A Call to Action: Urgently Strengthening the Future Physician-Scientist Workforce in Infectious Diseases.

Infectious diseases (ID) research is vital for global public health, typically led by physician-scientists. This Perspective addresses challenges in the ID workforce and suggests solutions. Physician-scientists have made key discoveries that have significantly impacted human health. The importance of ID research in understanding diseases, leading to treatments and vaccines, is emphasized, along with the need to address persistent and new infections, antimicrobial resistance, and threats like HIV and influenza. The paper analyzes the physician-scientist workforce's struggles, including funding, training, and research-practice integration gaps. We suggest increased funding, better training, and mentorship, more collaborative and interdisciplinary research, and improved recognition systems. The article stresses the urgency of supporting physician-scientists in ID, advocating for proactive prevention and preparedness, and calls for immediate action to enhance ID research and care.

HIV-1 infection of genetically engineered iPSC-derived central nervous system-engrafted microglia in a humanized mouse model.

IMPORTANCE: Our mouse model is a powerful tool for investigating the genetic mechanisms governing central nervous system (CNS) human immunodeficiency virus type-1 (HIV-1) infection and latency in the CNS at a single-cell level. A major advantage of our model is that it uses induced pluripotent stem cell-derived microglia, which enables human genetics, including gene function and therapeutic gene manipulation, to be explored in vivo, which is more challenging to study with current hematopoietic stem cell-based models for neuroHIV. Our transgenic tracing of xenografted human cells will provide a quantitative medium to develop new molecular and epigenetic strategies for reducing the HIV-1 latent reservoir and to test the impact of therapeutic inflammation-targeting drug interventions on CNS HIV-1 latency.

Preserving the Future of Infectious Diseases: Why We Must Address the Decline in Compensation for Clinicians and Researchers.

Infectious diseases (ID) physicians play a pivotal role in patient care and public health, yet concerns are mounting about their under-compensation compared with other medical specialties. This trend sees ID physicians, including new graduates, receiving lower remuneration than their general and hospital medicine peers, despite their significant contributions. The persistent disparity in compensation has been identified as a key factor behind the declining interest in the ID specialty among medical students and residents, potentially threatening patient care quality, research advancement, and diversity within the ID workforce. This viewpoint underscores the urgent need for the ID community to rally behind the Infectious Diseases Society of America in advocating for fair compensation for ID physicians and researchers. While focusing on wellness and work-life balance is vital, it is critical to address compensation, a significant source of distress for physicians. Failure to confront the issue of under-compensation promptly may jeopardize the future growth and sustainability of the ID specialty.

Digital Strategy and Social Media for Infectious Diseases.

This supplement demonstrates the profound reach of social media across several domains: improved clinical care and advocacy, data analysis, broad reach to diverse patient populations, educational access, best practices in medical education, peer review, digital strategy for individuals and institutions, and combating misinformation.

Social Media: Flattening Hierarchies for Women and Black, Indigenous, People Of Color (BIPOC) to Enter the Room Where It Happens.

Social media platforms are widely used to connect people across multiple settings, including country of origin, profession, race/ethnicity, sexual orientation, gender identity, seniority, and training. Groups that have been marginalized or historically excluded from decision-making encounters may lack formal mentors/sponsors because of a lack of representation of women and Black, Indigenous, People Of Color (BIPOC) in senior leadership positions. This can serve as a barrier to professional advancement at all stages of career development. Identifying and connecting with these potential mentors/sponsors outside of one's institutional space can be challenging. For this reason, leveraging social media to develop these professional relationships through flattened hierarchies can allow for professional networking beyond traditional mechanisms. Here we aim to describe how individuals can connect through social media to advance their careers and scientific and clinical expertise, advocate for communities, and provide high-quality communication to the public.

Lesbian, Gay, Bisexual, Transgender, and Queer (LGBTQ+) Communities and the Coronavirus Disease 2019 Pandemic: A Call to Break the Cycle of Structural Barriers.

