Attacking HIV by stabilizing its capsid: Current HIV treatments require drugs that must be taken daily, and care would be improved with an effective drug that is long-acting. GS-6207 (Lenacapavir) is a drug developed by Gilead Sciences that shows potential for a 6-month dosing interval and is in phase 2/3 clinical trials. Bester et al. describe structural and biophysical studies that provide a basis for the potent antiviral activity of GS-6207. The HIV capsid is cone shaped, and GS-6207 binds two neighboring capsid subunits and stabilizes the curved capsid. GS-6207 also interferes with capsid binding of cofactors that play a role in viral infection. This insight into GS-6207 activity provides a platform for the rational development of improved long-acting therapies. Science , this issue p. 360

Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1 infection. While weak interactions of short phenylalanine-glycine (FG) containing peptides with isolated capsid hexamers have been characterized, how these cellular factors functionally engage with biologically relevant mature HIV-1 capsid lattices is unknown. Here we show that prion-like low complexity regions (LCRs) enable avid CPSF6, NUP153 and SEC24C binding to capsid lattices. Structural studies revealed that multivalent CPSF6 assembly is mediated by LCR-LCR interactions, which are templated by binding of CPSF6 FG peptides to a subset of hydrophobic capsid pockets positioned along adjoining hexamers. In infected cells, avid CPSF6 LCR-mediated binding to HIV-1 cores is essential for functional virus-host interactions. The investigational drug lenacapavir accesses unoccupied hydrophobic pockets in the complex to potently impair HIV-1 inside the nucleus without displacing the tightly bound cellular cofactor from virus cores. These results establish previously undescribed mechanisms of virus-host interactions and antiviral action.

HBsAg loss is only observed in a small proportion of patients with chronic hepatitis B (CHB) who undergo interferon treatment. Investigating the host factors crucial for CHB functional cure can aid in identifying individuals who would benefit from Peginterferon-alpha (Peg-IFNα) therapy. We conducted a Genome-wide association study (GWAS) by enrolling 48 CHB patients with HBsAg loss and 47 with HBsAg persistence after Peg-IFNα treatment. In the validation stage, we included a total of 224 samples, out of which 90 achieved HBsAg loss, to validate the identified significant SNPs. To verify the functional involvement of candidate genes identified, we performed a series of in vitro and in vivo experiments. GWAS results indicated a significant association between the rs7519753 C allele and serum HBsAg loss in CHB patients after Peg-IFNα treatment (P = 4.85 × 10^-8, OR = 14.47). This association was also observed in two independent validation cohorts. eQTL analysis revealed higher hepatic TP53BP2 expression in individuals carrying the rs7519753 C allele (P = 2.90 × 10^-6). Liver biopsy RNA-seq from patients with CHB after Peg-IFNα treatment revealed that hepatic TP53BP2 level in the HBsAg loss group was significantly higher compared to the HBsAg persistence group (P = 0.035). In vitro and in vivo experiments demonstrated that loss of TP53BP2 decreased interferon-stimulated genes (ISGs) level and the anti-HBV effect of IFN-α. Mechanistically, TP53BP2 was found to downregulate SOCS2, thereby facilitating JAK/STAT signaling. Rs7519753 C allele is associated with an increased probability of serum HBsAg loss in patients with CHB post-Peg-IFNα treatment and elevated hepatic TP53BP2 expression. TP53BP2 enhances the response of the hepatocyte to IFN-α by suppressing SOCS2 expression. Chronic Hepatitis B (CHB) remains a global public health issue. Although current antiviral therapies are more effective in halting disease progression, only a few patients achieve functional cure for hepatitis B with HBsAg loss, highlighting the urgent need for a cure for CHB. This study revealed that the SNP rs7519753 C allele, which is associated with high expression of hepatic TP53BP2, significantly increases the likelihood of serum HBsAg loss in CHB patients undergoing Peg-IFNα therapy. This finding not only provides an exciting predictor for HBsAg loss but identifies a potential therapeutic target for Peg-IFNα treatment. We believe our results are of great interest to a wide range of stakeholders, including patients and patient organizations, the medical community, academia, the life science industry, and the general public.

CagA, a virulence factor of Helicobacter pylori (H. pylori), is known to drive inflammation in gastric epithelial cells and is typically degraded through autophagy. However, the molecular mechanism by which CagA evades autophagy-mediated degradation remains elusive. This study found that H. pylori inhibits autophagic flux by upregulating the expression of AU-rich element RNA-binding factor 1 (AUF1). We confirmed that AUF1 does not affect autophagy initiation but instead hampers lysosomal clearance, as evidenced by treatments with 3-MA, CQ and BafA1. Upregulated AUF1 stabilizes CagA protein levels by inhibiting the autolysosomal degradation of intracellular CagA in H. pylori-infected gastric epithelial cells. Knocking down AUF1 promotes CagA degradation, an effect that can be reversed by the lysosome inhibitor BafA1 and CQ. Transcriptome analysis of AUF1-knockdown gastric epithelial cells infected with H. pylori indicated that AUF1 regulates the expression of lysosomal-associated hydrolase genes, specifically CTSD, to inhibit autolysosomal degradation. Moreover, we observed that knockdown of AUF1 enhanced the stability of CTSD mRNA and identified AUF1 binding to the 3'UTR region of CTSD mRNA. AUF1-mediated downregulation of CTSD expression contributes to CagA stability, and AUF1 overexpression leads to an increase in CagA levels in exosomes, thus promoting extracellular inflammation. In clinical gastric mucosa, the expression of AUF1 and its cytoplasmic translocation are associated with H. pylori-associated gastritis, with CagA being necessary for the translocation of AUF1 into the cytoplasm. Our findings suggest that AUF1 is a novel host-positive regulator of CagA, and dysregulation of AUF1 expression increases the risk of H. pylori-associated gastritis.

Within the family of Retroviridae, foamy viruses (FVs) are unique and unconventional with respect to many aspects in their molecular biology, including assembly and release of enveloped viral particles. Both components of the minimal assembly and release machinery, Gag and Env, display significant differences in their molecular structures and functions compared to the other retroviruses. This led to the placement of FVs into a separate subfamily, the Spumaretrovirinae. Here, we describe the molecular differences in FV Gag and Env, as well as Pol, which is translated as a separate protein and not in an orthoretroviral manner as a Gag-Pol fusion protein. This feature further complicates FV assembly since a specialized Pol encapsidation strategy via a tripartite Gag-genome–Pol complex is used. We try to relate the different features and specific interaction patterns of the FV Gag, Pol, and Env proteins in order to develop a comprehensive and dynamic picture of particle assembly and release, but also other features that are indirectly affected. Since FVs are at the root of the retrovirus tree, we aim at dissecting the unique/specialized features from those shared among the Spuma- and Orthoretrovirinae. Such analyses may shed light on the evolution and characteristics of virus envelopment since related viruses within the Ortervirales, for instance LTR retrotransposons, are characterized by different levels of envelopment, thus affecting the capacity for intercellular transmission.