Hiroshi Matsuo

Primate lentiviruses counteract antiviral APOBEC3 (A3) cytidine deaminases through virion infectivity factor (Vif), which recruits A3 proteins to a Cullin–RING E3 ubiquitin ligase for proteasomal degradation. While HIV-1 Vif is well characterized, HIV-2 Vif remains poorly defined due to divergent sequences. Here we report a 3.08 Å cryo-EM structure of HIV-2 Vif bound to chimpanzee A3H (cpzA3H) and E3 ligase components. HIV-2 Vif adopts a conserved global fold but engages cpzA3H through a binding interface distinct from HIV-1 Vif, achieving target recognition through numerous weak contacts distributed across an extended interface. The structure reveals a direct CBFβ–cpzA3H interface absent in HIV-1 Vif-A3H complexes, establishing CBFβ as a bivalent adaptor that actively contributes to substrate recruitment. Despite these structural differences, lysine 50 of cpzA3H is the shared ubiquitination target of both HIV-1- and HIV-2 Vif-induced degradation, revealing convergent function achieved through divergent structural solutions.

Spatially resolved multiwavelength analysis is essential to study galaxy formation and evolution. A UV-bright galaxy COS-2987030247 at z = 6.81 is one of the Rosetta Stones in the epoch of reionization for which JWST NIRSpec Integral Field Spectroscopy, NIRCam imaging, and Atacama Large Millimeter/submillimeter Array data are available thanks to the RIOJA program. We identified the rest-frame optical emission lines from the ionized hydrogen, oxygen, and neon gas. The [O iii ] 5008 Å line emission and the NIRCam images show a complex kinematical and morphological structure where two bright main and three faint clumps are identified in a 10 kpc extent. The system is not classified as a purely rotation-dominated disk. The multiple clumps are instead consistent with a merger-related origin, including either distinct galaxies in interaction or star-forming clumps formed through tidal gas compression during a merger. The spatially resolved emission line fluxes show that dust attenuation, metal enrichment, and ionization parameter are preferentially enhanced in the star formation peaks. Our spectral energy distribution fitting suggests that the main clumps are in a moderately dust-attenuated star-forming phase ( A _V   = 0.2–0.3 and SFR(H α ) ∼10 M _⊙ yr ⁻¹ ) with almost zero escape fraction of ionizing photons. In contrast, the subclumps are dust-free and lying on or below the main sequence of star-forming galaxies. These subclumps may work as a perturber that triggers the clumpy starburst in the surrounding gas through the merger event.

We report the discovery of a complex density-stratified interstellar medium (ISM) in the star-forming galaxy COS-2987 at z = 6.81, revealed by the unprecedented synergy between James Webb Space Telescope (JWST)/NIRSpec integral field spectroscopy and Atacama Large Millimeter/submillimeter Array (ALMA) observations. These observations detect key emission lines, including [O ii] λλ 3727, 3730, [O iii] 4364, [O iii] λλ 4960, 5008, and [O iii] 88 μm, as well as Hα and Hβ. JWST spectroscopy alone indicates ISM properties that are typical for galaxies at z ∼ 7. These include low dust extinction (A _V ≈ 0.14 mag), moderate electron density (n _e ≈ 500 cm⁻³), and low gas-phase metallicity (∼10%). However, the strong far-infrared [O iii] 88 μm emission detected by ALMA cannot be explained by a single-component ionized medium with uniform electron density and temperature. Instead, a two-component ISM model—comprising compact, high-temperature, and high-density gas components (T _e ≈ 26,000 K; n _e ≈ 600 cm⁻³) and an extended, cooler, and lower-density component (T _e ≈ 8​​​​​​000 K; n _e ≈ 50 cm⁻³)—successfully reproduces the observed line ratios of [O iii] 88 μm/[O iii] 5008 Å and [O iii] 4364/[O iii] 5008 Å, with a volume ratio of 1 : 300 between the two components. Our results demonstrate that JWST alone probes only a fraction of the ISM and highlight the critical importance of combining JWST and ALMA to reveal the density-stratified ISM of early galaxies.

We observed the gravitationally lensed (μ = 9.6 ± 0.19) galaxy A1689-zD1 at z = 7.1 in bands 3, 6, and 8 of the Atacama Large Millimeter/submillimeter Array. These high-resolution observations (≈200 pc) enabled us to separate the source into five components in the [C II] 158 μm and [O III] 88 μm emission lines within a projected distance of 2 kpc. Even though these components appear to vary strongly from one another in both their line, continuum, and optical characteristics, the assembly of components do not show ordered rotation and appear consistent with simulations of a galaxy system undergoing the process of assembly. The total dynamical mass of the galaxy (2 × 10¹⁰ M_⊙) is an order of magnitude larger than the spectrally estimated stellar mass, suggesting a near-complete optical obscuration of the bulk of the stellar component. Comparing the line ratios as well as the line properties to other properties such as the star formation rate, we find that A1689-zD1 is consistent with the relations derived from local star-forming galaxies. Even though A1689-zD1 lies on local star formation scaling relations and has a high dust and stellar mass estimate, the kinematics suggest it is in an early assembly stage, which could lead to it becoming a disk galaxy at a later stage.

