Diversity in online resources for breast reconstruction: What do patients see?

BACKGROUND: Online resources are commonly used by patients to obtain information on breast reconstruction. Despite the key role of these resources in patient decision-making, their visual content has not yet been evaluated. This study sought to 1) characterize the presence and content of visual aids in online patient education breast reconstruction resources and 2) determine if the women represented in these visual aids reflect the breast reconstruction patient population in the United States. METHODS: The top 10 Google websites and the first 400 Google Images containing photographs/graphics depicting human skin for the search phrase "breast reconstruction" were analyzed. Images were categorized by content as "Before/After," "Surgical/Anatomical," "Step-by-Step," or "Breast-Centric Stock Images." Image subjects were classified by skin tone into "White" or "Non-White" using the Fitzpatrick scale and by body type into "Lean" or "Full-Figured." RESULTS: In total, 471 images were analyzed. These were predominantly "Before/After" images (43.9%), followed by "Breast-Centric Stock Images" (27.4%), "Surgical/Anatomical" (24.2%), and "Step-by-Step" (4.5%). The majority of all images depicted "White" skin types (90.7%) and "Lean" body types (73.0%). "Before/After" images were more likely to show "Full-Figured" women than the other content categories (p < 0.0001) and had the highest percentage of "Non-White" skin types (35.3%). CONCLUSIONS: Our findings demonstrate that breast reconstruction online resources are not reflective of the patient population seeking reconstruction. Improving the diversity of online image resources can both better represent our diverse patient population as well as better align patient expectations with postoperative outcomes, likely improving patient satisfaction.

Evaluating Diversity Promotion on Integrated Plastic Surgery Residency Program Websites and Instagram Accounts.

BACKGROUND: Medical students applying to residency, including those from underrepresented groups, strongly value cultural fit and program diversity. Program websites and social media are thus an influential information source for prospective applicants and recruitment tool for residencies. We evaluated whether and how integrated plastic surgery residency program websites and social media display commitments to diversity online. METHODS: We evaluated program websites for 8 predetermined diversity elements, (1) nondiscrimination and (2) diversity statements, (3) community resources, (4) faculty and (5) resident biographies, (6) faculty and (7) resident photographs, and (8) resident resources, and assessed Instagram accounts for diversity-related images, captions, and hashtags. Our analysis used Mann-Whitney U , chi-squared, and t tests; significance level was P < 0.05. RESULTS: We reviewed 82 program websites with a mean of 3.4 ± 1.4 diversity elements. Resident (n = 76, 92.7%) and faculty photographs (n = 65, 79.3%) and resident biographies (n = 43, 52.4%) were the most common. Seventy programs (85.4%) had Instagram accounts, the majority of which (n = 41, 58.6%) shared content related to diversity in race, ethnicity, gender, and/or sexual orientation. Programs located in smaller cities were more likely to have ≥4 website diversity elements ( P = 0.014) and mention diversity on Instagram ( P = 0.0037). Programs with women chairs/chiefs were more likely to mention diversity on Instagram ( P = 0.007). CONCLUSIONS: In the age of virtual recruitment, program websites and social media should provide sufficient information, described in our diversity element checklist, to help prospective applicants determine fit from a diversity perspective. Residents, who often contribute to program social media, and women chairs/chiefs may be critical to driving diversity promotion.

Gender and Ethnic Diversity in Plastic Surgery: Temporal Trends among Speakers at National and Regional Plastic Surgery Conferences.

BACKGROUND: Scientific leadership among women and underrepresented minorities is lacking in plastic surgery. It is unknown whether the underrepresentation of women and ethnic minorities extends into academic conferences. The authors evaluated the temporal trends of female and ethnic minority representation at plastic surgery conferences in the United States. METHODS: A retrospective analysis of all presentations from seven national and regional plastic surgery meetings between 2014 and 2018 was conducted. Gender, ethnicity, and academic rank of the first authors were determined by analyzing pronouns, institutional biographies, and accompanying images identified in online searches. RESULTS: A total of 4180 abstracts were presented by 3452 first authors. The majority of first authors were of European descent (53%), male (65%), and most commonly a resident physician (42%). Women were found to have a greater representation at plastic surgery conferences than in the plastic surgery workforce (34% versus 17%; P < 0.0001). Similarly, relative to American Association of Medical Colleges demographics, individuals of Asian descent were overrepresented as first authors (27% versus 12%; P < 0.0001), whereas first authors of European descent were less prevalent (53% versus 64%; P < 0.0001). When compared with national plastic surgery conferences, regional conferences had a greater proportion of first authors of European descent (51% versus 58%; P < 0.0001) but a lower proportion of first authors of East Asian descent (21% versus 16%; P = 0.0001). Ethnic representation remained persistently low, with first authors of South Asian descent decreasingly represented [from 2014 (10%) to 2018 (6%); P = 0.0062]. CONCLUSIONS: Collectively, we present multilevel data that show a promising trend of increased female representation at national meetings. However, there appears to be a decline in ethnic diversity.

