The eradication of the viral reservoir represents the major obstacle to the development of a clinical cure for established HIV-1 infection. Here, we demonstrate that the administration of N-803 (brand name Anktiva) and broadly neutralizing antibodies (bNAbs) results in sustained viral control after discontinuation of antiretroviral therapy (ART) in simian-human AD8 (SHIV-AD8)–infected, ART-suppressed rhesus macaques. N-803+bNAbs treatment induced immune activation and transient viremia but only limited reductions in the SHIV reservoir. Upon ART discontinuation, viral rebound occurred in all animals, which was followed by durable control in approximately 70% of all N-803+bNAb–treated macaques. Viral control was correlated with the reprogramming of CD8 ⁺ T cells by N-803+bNAb synergy. Thus, complete eradication of the replication-competent viral reservoir is likely not a prerequisite for the induction of sustained remission after discontinuation of ART.

A prophylactic vaccine against human immunodeficiency virus (HIV) remains a top priority in biomedical research. Given the failure of conventional immunization protocols to confer robust protection against HIV, new and unconventional approaches may be needed to generate protective anti-HIV immunity. Here we vaccinated rhesus macaques (RMs) with a recombinant (r)DNA prime (without any exogenous adjuvant), followed by a booster with rhesus monkey rhadinovirus (RRV)−a herpesvirus that establishes persistent infection in RMs (Group 1). Both the rDNA and rRRV vectors encoded a near-full-length simian immunodeficiency virus (SIVnfl) genome that assembles noninfectious SIV particles and expresses all nine SIV gene products. This rDNA/rRRV-SIVnfl vaccine regimen induced persistent anti-Env antibodies and CD8+ T-cell responses against the entire SIV proteome. Vaccine efficacy was assessed by repeated, marginal-dose, intrarectal challenges with SIVmac239. Encouragingly, vaccinees in Group 1 acquired SIVmac239 infection at a significantly delayed rate compared to unvaccinated controls (Group 3). In an attempt to improve upon this outcome, a separate group of rDNA/rRRV-SIVnfl-vaccinated RMs (Group 2) was treated with a cytotoxic T-lymphocyte antigen-4 (CTLA-4)-blocking monoclonal antibody during the vaccine phase and then challenged in parallel with Groups 1 and 3. Surprisingly, Group 2 was not significantly protected against SIVmac239 infection. In sum, SIVnfl vaccination can protect RMs against rigorous mucosal challenges with SIVmac239, a feat that until now had only been accomplished by live-attenuated strains of SIV. Further work is needed to identify the minimal requirements for this protection and whether SIVnfl vaccine efficacy can be improved by means other than anti-CTLA-4 adjuvant therapy. Given the remarkable immune evasion properties of human immunodeficiency virus (HIV), unorthodox vaccine approaches might be needed to elicit protective anti-HIV immunity. Here we investigated whether vaccination with a near-full-length simian immunodeficiency virus (SIVnfl) genome could protect rhesus macaques (RMs) against pathogenic SIV challenge. To deliver SIVnfl, we used a DNA prime followed by a booster with a herpesvirus that establishes persistent infection in RMs. SIVnfl vaccinees developed long-lasting antibodies against the SIV Envelope protein and T-cell responses against the entire SIV proteome. Encouragingly, SIVnfl vaccinees were significantly protected against intrarectal challenge with SIVmac239, a feat that until now had only been accomplished by live-attenuated strains of SIV. Curiously, combining the aforementioned vaccine regimen with immune checkpoint blockade did not result in protection against SIVmac239 infection in a separate group of RMs. Vaccination with inactivated immunodeficiency virus genomes should, therefore, be considered as a potential strategy for eliciting anti-HIV immunity.

HIV-1 Vpu targets the host cell proteins CD4 and BST-2/Tetherin for degradation, ultimately resulting in enhanced virus spread and host immune evasion. The discovery and characterization of small molecules that antagonize Vpu would further elucidate the contribution of Vpu to pathogenesis and lay the foundation for the study of a new class of novel HIV-1 therapeutics. To identify novel compounds that block Vpu activity, we have developed a cell-based ‘gain of function’ assay that produces a positive signal in response to Vpu inhibition. To develop this assay, we took advantage of the viral glycoprotein, GaLV Env. In the presence of Vpu, GaLV Env is not incorporated into viral particles, resulting in non-infectious virions. Vpu inhibition restores infectious particle production. Using this assay, a high throughput screen of >650,000 compounds was performed to identify inhibitors that block the biological activity of Vpu. From this screen, we identified several positive hits but focused on two compounds from one structural family, SRI-41897 and SRI-42371. We developed independent counter-screens for off target interactions of the compounds and found no off target interactions. Additionally, these compounds block Vpu-mediated modulation of CD4, BST-2/Tetherin and antibody dependent cell-mediated toxicity (ADCC). Unfortunately, both SRI-41897 and SRI-42371 were shown to be specific to the N-terminal region of NL4-3 Vpu and did not function against other, more clinically relevant, strains of Vpu; however, this assay may be slightly modified to include more significant Vpu strains in the future.

We report severe neutropenia in a 77-year-old female with mosaic TLR8 gain-of-function due to a novel variant. Treatment with ruxolitinib, prednisone, and GM-CSF resulted in clinical improvement. This case expands the phenotypic spectrum beyond pediatric and male cohorts, highlighting mosaicism in late-onset immune dysregulation.

The pathogenic mechanisms underlying pyoderma gangrenosum (PG) remain unclear. Here we report three patients with PG from two unrelated kindreds with homozygous R57C mutation of the linear deubiquitinase OTULIN. The patients have isolated, pediatric-onset, OTULIN-related PG (ORP). In contrast to OTULIN-related autoinflammatory syndrome (ORAS), caused by mutations affecting the catalytic domain, R57C affects the PUB-interacting motif with distinct biochemical, immunological and clinical consequences. OTULIN-R57C is catalytically active but is unable to bind the linear ubiquitin assembly complex (LUBAC). Patient monocytes show heightened expression of IL1B , and OTULIN-R57C fails to suppress inflammasome activity. Patients have elevated levels of TNF, and their dermal fibroblasts show heightened susceptibility to TNF-dependent cell death. Homozygosity for OTULIN-R57C leads to accumulation of linear ubiquitin and LUBAC autoubiquitination in patients’ dermal fibroblasts, consistent with pathogenic LUBAC activity. These findings identify a genetic etiology of isolated PG of childhood. We propose a multifactorial mechanism of ORP, including myeloid IL-1β production and TNF-driven death of skin-resident cells, suggesting that blockade of IL-1β or TNF are therapeutic options in PG.

Mutations in the gene PSTPIP1 may cause several different autoinflammatory syndromes, but the mechanisms by which distinct PSTPIP1 mutations lead to these differing phenotypes are not fully understood. The two best characterized autoinflammatory conditions resulting from PSTPIP1 mutation are pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome. Here, we report a novel gain-of-function PSTPIP1 mutation (p.N236K) causing PAMI syndrome in a patient with systemic autoinflammation and severe neutropenia. This mutant form of PSTPIP1 shows increased binding to pyrin and leads to heightened inflammasome formation, relative to WT PSTPIP1. We also identify a transcriptional signature in blood from PAMI patients suggestive of enhanced T cell activation and altered neutrophil survival and/or function. Further research on PSTPIP1-related autoinflammatory conditions is needed to more deeply understand the genetic and immunological drivers of disease and contribute to improving patient outcomes.