Tetherin-Driven Adaptation of Vpu and Nef Function and the Evolution of Pandemic and Nonpandemic HIV-1 Strains

Vpu proteins of pandemic HIV-1 M strains degrade the viral receptor CD4 and antagonize human tetherin to promote viral release and replication. We find that Vpus from SIVgsn, SIVmus and SIVmon infecting Cercopithecus primate species also degrade CD4 and antagonize tetherin. In contrast, SIVcpz, the immediate precursor of HIV-1, whose Vpu shares a common ancestry with SIVgsn/mus/mon Vpu, uses Nef rather than Vpu to counteract chimpanzee tetherin. Human tetherin, however, is resistant to Nef and thus poses a significant barrier to zoonotic transmission of SIVcpz to humans. Remarkably, Vpu from non-pandemic HIV-1 O strains are poor tetherin antagonists while those from the rare group N viruses do not degrade CD4. Thus, only HIV-1 M evolved a fully functional Vpu following the three independent cross-species transmissions that resulted in HIV-1 groups M, N, and O. This may explain why group M viruses are almost entirely responsible for the gobal HIV/AIDS pandemic

SIV Nef Proteins Recruit the AP-2 Complex to Antagonize Tetherin and Facilitate Virion Release

Lentiviral Nef proteins have multiple functions and are important for viral pathogenesis. Recently, Nef proteins from many simian immunodefiency viruses were shown to antagonize a cellular antiviral protein, named Tetherin, that blocks release of viral particles from the cell surface. However, the mechanism by which Nef antagonizes Tetherin is unknown. Here, using related Nef proteins that differ in their ability to antagonize Tetherin, we identify three amino-acids in the C-terminal domain of Nef that are critical specifically for its ability to antagonize Tetherin. Additionally, divergent Nef proteins bind to the AP-2 clathrin adaptor complex, and we show that residues important for this interaction are required for Tetherin antagonism, downregulation of Tetherin from the cell surface and removal of Tetherin from sites of particle assembly. Accordingly, depletion of AP-2 using RNA interference impairs the ability of Nef to antagonize Tetherin, demonstrating that AP-2 recruitment is required for Nef proteins to counteract this antiviral protein

Toward Microsurgical Correction of Cleft Lip Ex Utero through Restoration of Craniofacial Developmental Programs

BackgroundCleft lip with or without cleft palate is present in approximately one in 500 to 700 live births, representing the most common congenital craniofacial anomaly. Previously, the authors developed a unique murine model with compound Pbx deficiency that exhibits fully penetrant cleft lip with or without cleft palate. To investigate the possibility of tissue repair at an early gestational stage, the authors designed a minimally invasive surgical approach suitable for intrauterine repair using Wnt9b-soaked collagen microspheres to restore craniofacial developmental programs for cleft correction.MethodsCollagen microspheres with diameters ranging from 20 to 50 μm were fabricated to serve as a delivery vehicle for Wnt9b. At gestational day 11.5, wild-type and Pbx-deficient murine embryos were isolated. Microspheres soaked in murine purified Wnt9b protein were microsurgically implanted at the midface lambdoidal junction. Embryos were cultured in a 37°C modified whole-embryo culture system.ResultsTargeted release of Wnt9b resulted in augmented Wnt expression at the lambdoidal junction. Microsurgical implantation of Wnt9b-soaked microspheres resulted in cleft correction in 27.1 percent of the Pbx-deficient embryos. The difference in the ratio of the areas of clefting between implanted and nonimplanted embryos was significant (p < 0.05).ConclusionsEx utero correction of cleft lip with or without cleft palate in the authors' murine model by means of microsurgical intervention and targeted delivery of Wnt proteins is an innovative and promising strategy. Although further refinement and optimization of this technique will be required to improve efficacy, the authors believe that this approach will open new avenues toward unconventional prenatal interventions for patients with cleft lip with or without cleft palate, and provide future approaches for prenatal repair of other congenital head and neck disorders

Follow the money: Investigating gender disparity in industry payments among senior academics and leaders in plastic surgery.

IntroductionDifferences in academic qualifications are cited as the reason behind the documented gender gap in industry sponsorship to academic plastic surgeons. Gendered imbalances in academic metrics narrow among senior academic plastic surgeons. However, it is unknown whether this gender parity translates to industry payments.MethodsWe conducted a cross-sectional analysis of industry payments disbursed to plastic surgeons in 2018. Inclusion criteria encompassed (i) faculty with the rank of professor or a departmental leadership position. Exclusion criteria included faculty (i) who belonged to a speciality besides plastic surgery; (ii) whose gender could not be determined; or (iii) whose name could not be located on the Open Payment Database. Faculty and title were identified using departmental listings of ACGME plastic surgery residency programs. We extracted industry payment data through the Open Payment Database. We also collected details on H-index and time in practice. Statistical analysis included odds ratios (OR) and Pearson's correlation coefficient (R).ResultsWe identified 316 senior academic plastic surgeons. The cohort was predominately male (88%) and 91% held a leadership role. Among departmental leaders, women were more likely to be an assistant professor (OR 3.9, p = 0.0003) and heads of subdivision (OR 2.1, p = 0.0382) than men. Industry payments were distributed equally to male and female senior plastic surgeons except for speakerships where women received smaller amounts compared to their male counterparts (median payments of $3,675 vs$7,134 for women and men respectively, pConclusionDisparity in industry funding narrows at senior levels in academic plastic surgery. At higher academic levels, industry sponsorship may preferentially fund individuals based on academic productivity and career length. Increased transparency in selection criteria for speakerships is warranted

Nef proteins from simian immunodeficiency viruses are tetherin antagonists

The tetherin/BST2/CD317 protein blocks the release of HIV-1 and other enveloped viruses by inducing tethering of nascent particles to infected cell surfaces. The HIV-1 Vpu protein antagonizes the antiviral activity of human but not monkey tetherins and many simian immunodeficiency viruses (SIVs) do not encode Vpu. Here, we show that the apparently “missing” antitetherin activity in SIVs has been acquired by several SIV Nef proteins. Specifically, SIV<sub>MAC</sub>/SIV<sub>SMM</sub>, SIV<sub>AGM</sub>, and SIV<sub>BLU</sub> Nef proteins can suppress tetherin activity. Notably, tetherin antagonism by SIV Nef proteins is species specific, is genetically separable from other Nef activities, and is most evident with simian rather than human tetherin proteins. Accordingly, a critical determinant of sensitivity to SIV<sub>MAC</sub> Nef in the tetherin cytoplasmic tail is variable in nonhuman primate tetherins and deleted in human tetherin, likely due to selective pressures imposed by viral antagonists, perhaps including Nef proteins