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately impacted lesbian, gay, bisexual, transgender, and queer (LGBTQ+) communities. Many disparities mirror those of the human immunodeficiency virus (HIV)/AIDS epidemic. These health inequities have repeated throughout history due to the structural oppression of LGBTQ+ people. We aim to demonstrate that the familiar patterns of LGBTQ+ health disparities reflect a perpetuating, deeply rooted cycle of injustice imposed on LGBTQ+ people. Here, we contextualize COVID-19 inequities through the history of the HIV/AIDS crisis, describe manifestations of LGBTQ+ structural oppression exacerbated by the pandemic, and provide recommendations for medical professionals and institutions seeking to reduce health inequities.

A Diverse Physician-Scientist Pipeline to Fight Structural Racism.

Translational research plays a pivotal role in leveraging good science to serve humanity. Structural racism and a lack of diversity severely limit our potential as scientists to exert a maximum impact. This moment calls for a renewed commitment to ridding science of racism and bias and promoting diversity, which makes us more effective at innovating and delivering therapeutics to the patients we serve.

P2X1 Selective Antagonists Block HIV-1 Infection through Inhibition of Envelope Conformation-Dependent Fusion.

Purinergic receptors are well-established modulators of inflammatory processes, primarily through detection of extracellular nucleotides that are released by dying or infected cells. Emerging literature has demonstrated that inhibition of these inflammatory receptors can block HIV-1 productive infection and HIV-1-associated inflammation. The specificity of receptor type and mechanism of interaction has not yet been determined. Here, we characterize the inhibitory activity of P2X1 receptor antagonists, NF279 and NF449, in cell lines, primary cells, and a variety of HIV-1 envelope (Env) clades. NF279 and NF449 blocked productive infection at the level of viral membrane fusion, with a range of inhibitory activities against different HIV-1 Env isolates. A mutant virus carrying a truncation deletion of the C-terminal tail of HIV-1 Env glycoprotein 41 (gp41) showed reduced sensitivity to P2X1 antagonists, indicating that the sensitivity of inhibition by these molecules may be modulated by Env conformation. In contrast, a P2X7 antagonist, A438079, had a limited effect on productive infection and fusion. NF279 and NF449 interfered with the ability of the gp120 variable regions 1 and 2 (V1V2)-targeted broadly neutralizing antibody PG9 to block productive infection, suggesting that these drugs may antagonize HIV-1 Env at gp120 V1V2 to block viral membrane fusion. Our observations indicate that P2X1 antagonism can inhibit HIV-1 replication at the level of viral membrane fusion through interaction with Env. Future studies will probe the nature of these compounds in inhibiting HIV-1 fusion and the development of small molecules to block HIV-1 entry via this mechanism.IMPORTANCE While effective treatment can lower the severe morbidity and mortality associated with HIV-1 infection, patients infected with HIV-1 suffer from significantly higher rates of noncommunicable comorbidities associated with chronic inflammation. Emerging literature suggests a key role for P2X1 receptors in mediating this chronic inflammation, but the mechanism is still unknown. Here, we demonstrate that HIV-1 infection is reduced by P2X1 receptor antagonism. This inhibition is mediated by interference with HIV-1 Env and can impact a variety of viral clades. These observations highlight the importance of P2X1 antagonists as potential novel therapeutics that could serve to block a variety of different viral clades with additional benefits for their anti-inflammatory properties.

Location Matters: Geographic Disparities and Impact of Coronavirus Disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic in the United States has revealed major disparities in the access to testing and messaging about the pandemic based on the geographic location of individuals, particularly in communities of color, rural areas, and areas of low income. This geographic disparity, in addition to deeply rooted structural inequities, have posed additional challenges to adequately diagnose and provide care for individuals of all ages living in these settings. We describe the impact that COVID-19 has had on geographically disparate populations in the United States and share our recommendations on what might be done to ameliorate the current situation.

Racial Disparity of Coronavirus Disease 2019 in African American Communities.