The Digital Footprint of Academic Plastic Surgeons.

INTRODUCTION: The digital age and global pandemic have transformed the way patients select their plastic surgeon. However, as more patients turn to online resources, there is little information on the digital presence of academic plastic surgeons. METHODS: We identified all academic faculty from integrated and independent plastic surgery residency programs. Using a Google-based custom search, the top 10 search results for each surgeon were extracted and categorized as surgeon noncontrolled (eg, physician rating websites) or controlled (eg, social media, institutional, and research profiles). RESULTS: Eight hundred four academic plastic surgeons were included. Most search results were surgeon-noncontrolled sites (57%, n = 4547). Being male (odds ratio [OR], 0.60, P = 0.0020) and holding a higher academic rank (OR = 0.61, P < 0.0001) significantly decreased the prevalence of physician rating websites, whereas career length was significantly associated with a greater number of rating websites (OR = 1.04, P < 0.0001). Surgeon-controlled websites were significantly influenced by academic rank and years in practice; higher academic rank was associated with more social media platforms (OR = 1.42, P = 0.0008), institutional webpages (OR = 1.57, P < 0.0001), and research profiles (OR = 1.62, P = 0.0008). Conversely, longer career duration was a predictor for fewer social media platforms (OR = 0.95, P < 0.0001) and institutional webpages (OR = 0.95, P < 0.0001). CONCLUSIONS: Academic plastic surgeons do not hold control of the majority of their search results. However, digitally savvy plastic surgeons can focus attention by building on certain areas to optimize their digital footprint. This study can serve as a guide for academic plastic surgeons wishing to control their online presence.

Gender Affirming Surgery: A Comprehensive, Systematic Review of All Peer-reviewed Literature and Methods of Assessing Patient-centered Outcomes (Part 1: Breast/Chest, Face, and Voice).

OBJECTIVE: To perform the first systematic review of all available gender-affirming surgery (GAS) publications across all procedures to assess both outcomes reported in the literature and the methods used for outcome assessment. SUMMARY OF BACKGROUND DATA: Rapidly increasing clinical volumes of gender-affirming surgeries have stimulated a growing need for high-quality clinical research. Although some procedures have been performed for decades, each individual procedure has limited data, necessitating synthesis of the entire literature to understand current knowledge and guide future research. METHODS: A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify all outcomes measures in GAS cohorts, including PCOs, complications, and functional outcomes. Outcome data were pooled to assess currently reported complication, satisfaction, and other outcome rates. RESULTS: Overall, 15,186 references were identified, 4162 papers advanced to abstract review, and 1826 underwent full-text review. After review, there were 406 GAS cohort publications. Of non-genitoplasty titles, 35 were mastectomy, 6 mammoplasty, 21 facial feminization, and 31 voice/cartilage. Although 59.1% of non-genitoplasty papers addressed PCOs in some form, only 4.3% used instruments partially-validated in transgender patients. Overall, data were reported heterogeneously and were biased towards high-volume centers. CONCLUSIONS: This study represents the most comprehensive review of GAS literature. By aggregating all previously utilized measurement instruments, this study offers a foundation for discussions about current methodologic limitations and what dimensions must be included in assessing surgical success. We have assembled a comprehensive list of outcome instruments; this offers an ideal starting basis for emerging discussions between patients and providers about deficiencies which new, better instruments and metrics must address. The lack of consistent use of the same outcome measures and validated GAS-specific instruments represent the 2 primary barriers to high-quality research where improvement efforts should be focused.

Gender Affirming Surgery: A Comprehensive, Systematic Review of All Peer-reviewed Literature and Methods of Assessing Patient-centered Outcomes (Part 2: Genital Reconstruction).