Porous interstellar medium (ISM) structure in galaxies at the epoch of reionization gives us a hint to understand what types of galaxies contribute to reionization. Although recent studies have pointed out the positive correlation between high ionizing photon escape fractions and high [O iii] 88 μm/[C ii] 158 μm ratios found in UV-luminous star-forming galaxies at z > 6 with the Atacama Large Millimeter/submillimeter Array, previous studies have paid little attention to the neutral gas porosity that allows ionizing photons to escape. Here we present a detailed analysis of a z = 8.312 Lyman break galaxy, MACS0416_Y1 with a high L _{[O III] 88 μm}/L _{[C II] 158 μm} ratio (≈9) and dust continuum detection. We construct a multiphase ISM model incorporating the neutral gas covering fraction (c ov _PDR). The best-fit model reveals a cov _PDR ≈ 25%, indicating that ≈75% of the ionized gas region is exposed to intercloud space. We confirm that our conclusions hold even when varying star formation history, stellar age, gas/stellar metallicity, and carbon-to-oxygen abundance ratio. This finding meets one of the necessary conditions for galaxies to have a nonzero escape fraction of ionizing photons and supports recent studies that galaxies with a high [O iii] 88 μm/[C ii] 158 μm ratio, such as MACS0416_Y1, could contribute to cosmic reionization. Furthermore, the modeled H ii region with the best-fitting parameters has a typical size (D = 0.90 pc) and gas density ( log n H , c / cm − 3 = 2.7 ) that are comparable to local compact H ii regions. This suggests that the H ii regions in MACS0416_Y1 are in an early evolutionary stage.

The APOBEC3 family of cytidine deaminases restricts retroviruses like HIV-1 by mutating viral DNA. HIV-1 evades this restriction by producing Vif, which recruits the Cullin-5 (CUL5) E3 ubiquitin ligase complex to promote APOBEC3 degradation. Here we resolve key aspects of this counter-defense mechanism by determining a 3.6 Å cryo-EM structure of chimpanzee APOBEC3H (cpzA3H) in complex with HIV-1 Vif and three components of the CUL5 E3 ligase-CBFβ, EloB, and EloC (VCBC). The structure captures cpzA3H as an RNA-mediated dimer within the cpzA3H-VCBC complex, allowing us to examine the role of dimerization. We find that ubiquitination occurs specifically at two lysine residues on the Vif-proximal protomer, while the distal protomer remains unmodified. The structural model of the active cpzA3H–Vif–CUL5 E3 ligase holoenzyme reveals spatial preferences for ubiquitin transfer to the targeted lysine residues. These findings enhance our understanding of A3H degradation and suggest new antiviral strategies targeting this host-virus interface.

APOBEC3 (or A3) enzymes have emerged as potential therapeutic targets due to their role in introducing heterogeneity in viruses and cancer, often leading to drug resistance. Inhibiting these enzymes has remained elusive as initial phosphodiester (PO)-linked DNA-based inhibitors lack cellular stability and potency. We have enhanced both potency and nuclease stability of 2′-deoxyzebularine (dZ) substrate-based oligonucleotide inhibitors targeting two critical A3s: A3A and A3G. While replacing the phosphate backbone with phosphorothioate (PS) linkages increased nuclease stability, fully PS-modified inhibitors lost potency (up to three-fold) due to the structural constraints of the active site. For both enzymes, mixed PO/PS backbones enhanced potency (up to nine-fold), while also vastly improving nuclease resistance. We also strategically introduced 2′-fluoro sugar modifications, creating the first nanomolar inhibitor of A3G-CTD2. With hairpin-structured inhibitors containing optimized PS patterns and locked nucleic acid (LNA) sugar modifications, we characterize the first single-digit nanomolar inhibitor targeting A3A. These extremely potent A3A inhibitors were highly resistant to nuclease degradation and crucially, restricted A3A deamination in cellulo. Overall, our optimally designed A3 oligonucleotide inhibitors show improved potency and stability compared to previous inhibitors targeting these critical enzymes, toward realizing the therapeutic potential of A3 inhibition.

We present JWST NIRCam imaging of B14-65666 (“Big Three Dragons”), a bright Lyman-break galaxy system (M _UV = −22.5 mag) at z = 7.15. The high angular resolution of NIRCam reveals the complex morphology of two galaxy components: galaxy E has a compact core (E-core), surrounded by diffuse, extended, rest-frame optical emission, which is likely to be tidal tails; and galaxy W has a clumpy and elongated morphology with a blue UV slope (β _UV = −2.2 ± 0.1). The flux excess, F356W − F444W, peaks at the E-core ( 1.0 5 − 0.09 + 0.08 mag), tracing the presence of strong [O iii] λλ4960,5008 emission. Atacama Large Millimeter/submillimeter Array archival data show that the bluer galaxy W is brighter in dust continua than the redder galaxy E, while the tails are bright in [O iii] 88 μm. The UV/optical and submillimeter spectral energy distribution (SED) fitting confirms that B14-65666 is a major merger in a starburst phase as derived from the stellar mass ratio (3:1 to 2:1) and the star formation rate, ≃1 dex higher than the star formation main sequence at the same redshift. Galaxy E is a dusty (A _V = 1.2 ± 0.1 mag) starburst with a possible high dust temperature (≥63–68 K). Galaxy W would have a low dust temperature (≤27–33 K) or patchy stellar-and-dust geometry, as suggested by the IR excess and β _UV diagram. The high optical-to-far-IR [O iii] line ratio of the E-core shows its lower gas-phase metallicity (≃0.2–0.4 Z _⊙) than galaxy W. These results agree with a scenario where major mergers disturb morphology and induce nuclear dusty starbursts triggered by less-enriched inflows. B14-65666 shows a picture of complex stellar buildup processes during major mergers in the epoch of reionization.