozoites pass through the dermis using active motility, enter a capillary and then rapidly home to the liver. Once in the liver sporozoites enter the parenchyma and infect hepatocytes, wherein they then transmogrify into liver stages, which grow, replicate and ultimately differentiate into tens of thousands of first-generation merozoites. Merozoites of human malaria parasites emerge from the liver into the blood stream 7-10 days after transmission, where they undergo cyclic erythrocytic infection and intraerythrocytic replication. This blood-stage infection is responsible for all mortality and clinical symptoms of malaria, as well as infection of a new mosquito vector by sexual stage parasites for onward transmission [3,4]. Stages prior to blood-stage infection (i.e., the sporozoite and liver stages) are collectively known as preerythrocytic (PE) stages of infection and vaccine candidates targeting these stages are collectively termed PE vaccines. By preventing progression to ...

show abstract

Human immune system mice immunized with Plasmodium falciparum circumsporozoite protein induce protective human humoral immunity against malaria

Cited by 29 publications

References 38 publications

Capsid-CPSF6 Interaction Is Dispensable for HIV-1 Replication in Primary Cells but Is Selected during Virus Passage In Vivo

Capsid-CPSF6 Interaction Is Dispensable for HIV-1 Replication in Primary Cells but Is Selected during Virus Passage In Vivo

Respiratory Syncytial Virus (RSV) Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

Contact Info

Product

Resources

About