The complex challenges of HIV vaccine development require renewed and expanded global commitment

Bekker, Linda‐Gail; Tatoud, Roger; Dabis, François; Feinberg, Mark B.; Kaleebu, Pontiano; Marovich, Mary; Ndung’u, Thumbi; Russell, Nina D.; Johnson, Jeremiah; Luba, Maureen; Fauci, Anthony S.; Morris, Lynn; Pantaleo, Giuseppe; Buchbinder, Susan; Gray, Glenda; Vekemans, Johan; Kim, Jerome H.; Lévy, Yves; Corey, Lawrence; Shattock, Robin J.; Makanga, Michael; Williamson, Carolyn; Dieffenbach, Carl W.; Goodenow, Maureen M.; Shao, Yiming; Staprans, Silvija I.; Warren, Mitchell; Johnston, Margaret I.

doi:10.1016/s0140-6736(19)32682-0

Cited by 48 publications

(39 citation statements)

References 32 publications

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“…Despite successful prevention of HIV transmission with antiviral drugs, it is likely that an effective vaccine provides the only means of ending the HIV epidemic [2].…”

Section: Discussionmentioning

confidence: 99%

“…Over the past decades, several promising vaccine candidates have failed in large-scale safety and efficacy clinical trials [2]. The failure of those clinical trials suggests that improved "gate keeper" animal modeling systems are needed for better prediction of vaccine candidate outcomes in human clinical trials [119].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, HIV transmission remains endemic across the globe, and development of a functional cure and/or an effective vaccine will be required to end this epidemic [2]. HIV is a human specific pathogen; thus, animal models for evaluating the safety and efficacy of therapeutics and vaccines directly against HIV requires the incorporation of human lymphoid tissues and/or hematopoietic lineage cells.…”

Section: Introductionmentioning

confidence: 99%

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Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

et al. 2020

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The development of safe and effective combination antiretroviral therapies for human immunodeficiency virus (HIV) infection over the past several decades has significantly reduced HIV-associated morbidity and mortality. Additionally, antiretroviral drugs have provided an effective means of protection against HIV transmission. Despite these advances, significant limitations exist; namely, the inability to eliminate HIV reservoirs, the inability to reverse lymphoid tissues damage, and the lack of an effective vaccine for preventing HIV transmission. Evaluation of the safety and efficacy of therapeutics and vaccines for eliminating HIV reservoirs and preventing HIV transmission requires robust in vivo models. Since HIV is a human-specific pathogen, that targets hematopoietic lineage cells and lymphoid tissues, in vivo animal models for HIV-host interactions require incorporation of human hematopoietic lineage cells and lymphoid tissues. In this review, we will discuss the construction of mouse models with human lymphoid tissues and/or hematopoietic lineage cells, termed, human immune system (HIS)-humanized mice. These HIS-humanized mouse models can support the development of functional human innate and adaptive immune cells, along with primary (thymus) and secondary (spleen) lymphoid tissues. We will discuss applications of HIS-humanized mouse models in evaluating the safety and efficacy of therapeutics against HIV reservoirs and associated immunopathology, and delineate the human immune response elicited by candidate HIV vaccines. In addition to focusing on how these HIS-humanized mouse models have already furthered our understanding of HIV and contributed to HIV therapeutics development, we discuss how emerging HIS-humanized rat models could address the limitations of HIS-mouse models.

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“…Despite successful prevention of HIV transmission with antiviral drugs, it is likely that an effective vaccine provides the only means of ending the HIV epidemic [2].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

et al. 2020

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“…To identify peptide spectrum matches, data were searched with the Sequest HT algorithm through Proteome Discoverer 2.4 and matched with a mass error tolerance of 0.04 Da for MS/MS fragment ions 2 . GMP adducts were assigned by allowing a dynamic modification for the mass addition of 345.0474 (and 350.0326 or 355.0810 for 15 N and 13 C labeled GMP) to H, S, T, Y, K or R, based on known phosphodiester or phosphoramide attachment chemistry 3-5 , although all possible sites were considered in initial, preliminary searches. For the SARS-CoV-2 GMP localization on nsp7, initial searches assigned the modification site to the N-terminal glycine at peptide position 1, but the modification site was manually determined to be located at ser-2 (ser-1 in natural nsp7) because of the presence of the y13+ ion (ser-2) at an m/z of 1798.78857 that contained the GMP moiety.…”

