Selected Grantee Publications
Polyfunctional Tier 2–Neutralizing Antibodies Cloned Following HIV-1 Env Macaque Immunization Mirror Native Antibodies in a Human Donor
Spencer et al., Journal of Immunology. 2021.
https://doi.org/10.4049/jimmunol.2001082
HIV vaccine efforts are limited by viral strain diversity and the shielding of neutralization epitopes on the viral envelope, yet isolation of broadly neutralizing antibodies from infected individuals suggests the potential for eliciting protective antibodies through vaccination. Researchers cloned 58 monoclonal antibodies (mAbs) from a rhesus monkey immunized with envelope glycoprotein immunogens from an HIV-1 clade C–infected volunteer. Twenty mAbs exhibited some neutralizing activity. Cloned mAbs targeting the V3 region and CD4 binding site were capable of tier 2 (i.e., moderate) neutralization. This study demonstrates partial recapitulation of the human donor’s humoral immune response through nonhuman primate vaccination. Supported by ORIP (P51OD011092) and NIAID.
Modified Adenovirus Prime–Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge
Malherbe et al., Frontiers in Immunology. 2021.
https://doi.org/10.3389/fimmu.2020.626464
Researchers conducted a comparative vaccine challenge study in rhesus macaques. One group of monkeys was vaccinated using co-immunization with DNA Gag and Env expression plasmids and trimeric Env gp140 glycoprotein. The other group was primed with two replicating simian adenovirus-vectored vaccines expressing Gag and boosted with trimeric Env gp140. Both strategies elicited antigen-specific humoral and cellular immune responses, but neither approach provided significant protection from viral acquisition upon repeated mucosal challenges with a heterologous Tier 2 SHIV. Nevertheless, both regimens significantly lowered cell-associated viral DNA in multiple tissues, thus potentially dampening the infection and providing clues for further vaccine development. Supported by ORIP (U42OD023038, P51OD011092) and NIAID.
Evaluating a New Class of AKT/mTOR Activators for HIV Latency-Reversing Activity Ex Vivo and In Vivo
Gramatica et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.02393-20
Activation of latent HIV-1 expression could benefit many HIV cure strategies. Researchers evaluated two AKT/mTOR activators, SB-216763 and tideglusib, as a potential new class of LRAs. The drugs reactivated latent HIV-1 present in blood samples from aviremic individuals on antiretroviral therapy without causing T cell activation or impaired effector function of cytotoxic T lymphocytes or NK cells. When tested in vivo in monkeys, tideglusib showed unfavorable pharmacodynamic properties and did not reverse SIV latency. The discordance between the ex vivo and in vivo results underscores the importance of developing novel LRAs that allow systemic drug delivery to relevant anatomical compartments. Supported by ORIP (P51OD011092), NIAID, NIGMS, NIMH, and NCI.
Modified Vaccinia Ankara Vector-Based Vaccine Protects Macaques from SARS-CoV-2 Infection, Immune Pathology and Dysfunction in the Lung
Routhu et al., Immunity. 2021.
https://doi.org/10.1016/j.immuni.2021.02.001
Any SARS-CoV-2 vaccine may have limitations such as need for ultracold storage, poor induction of CD8+ T cell response, or lack of cross-reactivity with emerging strains. Thus, multiple vaccines may be needed to bring COVID-19 under control. Using rhesus macaques, researchers showed that a modified vaccinia Ankara (MVA) vector-based SARS-CoV-2 vaccine expressing prefusion-stabilized spike protein induced strong neutralizing antibody and CD8+ T cell responses. The vaccine protected macaques from SARS-CoV-2 infection as well as infection-induced inflammation and B cell abnormalities in the lung. These results are promising considering the excellent safety and performance of MVA vector-based vaccines for other pathogens. Supported by ORIP (P51OD011132, S10OD026799) and NIAID.
SARS-CoV-2 Induces Robust Germinal Center CD4 T Follicular Helper Cell Responses in Rhesus Macaques
Lakshmanappa et al., Nature Communications. 2021.
https://www.nature.com/articles/s41467-020-20642-x
SARS-CoV-2 infection in both sexes of rhesus macaques, either infused with convalescent plasma, normal plasma, or receiving no infusion, resulted in transient accumulation of pro-inflammatory monocytes and proliferating CD4 T follicular helper (Tfh) cells, which are critical for persistent antibody responses. CD4 helper cell responses skewed predominantly toward a Th1 response in blood, lung, and lymph nodes. This skewing is important to note, as weak interferon responses observed in COVID patients could hamper effective antiviral antibody and CD8 T-cell responses. Collectively, the data show induction of GC responses in a rhesus model of mild COVID-19. Supported by ORIP (P51OD011107 and P40OD010976) and NIAID.
