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Effect of Passive Administration of Monoclonal Antibodies Recognizing Simian Immunodeficiency Virus (SIV) V2 in CH59-Like Coil/Helical or β-Sheet Conformations on Time of SIVmac251 Acquisition
Stamos et al., Journal of Virology. 2023.
https://journals.asm.org/doi/10.1128/jvi.01864-22
Research suggests that the SIV variable region 2 (V2) is a region of virus vulnerability, likely because of its exposure on the apex of virions and on the surfaces of SIV-infected cells. Researchers examined the effects of two monoclonal antibodies, NCI05 and NCI09, on the acquisition of SIV using rhesus macaques (sex not specified). They found that NCI05, but not NCI09, delays SIV acquisition, highlighting the complexity of antibody responses to V2. Both antibodies were unable to decrease the risk of viral acquisition. This study demonstrates that such antibodies as NCI05 alone are insufficient to protect against SIV acquisition. Supported by ORIP (S10OD027000), NIAID, and NCI.
Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates
Maity et al., Molecular & Cellular Proteomics. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981268/
In this study, researchers examined the proteins expressed in cerebrospinal fluid (CSF) in nonhuman primates (NHPs) to better understand how COVID-19 infection can result in brain pathology, a common outcome. The study found that even in NHPs with minimal or mild COVID‑19, CSF proteins were significantly dysregulated compared with uninfected NHPs. Furthermore, the most affected proteins were enriched in the same brain regions that show lesions after COVID-19 infection, including the cerebral cortex, basal ganglia, and brain stem. Collectively, these regions have wide-ranging control over such crucial functions as cognition, motor control, and breathing, showing how even mild COVID-19 infection can result in significant neurological impairment. Supported by ORIP (P51OD011104, S10OD032453), NIGMS, NCI, and NICHD.
The Incompetence of Mosquitoes—Can Zika Virus Be Adapted to Infect Culex tarsalis Cells?
Gallichotte et al., mSphere . 2023.
Zika virus (ZIKV) is transmitted between humans by Aedes aegypti mosquitoes. However, the 2015 to 2017 outbreak raised questions regarding the role of Culex species mosquitoes in transmission. Investigators attempted to adapt ZIKV to C. tarsalis by serially passaging the virus on cocultured A. aegypti and C. tarsalis cells to identify viral determinants of species specificity. Next-generation sequencing of cocultured virus passages revealed variants of interest that were engineered into nine recombinant viruses. None of these viruses showed increased infection of Culex cells or mosquitoes. Thus, although ZIKV might infect Culex mosquitoes occasionally, Aedes mosquitoes likely drive transmission and human risk. Supported by ORIP (T32OD010437) and NIAID.
Pembrolizumab and Cabozantinib in Recurrent Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 2 Trial
Saba et al., Nature Medicine. 2023.
https://www.doi.org/10.1038/s41591-023-02275-x
A multicenter clinical trial was conducted in 33 evaluable (36 enrolled) patients with recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC) on a regimen combining cabozantinib, a tyrosine kinase inhibitor, with the standard of care of anti–programmed cell death protein 1 agent pembrolizumab. Results showed that 17 patients (52%) exhibited partial response and 13 (39%) exhibited stable disease, with an overall clinical benefit rate of 91%. Median progression-free survival (PFS) was 14.6 months, and the 1-year PFS was 54%. The pembrolizumab and cabozantinib regimen was well tolerated in patients with RMHNSCC. The promising clinical benefit warrants further investigation. Supported by ORIP (S10OD021644), NCI, and NIDCR.
Structural Insights Into the Broad Protection Against H1 Influenza Viruses by a Computationally Optimized Hemagglutinin Vaccine
Dzimianski et al., Communications Biology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37185989/
Influenza is an ongoing public health concern, and computationally optimized broadly reactive antigen (COBRA) hemagglutinin proteins represent a potential strategy for formulating broadly effective influenza vaccines. Researchers determined the crystal structure of COBRA P1, as well as its binding to 1F8, a broadly neutralizing antibody. This work provides valuable insights into the underlying molecular basis for the broad effectiveness of P1, and these insights can be applied to future vaccine designs. Supported by ORIP (K01OD026569), NIAID, and NIGMS.
