APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.

Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated Na+ import/K+ efflux triggered activation of GPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.

Evolution of HIV-1 envelope towards reduced neutralization sensitivity, as demonstrated by contemporary HIV-1 subtype B from the United States.

Subtype B HIV-1 has been the primary driver of the HIV-1 epidemic in the United States (U.S.) for over forty years and is also a prominent subtype in the Americas, Europe, Australia, the Middle East and North Africa. In this study, the neutralization profiles of contemporary subtype B Envs from the U.S. were assessed to characterize changes in neutralization sensitivities over time. We generated a panel of 30 contemporary pseudoviruses (PSVs) and demonstrated continued diversification of subtype B Env from the 1980s up to 2018. Neutralization sensitivities of the contemporary subtype B PSVs were characterized using 31 neutralizing antibodies (NAbs) and were compared with strains from earlier in the HIV-1 pandemic. A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 NAbs for the contemporary as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the NAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A meta-analysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.

Actinomyces turicensis secondary to oral breast trauma as a cause of recurrent breast abscess.

Actinomycosis is a rare chronic infection, caused by species of the bacterium Actinomyces spp. This report proposes oral breast trauma as a cause of infection. An adult female in her 30s presented with a recurrent left breast abscess to a local hospital. She had previously undergone nine operations for abscess in the past 2 years. Shortly prior to her first presentation, a sexual partner with reported dental infection bit her periareolar area. The treating team noted that her bacterial culture from the first operation was positive for Actinomyces spp. She was treated with long-term intravenous antibiotics and had no further recurrences of infection. Oral trauma to the periareolar area by an individual with pre-existing dental disease has led to the introduction and establishment of this pathogen in the ductal system of the breast. This infection should be considered in cases of treatment resistant recurrent breast abscess.

JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.

COVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.

Neutralizing antibody VRC01 failed to select for HIV-1 mutations upon viral rebound.

Infusion of the broadly neutralizing antibody VRC01 has been evaluated in individuals chronically infected with HIV-1. Here, we studied how VRC01 infusions affected viral rebound after cessation of antiretroviral therapy (ART) in 18 acutely treated and durably suppressed individuals. Viral rebound occurred in all individuals, yet VRC01 infusions modestly delayed rebound and participants who showed a faster decay of VRC01 in serum rebounded more rapidly. Participants with strains most sensitive to VRC01 or with VRC01 epitope motifs similar to known VRC01-susceptible strains rebounded later. Upon rebound, HIV-1 sequences were indistinguishable from those sampled at diagnosis. Across the cohort, participant-derived Env showed different sensitivity to VRC01 neutralization (including 2 resistant viruses), yet neutralization sensitivity was similar at diagnosis and after rebound, indicating the lack of selection for VRC01 resistance during treatment interruption. Our results showed that viremia rebounded despite the absence of HIV-1 adaptation to VRC01 and an average VRC01 trough of 221 µg/mL. Although VRC01 levels were insufficient to prevent a resurgent infection, knowledge that they did not mediate Env mutations in acute-like viruses is relevant for antibody-based strategies in acute infection.

Dynamics of Human Immunodeficiency Virus-1 Genetic Diversification During Acute Infection.

We analyzed human immunodeficiency virus envelope diversity in 98 acute infections. The within-host genetic diversity, divergence from transmitted/founder (T/F) strain, and the observed frequency of multiple T/F infections increased with Fiebig stage. These data identify rapid viral dynamics during acute infection with implications for clinical trials conducted in this setting.

Fatores de proteção para a redução da vulnerabilidade à saúde / Protective factors to reduce vulnerability to health / Factores de protección para reducir la vulnerabilidad de la salud

Estudo de natureza qualitativa, fundamentado na Teoria Bioecológica do Desenvolvimento Humano, que objetivou conhecer os fatores de proteção para a redução da vulnerabilidade à saúde, a partir da percepção de adolescentes. Foram realizadas 14 entrevistas semiestruturadas com adolescentes, em uma escola de um município do interior do estado de São Paulo. A partir da análise temática dos dados, foi possível identificar quatro eixos temáticos: conhecer para se proteger; valores humanos como fatores de proteção; proteção familiar; e melhora nos atendimentos dos serviços públicos. Apreende-se que esses fatores refletem aspectos pessoais, processuais, contextuais e temporais vivenciados pelos adolescentes no seu cotidiano e nas suas relações sociais ou entre pares, na família ou na comunidade. Devem ser considerados os fatores de proteção vislumbrados pelos adolescentes e fortalecê-los para a busca de espaço que garanta uma participação efetivamente protagônica, para gerir grandes e promissores caminhos de promoção de processos de enfrentamento às situações de vulnerabilidade.

This is a qualitative study based on the Bioecological Theory of Human Development. It aimed at identifying protective factors to reduce adolescent vulnerability to health from the perception of adolescents. Fourteen semi-structured interviews were conducted with adolescents at a school in the state of São Paulo. Thematic analysis identified four main themes: knowledge as protective factor; human values as protective factor; family protection and improvement in public health services. Results demonstrated that these factors reflect personal, procedural, contextual and temporal experiences undergone by adolescents in their daily lives and in their social relations (amongst peers, family or community). Protective factors projected by adolescents should be identified and strengthened in order to define spaces that ensure their leading participation, to administer coping strategies in situations of vulnerability.

Estudio cualitativo, basado en la Teoría Bioecológica del Desarrollo Humano, que tiene por objeto identificar los factores de protección para reducir la vulnerabilidad de la salud, a partir de la percepción de los adolescentes. Se llevaron a cabo 14 entrevistas semi-estructuradas a adolescentes de una escuela del estado de São Paulo. A partir del análisis temático de los datos se identificaron cuatro temas: conocer para protegerse; valores humanos como factores de protección; protección de la familia y mejor atención en los servicios públicos. Se deduce que estos factores reflejan aspectos personales, procesales, contextuales y temporales vividos por los adolescentes en su vida cotidiana y en sus relaciones sociales o entre pares, en la familia o en la comunidad. Deben considerarse los factores de protección mencionados por los adolescentes y fortalecerlos para buscar el espacio que garantice una participación verdaderamente protagónica con miras a promover procesos para enfrentar las situaciones de vulnerabilidad.