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Paramyxoviruses are significant human and animal pathogens that include mumps virus (MuV), Newcastle disease virus (NDV) and the murine parainfluenza virus Sendai (SeV). Despite their importance, few host factors implicated in paramyxovirus infection are known. Using a recombinant SeV expressing destabilized eGFP (rSeVC dseGFP ) in a loss-of-function CRISPR screen, we identified the CMP-sialic acid transporter (CST) gene SLC35A1 and the UDP-galactose transporter (UGT) gene SLC35A2 as essential for paramyxovirus infection. As expected, SLC35A1 knockout (KO) cells showed drastic reduction in infections with SeV, NDV and MuV due to the lack of cell surface sialic acids receptors. However, SLC35A2 KO cells revealed unknown critical roles for this factor in virus-cell and cell-to-cell fusion events for the different paramyxoviruses. While UGT was essential for virus-cell fusion during SeV entry to the cell, it was not required for NDV or MuV entry. Importantly, UGT promoted the formation of syncytia during MuV infection, suggesting a role in cell-to-cell virus spread. Our findings demonstrate that paramyxoviruses can bind to or enter A549 cells in the absence of canonical galactose-bound sialic-acid decorations and show that UGT facilitates paramyxovirus fusion processes involved in entry and spread.

Background Most HIV cure-related studies involve interrupting antiretroviral treatment to assess the efficacy of pharmacologic interventions – also known as analytical treatment interruptions (ATIs). ATIs imply the risk of passing HIV to sexual partners due to the loss of undetectable HIV status. There has been a notable lack of attention paid to perceptions of ATIs among racial, ethnic, sex and gender minorities, and HIV serodifferent couples. These populations are among those most impacted by HIV in the United States. Future HIV cure research paradigms should equitably include considerations from these groups. Methods From August – October 2020, we conducted in-depth interviews with 10 racial, ethnic, sex, and gender minority HIV serodifferent couples in geographically diverse regions of the United States to understand their perspectives about ATIs and partner protection measures to prevent secondary HIV transmissions because of participation in ATI studies. We used framework analysis to analyze the qualitative data. Results Of the 10 couples recruited, four identified as a gay couple, two as a gay and bisexual couple, two as a heterosexual couple, one as a gay and queer couple, and one as a queer couple. We found that HIV serodifferent couples in our study viewed ATIs as contradicting HIV treatment adherence messages. Couples expressed discomfort around ATIs in HIV cure research. They were concerned with the return of HIV detectability and worried ATIs might result in secondary HIV transmission. Participants were strongly in favor of using a range of partner protection measures during ATIs that included PrEP, HIV risk reduction counseling, and alternatives for penetrative sex practices. Couples also recommended that sex partners be consulted or involved as part of ATI trials. Conclusions Our findings highlight new potential opportunities and strategies to mitigate risk of HIV transmission during ATIs among key groups historically under-represented in HIV cure research. Findings also underscore the relational aspects of ATI trials. We provide preliminary considerations for planning ATI trials with diverse HIV serodifferent partners. Future studies should continue to explore these issues among other types of partnerships, cultures, and socio-cultural settings.