Severely Ill COVID-19 Patients Display Impaired Exhaustion Features in SARS-CoV-2-Reactive CD8+ T Cells
Kusnadi et al., Science Immunology. 2021.
https://immunology.sciencemag.org/content/6/55/eabe4782.long
How CD8+ T cells respond to SARS-CoV-2 infection is not fully known. Investigators reported on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patient cells were segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was “exhausted” or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed less cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival Nuclear Factor κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. Overall, this single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2. Supported by ORIP (S10RR027366 and S10OD025052), NIAID, NHLBI, and NIGMS.
Thresholds for Post-Rebound SHIV Control after CCR5 Gene-Edited Autologous Hematopoietic Cell Transplantation
Cardozo-Ojeda et al., eLife. 2021.
https://elifesciences.org/articles/57646
Investigators developed a mathematical model to project the minimum threshold of C-C chemokine receptor type 5 (CCR5) gene-edited cells necessary for a functional cure from HIV. This was based on blood T cell reconstitution and plasma simian-HIV (SHIV) dynamics from SHIV-1157ipd3N4-infected juvenile pig-tailed macaques that underwent autologous transplantation with CCR5 gene editing. The model predicts that viral control can be obtained following analytical treatment interruption (ATI) when: (1) transplanted hematopoietic stem and progenitor cells (HSPCs) are at least fivefold higher than residual endogenous HSPCs after total body irradiation and (2) the fraction of protected HSPCs in the transplant achieves a threshold (76–94%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, spontaneous viral control is projected to occur. Supported by ORIP (P51OD010425), NCATS and NIAID.
Increased Proviral DNA in Circulating Cells Correlates With Plasma Viral Rebound in SIV-Infected Rhesus Macaques after Antiretroviral Therapy Interruption
Ziani et al., Journal of Virology. 2021.
https://jvi.asm.org/content/early/2021/01/05/JVI.02064-20
Investigators longitudinally tracked dynamic decay of cell-associated viral RNA/DNA in systemic and lymphoid tissues in SIV-infected rhesus macaques on prolonged combined antiretroviral therapy (cART) to evaluate predictors of viral rebound after treatment cessation. Suppressive cART substantially reduced plasma SIV RNA, cell-associated unspliced, and multiply spliced SIV RNA to undetectable levels, yet viral DNA remained detectable in systemic tissues and lymphoid compartments throughout cART. A rapid increase of integrated proviral DNA in peripheral mononuclear cells was detected once cART was withdrawn, accompanied by the emergence of detectable plasma viral load. The increase of peripheral proviral DNA post cART interruption correlated with the emergence and degree of viral rebound. These results suggest that measuring total viral DNA in SIV infection may be a relatively simple surrogate marker of reservoir size, and may predict viral rebound after treatment interruption, and inform treatment strategies. Supported by ORIP (P51OD011104), NIAID and NICHD.
Antibody-Mediated Depletion of Viral Reservoirs is Limited in SIV-Infected Macaques Treated Early With Antiretroviral Therapy
Swanstrom et al., Journal of Clinical Investigation. 2021.
https://doi.org/10.1172/JCI142421
Virus-specific strategies to target the latent HIV reservoir in individuals on combination antiretroviral therapy (cART) have been limited by inefficient induction of viral protein expression. Researchers used rhesus macaques to investigate an antibody-mediated reservoir targeting strategy, targeting the CD4 molecule rather than a viral protein, to deplete potential viral target cells irrespective of infection status. Despite profound CD4+ T cell depletion in blood and lymph nodes, time to viral rebound following cART cessation was not delayed in anti-CD4 treated animals compared with controls, likely due to the limited antibody-mediated cell depletion that occurred in rectal tissue and lymphoid follicles. Supported by ORIP (R24OD010976), NCI, and NIAID.
Responses to Acute Infection with SARS-CoV-2 in the Lungs of Rhesus Macaques, Baboons and Marmosets
Singh et al., Nature Microbiology. 2020.
https://www.nature.com/articles/s41564-020-00841-4
Investigators compared acute SARS-CoV-2 infection in young and old rhesus macaques and baboons. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies; both age groups recovered within 2 weeks. Baboons had prolonged viral RNA shedding and more lung inflammation compared with macaques; inflammation in bronchoalveolar lavage was increased in old versus young baboons. Macaques developed T-cell memory responses and bystander cytokine production. Old macaques had lower titers of SARS-CoV-2-specific IgG antibody levels compared with young macaques. The results indicate macaques and baboons experience acute respiratory distress that recapitulates the progression of COVID-19 in humans. Supported by ORIP (P51OD111033 and U42OD010442) and NIAID.