The coronavirus disease 2019 (COVID-19) pandemic has unveiled unsettling disparities in the outcome of the disease among African Americans. These disparities are not new but are rooted in structural inequities that must be addressed to adequately care for communities of color. We describe the historical context of these structural inequities, their impact on the progression of COVID-19 in the African American (black) community, and suggest a multifaceted approach to addressing these healthcare disparities. (Of note, terminology from survey data cited for this article varied from blacks, African Americans, or both; for consistency, we use African Americans throughout.).

How to make your research jump off the page: Co-creation to broaden public engagement in medical research.

Nina Finley and co-authors discuss public involvement in planning and reporting medical research.

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1ß in a Human Tonsil Explant Model.

HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. An ex vivo human tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1ß) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1ß. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.IMPORTANCE Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1ß in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.

The Science and Value of Diversity: Closing the Gaps in Our Understanding of Inclusion and Diversity.

Diversity drives excellence. Diversity enhances innovation in biomedical sciences and, as it relates to novel findings and treatment of diverse populations, in the field of infectious diseases. There are many obstacles to achieving diversity in the biomedical workforce, which create challenges at the levels of recruitment, retention, education, and promotion of individuals. Here we present the challenges, opportunities, and suggestions for the field, institutions, and individuals to adopt in mitigating bias and achieving greater levels of equity, representation, and excellence in clinical practice and research. Our findings provide optimism for a bright future of fair and collaborative approaches that will enhance the power of our biomedical workforce.

Risk of Invasive Anal Cancer in HIV-Infected Patients With High-Grade Anal Dysplasia: A Population-Based Cohort Study.

BACKGROUND: The progression rate and predictors of anal dysplastic lesions to squamous cell carcinoma of the anus remain unclear. Characterizing these parameters may help refine anal cancer screening guidelines. OBJECTIVE: This study aimed to determine the rate of progression of high-grade anal dysplasia to invasive carcinoma in HIV-infected persons. DESIGN: Using the Surveillance, Epidemiology, and End Results database linked to Medicare claims from 2000 to 2011, we identified HIV-infected subjects with incident anal intraepithelial neoplasia III. To estimate the rate of progression of anal intraepithelial neoplasia III to invasive cancer, we calculated the cumulative incidence of anal cancer in this cohort. We then fitted Poisson models to evaluate the potential risk factors for incident anal cancer. SETTINGS: This is a population-based study. PATIENTS: Included were 592 HIV-infected subjects with incident anal intraepithelial neoplasia III. MAIN OUTCOME MEASURES: The primary outcome measured was incident squamous cell carcinoma of the anus. RESULTS: Study subjects were largely male (95%) with a median age of 45.7 years. Within the median follow-up period of 69 months, 33 subjects progressed to anal cancer. The incidence of anal cancer was 1.2% (95% CI, 0.7%-2.5%) and 5.7% (95% CI, 4.0%-8.1%) at 1 and 5 years, following a diagnosis of anal intraepithelial neoplasia III. Risk of progression did not differ by anal intraepithelial neoplasia III treatment status. On unadjusted analysis, black race (p = 0.02) and a history of anogenital condylomata (p = 0.03) were associated with an increased risk of anal cancer incidence, whereas prior anal cytology screening was associated with a decreased risk (p = 0.04). LIMITATIONS: The identification of some incident cancer episodes used surrogate measures. CONCLUSIONS: In our population-based cohort of HIV-infected subjects with long-term follow-up, the risk of progression from anal intraepithelial neoplasia III to anal squamous cell carcinoma was higher than reported in other studies and was not associated with the receipt of anal intraepithelial neoplasia III treatment. See Video Abstract at http://links.lww.com/DCR/A933.

Differences in the Immune Microenvironment of Anal Cancer Precursors by HIV Status and Association With Ablation Outcomes.