Background This study is part of a state-wide effort to promote the safe disposal of prescription medications and mitigate prescription drug misuse. The objective of this study was to evaluate the implementation of a two-component prevention intervention through Community Prevention Organizations (CPOs) in Texas. The first component involved the distribution of in-home disposal products (IHDP) and the second focused on providing education of the risks of prescription drug misuse. Methods This study followed a mixed methods sequential explanatory study design. In the quantitative phase, the extent to which CPOs carried out the intervention was determined by the distribution rate – a proportion representing the number of IHDP distributed to end users from the amount of IHDP the CPO was shipped. This measure was used to organize the CPOs in to one of three performance categories. In the qualitative arm of the study, stratified random sampling was used to select five CPOs from each performance strata to participate in an in-depth, semi-structured interview about their distribution activity. The interview guide and the data analysis were guided by Bowen’s Feasibility Framework. The interviews were transcribed and analyzed using a content analysis approach by two research team members. All qualitative analyses were conducted in ATLAS.ti© V7. Results There was a total of 47 CPOs contacted and asked to be part of this study. Of them, 44 CPOs participated in the quantitative phase of the study. This phase revealed that all CPOs had existing relationships with organizations throughout the community such as pharmacies and schools that could act as points of distribution. Following the quantitative phase, 15 CPOs were selected for more in-depth interviews about their distribution practices. In the qualitative phase, this finding was reinforced through the theme “partnerships with local institutions and ability to implement the intervention at community events”. Similarly, education promotion efforts were unanimously emphasized as a strategy to increase utilization of IHDP among end users. All CPOs indicated that the intervention was supplemental to their overall goals. Conclusion CPOs have unparalleled access to community events, local institutions, and the general population they serve, thus, they have the potential to be active facilitators in implementing prevention interventions.

Background The pursuit of a cure for HIV is a high priority for researchers, funding agencies, governments and people living with HIV (PLWH). To date, over 250 biomedical studies worldwide are or have been related to discovering a safe, effective, and scalable HIV cure, most of which are early translational research and experimental medicine. As HIV cure research increases, it is critical to identify and address the ethical challenges posed by this research. Methods We conducted a scoping review of the growing HIV cure research ethics literature, focusing on articles published in English peer-reviewed journals from 2013 to 2021. We extracted and summarized key developments in the ethics of HIV cure research. Twelve community advocates actively engaged in HIV cure research provided input on this summary and suggested areas warranting further ethical inquiry and foresight via email exchange and video conferencing. Discussion Despite substantial scholarship related to the ethics of HIV cure research, additional attention should focus on emerging issues in six categories of ethical issues: (1) social value (ongoing and emerging biomedical research and scalability considerations); (2) scientific validity (study design issues, such as the use of analytical treatment interruptions and placebos); (3) fair selection of participants (equity and justice considerations); (4) favorable benefit/risk balance (early phase research, benefit-risk balance, risk perception, psychological risks, and pediatric research); (5) informed consent (attention to language, decision-making, informed consent processes and scientific uncertainty); and (6) respect for enrolled participants and community (perspectives of people living with HIV and affected communities and representation). Conclusion HIV cure research ethics has an unfinished agenda. Scientific research and bioethics should work in tandem to advance ethical HIV cure research. Because the science of HIV cure research will continue to rapidly advance, ethical considerations of the major themes we identified will need to be revisited and refined over time.

Rotaviruses pose a significant threat to young children. To identify novel pro- and anti-rotavirus host factors, we performed genome-wide CRISPR/Cas9 screens using rhesus rotavirus and African green monkey cells. Genetic deletion of either SERPINB1 or TMEM236 , the top two antiviral factors, in MA104 cells increased virus titers in a rotavirus strain independent manner. Using this information, we optimized the existing rotavirus reverse genetics systems by combining SERPINB1 knockout MA104 cells with a C3P3-G3 helper plasmid. We improved the recovery efficiency and rescued several low-titer rotavirus reporter and mutant strains that prove difficult to rescue otherwise. Furthermore, we demonstrate that TMEM236 knockout in Vero cells supported higher yields of two live-attenuated rotavirus vaccine strains than the parental cell line and represents a more robust vaccine-producing cell substrate. Collectively, we developed a third-generation optimized rotavirus reverse genetics system and generated gene-edited Vero cells as a new substrate for improving rotavirus vaccine production.

