Tomoyuki Miura

This review systematically summarizes the development and applications of Simian-Human Immunodeficiency Virus (SHIV) models in rhesus macaques conducted by our research group from 2001 to 2023. Over this two-decade span, we have made significant contributions to HIV/AIDS research through the development and characterization of various SHIV models. Beginning with the isolation and characterization of molecular clones with different pathogenicities from SHIV-89.6P, we progressed to investigating the mechanisms of small intestinal CD4+ T cell depletion in SHIV infection. Subsequently, we developed R5-tropic SHIV models that better mimic natural HIV infection and conducted in-depth studies on neutralizing antibody induction and neutralization resistance. This review examines these research achievements chronologically, discusses their significance in understanding HIV/AIDS pathogenesis, and presents future research prospects in this field. Our findings have contributed substantially to elucidating the molecular mechanisms of HIV pathogenicity and establishing platforms for vaccine and therapeutic development.

Objectives: The durability and breadth of neutralizing antibodies following SARS-CoV-2 mRNA vaccination remain incompletely understood. This study aimed to investigate how longitudinal changes in antibody isotype composition impact neutralization against structurally diverse SARS-CoV-2 variants. Methods: After screening a broader cohort of mRNA-vaccinated sera, time-matched samples collected one month (1 mpv) and three months post-vaccination (3 mpv) were selected for detailed analysis. Neutralization assays against live virus variants, enzyme-linked immunosorbent assays (ELISA), and immunogold electron microscopy were performed to assess antibody titers, isotype levels, and virion morphology. Results: Neutralization titers declined markedly at 3 mpv, particularly against immune-evasive variants. Notably, the Lambda variant showed disproportionately high sensitivity to early-phase sera despite its divergence from the vaccine strain. Antibody isotyping showed that IgA and IgM decreased over time, while IgG levels were relatively more sustained. Electron microscopy revealed broader virion size heterogeneity in Lambda (50–200 nm) compared to Wuhan (80–120 nm), potentially enhancing multivalent antibody engagement. Consistently, ELISA under reduced spike density conditions showed that IgA and IgM retained stronger binding than IgG. Conclusions: These findings indicate that the decline of IgA and IgM compromises neutralization breadth, especially against structurally divergent variants such as Lambda. Sustaining dynamic multivalent isotype responses that adapt to diverse spike morphologies may be critical for broad cross-variant immunity.

SARS-CoV-2 has evolved as several variants. Immunization to boost the Ab response to Spike antigens is effective, but similar vaccines could not enhance Ab efficacy enough. Effective Ab responses against the human ACE2 (hACE2)-mediated infection of the emerging SARS-CoV-2 variants are needed. We identified closed linear epitopes of the SARS-CoV-2 Spike molecule that induced neutralizing Abs (nAbs) against both S1-RBD, responsible for attachment to hACE2, and S2-HR1/2, in convalescents and vaccine recipients. They inhibited a pseudo-virus infection mediated by the hACE2 pathway. The epitope sequences included epitopes #7 (aa411-432), #11 (aa459-480) and #111 (aa1144-1161), in S1-RBD and S2-HR2. Epitope #111 was conserved in Wuhan and variant strains, whereas #7 and #11 were conserved in Wuhan carried mutations K417N and S477N/T478K in Omicron BA.4/5. These mutations were recognized by the original epitope-specific Abs. These epitopes in RBD and HR2 neither contained, nor overlapped with, those responsible for the antibody-dependent enhancement of the SARS-CoV-2 infection. The sublingual administration of multiple epitope-conjugated antigens increased the IgG and IgA Abs specific to the neutralizing epitopes in mice pre-immunized subcutaneously. The findings indicated that S1-RBD and S2-HR2 epitopes were responsible for pseudo-virus SARS-CoV-2 infections and that sublingual boosts with multiple epitope-conjugated antigens could enhance the protection by nAbs of IgG and IgA against infection by a wide range of variants.