Longitudinal Characterization of Circulating Extracellular Vesicles and Small RNA During Simian Immunodeficiency Virus Infection and Antiretroviral Therapy
Huang et al., AIDS. 2023.
https://www.doi.org/10.1097/QAD.0000000000003487
Antiretroviral therapy is effective for controlling HIV infection but does not fully prevent early aging disorders or serious non-AIDS events among people with HIV. Using pigtail and rhesus macaques (sex not specified), researchers profiled extracellular vesicle small RNAs during different phases of simian immunodeficiency virus infection to explore the potential relationship between extracellular vesicle–associated small RNAs and the infection process. They reported that average particle counts correlated with infection, but the trend could not be explained fully by virions. These findings raise new questions about the distribution of extracellular vesicle RNAs in HIV latent infection. Supported by ORIP (U42OD013117), NIDA, NIMH, NIAID, NCI, and NINDS.
Infant Rhesus Macaques Immunized Against SARS-CoV-2 Are Protected Against Heterologous Virus Challenge 1 Year Later
Milligan et al., Science Translational Medicine. 2023.
https://doi.org/10.1126/scitranslmed.add6383
The Moderna and Pfizer–BioNTech mRNA vaccines received emergency use authorization for infants 6 months and older in June 2022, but questions remain regarding the durability of vaccine efficacy against emerging variants in this age group. Using a two-dose vaccine regimen consisting of stabilized prefusion Washington-strain spike protein encoded by mRNA and encapsulated in lipid nanoparticles, the investigators immunized 2-month-old rhesus macaques of both sexes. They found that the immune responses persisted and protected from severe disease after heterologous challenge with the Delta variant 1 year later. The decay kinetics of vaccine-induced neutralizing antibody responses in the infant monkeys are comparable to those observed in adult humans and nonhuman primates. Supported by ORIP (P51OD011107), NIAID, and NCI.
Fc-Mediated Pan-Sarbecovirus Protection After Alphavirus Vector Vaccination
Adams et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37000623/
Group 2B β-coronaviruses (i.e., sarbecoviruses) have resulted in regional and global epidemics. Here, the authors evaluate the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. They reported that vaccination does not prevent virus replication, but it protects against lethal heterologous disease outcomes in SARS-CoV-2 and clade 2 bat sarbecovirus challenge models. Full-length spike vaccines elicited the broadest pan-sarbecovirus protection. Additionally, antibody-mediated cross-protection was lost in absence of FcR function, supporting a model for non-neutralizing, protective antibodies. Taken together, these findings highlight the value of universal sarbecovirus vaccine designs that couple FcR-mediated cross-protection with potent cross-neutralizing antibody responses. Supported by ORIP (K01OD026529), NIAID, and NCI.
A Live Dengue Virus Vaccine Carrying a Chimeric Envelope Glycoprotein Elicits Dual DENV2–DENV4 Serotype-Specific Immunity
Young et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/36914616/
Dengue vaccine development is challenging because some virus-specific antibodies are protective, whereas others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to induce balanced protective immunity. To simplify live-virus vaccine design, investigators identified co-evolutionary constraints inherent in flavivirus virion assembly. They found that the chimeric virus replicated efficiently in vitro and in vivo and that a single inoculation induced type-specific neutralizing antibodies in male macaques. These findings can be applied to the development of bivalent live dengue vaccines that induce independent immunity to multiple serotypes. Supported by ORIP (P40OD012217) and NIAID.
Anti–Human Immunodeficiency Virus‑1 Activity of MoMo30 Protein Isolated from the Traditional African Medicinal Plant Momordica balsamina
Khan et al., Virology Journal. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035133/
Momordica balsamina has been reported to produce a ribosome-inactivating protein with anti‑HIV-1 activity and is commonly used by traditional African healers for treatment of HIV. Investigators characterized the mechanism of action of the MoMo30 protein, as well as the sequence of the protein-coding gene. They reported that MoMo30 functions as a lectin or carbohydrate-binding agent (CBA) and inhibits HIV-1 at nanomolar levels, with minimal cellular toxicity at inhibitory levels. CBAs can block the binding of envelope glycoproteins with their target receptors on cells. Thus, this protein could represent a potential new treatment strategy for HIV. Supported by ORIP (R24OD010947), NCI, NIGMS, and NIMHD.