OBJECTIVE: To perform the first systematic review of all available GAS publications across all procedures to assess outcomes reported in the literature and the methods used for outcome assessment. SUMMARY OF BACKGROUND DATA: Assessment of GAS results is complex and multidimensional, involving not only complication rates but also anatomic (eg, vaginal depth), functional (eg, urinary), and psychosocial outcomes. A fully comprehensive aggregation of all prior research would offer an essential cornerstone for continued progress. METHODS: A systematic review was performed after PRISMA guidelines to identify all outcomes measures in GAS cohorts, including patient-centered outcomes, complications, and functional outcomes. Data were aggregated to assess pooled rates of complications, satisfaction, and other outcomes. RESULTS: Overall, 15,186 references were identified, 4162 papers advanced to abstract review, and 1826 underwent full-text review. After review, there were 406 GAS cohort publications, including 171 vaginoplasty, 82 phalloplasty, 16 metoidioplasty, 23 oophorectomy/vaginectomy, and 21 with multiple procedures.Although 68.7% of genitoplasty papers addressed patient-centered outcomes, only 1.0% used metrics validated in the transgender population. Forty-three different outcome instruments were used. No instrument was used in more than 15% of published series and 38 were used in only 1 or 2 publications. CONCLUSIONS: Our review found high patient satisfaction for genital procedures but little concordance between study methods, with almost 90% of patient-focused outcome metrics appearing only once or twice. Standardization of outcome instruments and measurement methods through patient-inclusive, multidisciplinary consensus efforts is the essential next step for quality improvement. As GAS continues to mature, building on current foundations with the goal of improving both surgical and patient-reported outcomes is essential.

Occupational exposures in the operating room: Are surgeons well-equipped?

BACKGROUND: Occupational health hazards are ubiquitously found in the operating room, guaranteeing an inevitable risk of exposure to the surgeon. Although provisions on occupational health and safety in healthcare exist, they do not address non-traditional hazards found in the operating room. In order to determine whether surgeons or trainees receive any form of occupational health training, we examine the associations between occupational health training and exposure rate. STUDY DESIGN: A cross-sectional survey was distributed. Respondent characteristics included academic level, race/ethnicity, and gender. The survey evaluated seven surgical disciplines and 13 occupational hazards. Multivariable logistic regression was used to examine the association between academic level, surgical specialty, and exposure rate. RESULTS: Our cohort of 183 respondents (33.1% response rate) consisted of attendings (n = 72, 39.3%) and trainees (n = 111, 60.7%). Surgical trainees were less likely to have been trained in cytotoxic drugs (OR 0.22, p<0.001), methylmethacrylate (OR 0.15, p<0.001), patient lifting (OR 0.43, p = 0.009), radiation (OR 0.40, p = 0.007), and surgical smoke (OR 0.41, p = 0.041) than attending surgeons. Additionally, trainees were more likely to experience frequent exposure to bloodborne pathogens (OR 5.26, p<0.001), methylmethacrylate (OR 2.86, p<0.001), cytotoxic drugs (OR 3.03, p<0.001), and formaldehyde (2.08, p = 0.011), to name a few. CONCLUSION: Although surgeon safety is not a domain in residency training, standardized efforts to educate and change the culture of safety in residency programs is warranted. Our study demonstrates a disparity between trainees and attendings with a recommendation to provide formal training to trainees independent of their anticipated risk of exposure.

Trends in the research profile of matched independent plastic surgery fellows.

ABSTRACT: The independent plastic surgery pathway recruits candidates with 5 years of surgical training who are typically more advanced in research than their integrated counterparts. Research productivity helps to discriminate between applicants. However, no studies exist detailing the academic attributes of matched independent plastic surgery candidates.We performed a cohort study of 161 independent plastic surgery fellows from accredited residency programs from the 2015 to 2017 application cycles. We performed a bibliometric analysis utilizing Scopus, PubMed, and Google Scholar to identify research output measures at the time of application.The cohort was predominantly men (66%) with a median of 3 articles and a H-index of 1 at the time of application. Interestingly, 16% of successful candidates had no published articles at the time of application, and this did not change significantly over time (P = .0740). Although the H-index remained stable (R 0.13, P = .1095), the number of published journal articles per candidate significantly decreased over 3 consecutive application cycles (R -0.16, P = .0484). Analysis of article types demonstrated a significant increase in basic science articles (R 0.18, P = .0366) and a concurrent decrease in editorial-type publications (R = -0.18, P = .0374).Despite the decline in publication volume of matched independent plastic surgery fellows, the quality of their research portfolio has remained constant. Matched applicants appear to be shifting focus from faster-to-publish articles to longer but higher impact projects. In selecting a training route, applicants must weigh the highly competitive integrated path against the dwindling number of independent positions.

A Roadmap for Navigating Occupational Exposures for Surgeons: A Special Consideration for the Pregnant Surgeon.