Background Reproductive coercion victimization (RCV) is a significant public health issue that negatively affects women’s sexual and reproductive health outcomes. Less is known about reproductive coercion perpetration (RCP). Few studies have examined these phenomena among representative samples of Black women. Methods Retrospective data of women (n = 298) attending STD clinics in Baltimore, MD were analyzed. We calculated lifetime and 12-month prevalence reports of reproductive coercion, and reported values stratified by forced sex history. Binomial logistic regression models were used to examine the association between forced sex history and RCV, accounting for other types of violence typologies. Results Lifetime and past 12-month RCV and RCP prevalence were higher among women with forced sex experiences than their counterparts (Lifetime RCV: 46.9% versus 17.5%; past 12-month RCV: 19.4% versus 8.5%. Lifetime RCP: 24.5% versus 17%; past 12-month RCP: 13.3% versus 10.5%). Adjusted models, lifetime reproductive coercion: Women reporting forced sex had a 3.58 times higher odds of having had experienced RCV compared to women not reporting forced sex (AOR 3.58; 95% CI 2.00, 6.46). Women reporting forced sex had a 3.66 times higher odds of having ever experienced pregnancy coercion compared to their counterparts (AOR 3.66; 95% CI 1.93, 7.03) and 4.30 times higher odds of having ever experienced condom manipulation (AOR 4.30; 95% CI 2.15, 8.86). Adjusted models, past 12-month reproductive coercion: Women reporting forced sex had a 2.72 times higher odds of having had experienced past 12-month RCV compared to women not reporting forced sex (AOR 2.72; 95% CI 1.27, 5.91). Women reporting forced sex had a 3.25 times higher odds of having experienced past 12-month pregnancy coercion compared to their counterparts (AOR 3.25; 95% CI 1.38, 7.83) and 3.41 times higher odds of having experienced past 12-month condom manipulation (AOR 3.41; 95% CI 1.14, 10.98). Conclusions Participants in our study reported high rates of RCV. Our novel exploration revealed significantly high rates of co-occurring forced sex experiences and RCV and initial prevalence report of RCP. Agencies have a unique opportunity to intervene by implementing screening protocols and referrals for supportive services. These findings may inform future intervention research efforts aimed at improving reproductive health outcomes among Black women.

Enteric fever is a systemic infection caused by Salmonella Typhi or Paratyphi A. In many endemic areas, these serovars co-circulate and can cause multiple infection-episodes in childhood. Prior exposure is thought to confer partial, but incomplete, protection against subsequent attacks of enteric fever. Empirical data to support this hypothesis are limited, and there are few studies describing the occurrence of heterologous-protection between these closely related serovars. We performed a challenge-re-challenge study using a controlled human infection model (CHIM) to investigate the extent of infection-derived immunity to Salmonella Typhi or Paratyphi A infection. We recruited healthy volunteers into two groups: naïve volunteers with no prior exposure to Salmonella Typhi/Paratyphi A and volunteers previously-exposed to Salmonella Typhi or Paratyphi A in earlier CHIM studies. Within each group, participants were randomised 1:1 to oral challenge with either Salmonella Typhi (104 CFU) or Paratyphi A (103 CFU). The primary objective was to compare the attack rate between naïve and previously challenged individuals, defined as the proportion of participants per group meeting the diagnostic criteria of temperature of ≥38°C persisting for ≥12 hours and/or S. Typhi/Paratyphi bacteraemia up to day 14 post challenge. The attack-rate in participants who underwent homologous re-challenge with Salmonella Typhi was reduced compared with challenged naïve controls, although this reduction was not statistically significant (12/27[44%] vs. 12/19[63%]; Relative risk 0.70; 95% CI 0.41-1.21; p = 0.24). Homologous re-challenge with Salmonella Paratyphi A also resulted in a lower attack-rate than was seen in challenged naïve controls (3/12[25%] vs. 10/18[56%]; RR0.45; 95% CI 0.16-1.30; p = 0.14). Evidence of protection was supported by a post hoc analysis in which previous exposure was associated with an approximately 36% and 57% reduced risk of typhoid or paratyphoid disease respectively on re-challenge. Individuals who did not develop enteric fever on primary exposure were significantly more likely to be protected on re-challenge, compared with individuals who developed disease on primary exposure. Heterologous re-challenge with Salmonella Typhi or Salmonella Paratyphi A was not associated with a reduced attack rate following challenge. Within the context of the model, prior exposure was not associated with reduced disease severity, altered microbiological profile or boosting of humoral immune responses. We conclude that prior Salmonella Typhi and Paratyphi A exposure may confer partial but incomplete protection against subsequent infection, but with a comparable clinical and microbiological phenotype. There is no demonstrable cross-protection between these serovars, consistent with the co-circulation of Salmonella Typhi and Paratyphi A. Collectively, these data are consistent with surveillance and modelling studies that indicate multiple infections can occur in high transmission settings, supporting the need for vaccines to reduce the burden of disease in childhood and achieve disease control. Trial registration NCT02192008; clinicaltrials.gov.