Section: Methodsmentioning

confidence: 99%

Mass spectrometric based detection of protein nucleotidylation in the RNA polymerase of SARS-CoV-2

Conti

Kirchdoerfer

Sussman

2020

Preprint

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SummaryCoronaviruses, like SARS-CoV-2, encode a nucleotidyl transferase in the N-terminal NiRAN domain of the non-structural protein (nsp) 12 protein within the RNA dependent RNA polymerase (RdRP) 1-3. Though the substrate targets of the viral nucleotidyl transferase are unknown, NiRAN active sites are highly conserved and essential for viral replication 3. We show, for the first time, the detection and sequence location of GMP-modified amino acids in nidovirus RdRP-associated proteins using heavy isotope-assisted MS and MS/MS peptide sequencing. We identified lys-143 in the equine arteritis virus (EAV) protein, nsp7, as a primary site of nucleotidylation in vitro that uses a phosphoramide bond to covalently attach with GMP. In SARS-CoV-2 replicase proteins, we demonstrate a unique O-linked GMP attachment on nsp7 ser-1, whose formation required the presence of nsp12. It is clear that additional nucleotidylation sites remain undiscovered, which includes the possibility that nsp12 itself may form a transient GMP adduct in the NiRAN active site that has eluted detection in these initial studies due to instability of the covalent attachment. Our results demonstrate new strategies for detecting GMP-peptide linkages that can be adapted for higher throughput screening using mass spectrometric technologies. These data are expected to be important for a rapid and timely characterization of a new enzymatic activity in SARS-CoV-2 that may be an attractive drug target aimed at limiting viral replication in infected patients.

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“…Due to the genetic differences, the results from animals are not necessarily going to be the same in humans. To the contrary, many vaccines that are effective in animal experiments but showed inadequate protective effects in humans, such as RSV [64] and HIV [65]. Nevertheless, animal experiments are the essential step before trials in human for any vaccines.…”

Section: Coronavirus Vaccine Candidates Evaluated In Animal Modelsmentioning

confidence: 99%

Animal models for emerging coronavirus: progress and new insights

Yuan

Tang

Cheng

et al. 2020

Emerging Microbes & Infections

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The emergences of coronaviruses have caused a serious global public health problem because their infection in humans caused the severe acute respiratory disease and deaths. The outbreaks of lethal coronaviruses have taken place for three times within recent two decades (SARS-CoV in 2002, MERS-CoV in 2012 and SARS-CoV-2 in 2019). Much more serious than SARS-CoV in 2002, the current SARS-CoV-2 infection has been spreading to more than 213 countries, areas or territories and causing more than two million cases up to date (17 April 2020). Unfortunately, no vaccine and specific anticoronavirus drugs are available at present time. Current clinical treatment at hand is inadequate to suppress viral replication and inflammation, and reverse organ failure. Intensive research efforts have focused on increasing our understanding of viral biology of SARS-CoV-2, improving antiviral therapy and vaccination strategies. The animal models are important for both the fundamental research and drug discovery of coronavirus. This review aims to summarize the animal models currently available for SARS-CoV and MERS-CoV, and their potential use for the study of SARS-CoV-2. We will discuss the benefits and caveats of these animal models and present critical findings that might guide the fundamental studies and urgent treatment of SARS-CoV-2-caused diseases.

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The complex challenges of HIV vaccine development require renewed and expanded global commitment

Cited by 48 publications

References 32 publications

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

Mass spectrometric based detection of protein nucleotidylation in the RNA polymerase of SARS-CoV-2

Animal models for emerging coronavirus: progress and new insights

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