SUMMARY: Surgeons are exposed to occupational hazards daily. Risks include chemical, biological, and physical hazards that place providers at risk of serious harm. Departmental policies or written guides to help pregnant surgeons navigate the hospital are lacking. In response to the scarcity in the literature, the authors have summarized current guidelines and recommendations to aid surgeons in making an informed decision. In addition, the authors present a brief narrative of the impact of these exposures during pregnancy and methods of transmission and, where relevant, include specialties that are at risk of these exposures.

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

INTRODUCTION: Differences 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. METHODS: We 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). RESULTS: We 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, p<0.0001). Career length and H-index were positively associated with dollar value of total industry payments (R = 0.17, p = 0.0291, and R = 0.14, p = 0.0405, respectively). CONCLUSION: Disparity 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.

The Glass Ceiling in Plastic Surgery: A Propensity-Matched Analysis of the Gender Gap in Career Advancement.

BACKGROUND: Gender parity remains elusive in academic plastic surgery. It is unknown whether this disparity is attributable to differences in qualifications or to the glass ceiling of gender bias. To parse this, the authors compared academic titles and departmental leadership of female academic plastic surgeons to a matched group of their male counterparts. METHODS: The authors conducted a cross-sectional analysis of academic plastic surgeons. The authors identified faculty, sex, academic rank, and leadership positions from plastic surgery residency program websites. The authors then collected details on training institution, advanced degrees, years in practice, and h-index for use as independent variables. The authors performed a propensity score analysis to 1:1 match male and female academic plastic surgeons. RESULTS: A total of 818 academic plastic surgeons were included. The cohort was predominately male [n = 658 (81 percent)], with a median 12 years in practice and a median h-index of 9. Before matching, men had more years in practice (13 years versus 9 years; p < 0.0001), a greater h-index (11 versus 5; p < 0.0001), were more likely to be professors (34 percent versus 13 percent; p < 0.0001), and held more leadership positions than women (41 percent versus 30 percent; p = 0.0221). Following matching, gender parity was demonstrated in academic rank and departmental leadership. CONCLUSIONS: Differences in training, qualifications, career length, and academic productivity may account for the leadership gap in academic plastic surgery. Gendered difficulties in reaching qualification benchmarks must be addressed before gender parity in promotion can be achieved.

Breast Augmentation in the Transfemale Patient: Comprehensive Principles for Planning and Obtaining Ideal Results.

BACKGROUND: A growing number of transgender women present to plastic surgeons seeking breast augmentation. Despite some advocating their technical similarity, the authors have found substantially different planning and techniques are needed to obtain aesthetic results in transgender patients versus cosmetic breast augmentation. The authors sought to develop an approach for operative planning and technique to elucidate these differences and obtain consistent results. METHODS: All patients who underwent breast augmentation at the Johns Hopkins Center for Transgender Health were included in this study. Anthropometric assessments were obtained and comparative statistics between operative and nonoperative cohorts were calculated. Outcomes were analyzed and a patient-reported survey was performed to evaluate patient satisfaction. RESULTS: Fifty-nine consecutive transfemale patients presented for evaluation. Anthropometric measurements included base width (median, 15.0 ± 2.1 cm), notch-to-nipple distance (median, 22.0 cm), nipple-to-midline distance (median, 12.0 cm), areolar diameter (median, 3.5 ± 1.5 cm), and upper pole pinch (mean, 1.8 ± 1.1 cm). Thirty-six patients underwent augmentation mammaplasty. Postoperative complications (8.3 percent) included a minor hematoma and grade III capsular contracture in two patients. Patients were asked to complete a brief outcomes survey and reported an improvement in psychosocial well-being and high satisfaction rate (100 percent) with the overall cosmetic result. CONCLUSIONS: Transgender female patients represent a unique patient population requiring special consideration of anatomical differences in key planning decisions. The authors delineate the first systematic algorithm that addresses these differences, emphasizing maneuvers such as routine inframammary fold lowering. This can allow experienced augmentation surgeons to obtain excellent aesthetic and patient-reported outcomes in this population. As with cosmetic breast augmentation, patient satisfaction rates are high. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Cost Utility of Breast Tissue Expansion using Carbon Dioxide versus Saline: An Analysis of Infection Risk.