Background: Anal high-grade squamous intraepithelial lesions (HSILs) are the precursors to anal cancer and frequently persist or recur following electrocautery ablation (EA). Impaired mucosal immunity may facilitate anal carcinogenesis. We characterized the immune microenvironment of anal HSILs in correlation with human immunodeficiency virus (HIV) serostatus and ablation outcomes. Methods: Using immunohistochemistry, mucosa-infiltrating CD4+ and CD8+ lymphocytes were quantified in HSILs and benign mucosa from 70 HIV+ and 45 HIV- patients. Clinicopathological parameters were compared. Results: Anal HSILs harbored more T lymphocytes than benign mucosa regardless of HIV status (P ≤ .03). Total T lymphocyte count and CD8+ subset were significantly higher in HIV+ HSILs versus HIV- HSILs (median cell count, 71 vs 47; 47 vs 22/high power field [HPF]; P < .001), whereas the CD4+ subset was comparable between groups (median, 24 vs. 25; P = .40). Post EA, HSILs persisted in 41% of HIV+ and 19% of HIV- patients (P = .04). Unadjusted analysis showed trends toward EA failures associated with HIV seropositivity (incidence rate ratio [IRR], 2.0; 95% CI, .8-4.9) and increased CD8+ cells (IRR, 2.3; 95% CI, .9-5.3). Conclusions: Human immunodeficiency virus is associated with alterations of the immune microenvironment of anal HSILs manifested by increased local lymphocytic infiltrates, predominately CD8+. Human immunodeficiency virus seropositivity and excess mucosa-infiltrating CD8+ cells may be associated with ablation resistance.

P2X-selective purinergic antagonists are strong inhibitors of HIV-1 fusion during both cell-to-cell and cell-free infection.

UNLABELLED: Human immunodeficiency virus type 1 (HIV-1) infection is chronic and presently still incurable. Antiretroviral drugs effectively suppress replication; however, persistent activation of inflammatory pathways remains a key cause of morbidity. Recent studies proposed that purinergic signaling is required for HIV-1 infection. Purinergic receptors are distributed throughout a wide variety of tissue types and detect extracellular ATP as a danger signal released from dying cells. We have explored how these pathways are involved in the transmission of HIV-1 from cell to cell through virological synapses. Infection of CD4+ T lymphocytes with HIV-1 in the presence of an inhibitor of P2X receptors effectively inhibited HIV-1 infection through both cell-free and cell-to-cell contact in a dose-dependent manner. Inhibition of direct cell-to-cell infection did not affect the formation of virological synapses or the subsequent cell-to-cell transfer of HIV-1. During both cell-free and cell-to-cell CD4+ T lymphocyte infection, purinergic antagonists blocked infection at the level of viral membrane fusion. During cell-to-cell transmission, we observed CXCR4 colocalization with the newly internalized virus particles within target lymphocytes and found that the purinergic antagonists did not impair the recruitment of the coreceptor CXCR4 to the site of Gag internalization in the target cell. In a screen of a library of purinergic antagonists, we found that the most potent inhibitors of HIV-1 fusion were those that target P2X receptors, while P2Y-selective receptor antagonists or adenosine receptor antagonists were ineffective. Our results suggest that P2X receptors may provide a therapeutic target and that purinergic antagonists may have potent activity against viral infection of CD4+ T lymphocytes by both cell-free and cell-to-cell transmission. IMPORTANCE: This study identifies purinergic antagonists to be potent inhibitors of HIV-1 cell-free and cell-to-cell-mediated infection and provides a stepwise determination of when these compounds inhibit HIV-1 infection. These data provide a rationale for the development of novel antiretroviral therapies that have a dual role in both direct antiviral activity and the reduction of HIV-associated inflammation. Purinergic antagonists are shown here to have equivalent efficacy in inhibiting HIV infection via cell-free and cell-to-cell infection, and it is shown that purinergic receptors could provide an attractive therapeutic anti-HIV target that might avoid resistance by targeting a host signaling pathway that potently regulates HIV infection. The high-throughput screen of HIV-1 fusion inhibitors further defines P2X-selective compounds among the purinergic compounds as being the most potent HIV entry inhibitors. Clinical studies on these drugs for other inflammatory indications suggest that they are safe, and thus, if developed for use as anti-HIV agents, they could reduce both HIV replication and HIV-related inflammation.