BACKGROUND: The AeroForm System, a needle-free, patient-controlled carbon dioxide-filled tissue expander, represents a novel option for tissue expansion in 2-stage breast reconstruction. This technology has previously been found to decrease time to expansion, health-care utilization, and infection rates. The purpose of this study was to determine the economic impact of the reduced infection rate observed with the AeroForm tissue expander as compared with saline tissue expansion. METHODS: A decision model incorporating costs, quality-adjusted life years, and clinical outcomes of infection was designed to evaluate the cost-efficacy of AeroForm tissue expanders versus conventional saline expanders. All statistical calculations were performed in the R statistical computing environment. RESULTS: Pooled infection rates from the published literature following saline and AeroForm tissue expander placement were 5.83% and 2.62%, respectively. Cost-utility analysis resulted in a baseline expected savings of $253.29 and an expected gain of 0.00122 quality-adjusted life years with AeroForm tissue expanders. One-way sensitivity analysis revealed that AeroForm tissue expanders were dominant when the surgical site infection rate was greater than 4.56% with traditional saline expanders. CONCLUSIONS: Clinical benefits of an innovation are no longer sufficient to justify its acquisition costs. Novel technologies must also demonstrate favorable economic outcomes. This cost-utility analysis demonstrates that the use of AeroForm expanders is likely a cost-saving technology for 2-stage breast reconstruction.

Complete Human Penile Scaffold for Composite Tissue Engineering: Organ Decellularization and Characterization.

Reconstruction for total penile defects presents unique challenges due to its anatomical and functional complexity. Standard methods suffer from high complication rates and poor functional outcomes. In this work we have developed the first protocol for decellularizing whole-organ human penile specimens for total penile tissue engineering. The use of a hybrid decellularization scheme combining micro-arterial perfusion, urethral catheter perfusion and external diffusion enabled the creation of a full-size scaffold with removal of immunogenic components. Decellularization was complete as assessed by H&E and immunohistochemistry, while quantification of residual DNA showed acceptably low levels (<50 ng/mg). An intact ECM was maintained with histologic architecture preservation on H&E and SEM as well as preservation of key proteins such as collagen-1, laminin and fibronectin and retention of growth factors VEGF (45%), EGF (57%) and TGF-beta1 (42%) on ELISA. Post-decellularization patency of the cavernosal arteries for future use in reseeding was demonstrated. Scaffold biocompatibility was evaluated using human adipose-derived stromal vascular cells. Live/Dead stains showed the scaffold successfully supported cell survival and expansion. Influence on cellular behavior was seen with significantly higher expression of VWF, COL1, SM22 and Desmin as compared to cell monolayer. Preliminary evidence for regional tropism was also seen, with formation of microtubules and increased endothelial marker expression in the cavernosa. This report of successful decellularization of the complete human phallus is an initial step towards developing a tissue engineered human penile scaffold with potential for more successfully restoring cosmetic, urinary and sexual function after complete penile loss.

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

BACKGROUND: Cleft 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. METHODS: Collagen 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. RESULTS: Targeted 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). CONCLUSIONS: Ex 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.

A Simple, Visually Oriented Communication System to Improve Postoperative Care Following Microvascular Free Tissue Transfer: Development, Results, and Implications.

Background Communication, particularly transmission of information between the surgical and nursing teams, has been identified as one of the most crucial determinants of patient outcomes. Nonetheless, transfer of information among and between the physician and nursing teams in the immediate postoperative period is often informal, verbal, and inconsistent. Methods An iterative process of multidisciplinary information gathering was undertaken to create a novel postoperative communication system (the "Pop-form"). Once developed, nurses were surveyed on multiple measures regarding the perceived likelihood that it would improve their ability to provide directed patient care. Data were quantified using a Likert scale (0-10), and statistically analyzed. Results The Pop-form records and transfers operative details, specific anatomic monitoring parameters, and senior physician contact information. Sixty-eight nurses completed surveys. The perceived usefulness of different components of the Pop-form system was as follows: 8.9 for the description of the procedure; 9.3 for the operative diagram; 9.4 for the monitoring details and parameters; and 9.4 for the direct contact information for the appropriate surgical team member. All respondents were in favor of widespread adoption of the Pop-form. Conclusion This uniform, visual communication system requires less than 1 minute to compose, yet formalizes and standardizes inter-team communication, and therefore shows promise for improving outcomes following microvascular free tissue transfer. We believe that this simple, innovative communication tool has the potential to be more broadly applied to many other health care settings.

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.

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 show 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, Vpus from nonpandemic HIV-1 O strains are poor tetherin antagonists, whereas 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 global HIV/AIDS pandemic.

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(MAC)/SIV(SMM), SIV(AGM), and SIV(BLU) 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(MAC) 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.