Background Organizational context plays a critical role in the implementation of evidence-based interventions. Implementation research to date has focused largely on internal, rather than external, context. This paper presents key features of external context and their impact on implementation of Eban II, an evidence-based HIV/AIDS prevention intervention currently being tested in community-based organizations (CBOs). We examine external context factors that have influenced implementation, highlighting the ways in which client needs, agency resources, and changing policies permeate the theorized boundary between internal and external context, affecting both organizational capacity for implementation research and implementation processes themselves. Methods Staff (n = 91) across participating CBOs completed a baseline survey of organizational functioning; a subset of key stakeholders (n = 15) completed semi-structured interviews. Client participants (n = 84) completed a baseline survey. Process notes and organizational documents were also analyzed. Results Organizational readiness for implementation was high across the organizations. However, despite apparent readiness, external contextual barriers to implementation were substantial. Three categories of barriers were identified: (1) client needs as a manifestation of social determinants of poverty, (2) community agency resources, and (3) local and national policy changes. Clients’ psychosocial vulnerability affected their everyday lives and priorities, which thereby affected the regularity and intensity of their interface with CBOs, and hence their participation in our intervention. CBOs typically lacked staffing and space. Furthermore, changing federal and state policy priorities destabilized the CBOs, which had a ripple effect on our study. Drawing on community-engaged research principles, we made numerous adjustments to the intervention format and structure according to the preferences and contexts of the CBOs. Had we not adjusted to external contextual factors, the organizations would not have been able to maintain their involvement and provide the intervention to their clients, despite expressed, genuine commitment to shared goals. Conclusions Community-based implementation studies need to address complex organizational and client needs, using community-engaged research principles. If these studies are community-based among vulnerable populations, they need to more thoroughly evaluate, monitor, and address the ways in which external contextual factors impinge upon implementation processes and outcomes, with a parallel need for more comprehensive measures of fiscal, political, and social determinants of implementation success. Trial registration number NCT01829282 (Registered April 11, 2013).

Black women bear a disproportionate burden of HIV, accounting for nearly 60% of new diagnoses among US women. Black women living with HIV often experience mutually reinforcing epidemics, known as syndemics, including interpersonal violence and substance use. Syndemics are associated with decreased HIV care engagement and treatment adherence and worsening HIV outcomes. Few HIV services and resources are tailored to be culturally and gender-responsive and trauma informed for Black women living with HIV. Technology-based, psychoeducational, and peer navigation programs offer promising pathways to tailored HIV support and improved HIV care outcomes. Therefore, the web-based, trauma-informed intervention LinkPositively was developed in collaboration with Black women living with HIV to promote uptake of HIV care and ancillary support services. This study primarily determines the feasibility and acceptability of the LinkPositively intervention among Black women living with HIV affected by interpersonal violence. The secondary aim is to examine the preliminary impact of the LinkPositively intervention on retention in HIV care, antiretroviral therapy adherence, and viral suppression while evaluating the role of mechanism of change variables (eg, social support) in the associations. The LinkPositively trial is a pilot randomized controlled trial conducted in California, United States, among 80 adult Black women living with HIV who have experienced interpersonal violence. Core components of LinkPositively include one-on-one peer navigation with phone and SMS text message check-ins; 5 weekly one-on-one video sessions to build coping and care navigation skills; and a mobile app that contains a peer support social networking platform, an educational database with healthy living and self-care tips, a GPS-enabled HIV and ancillary care resource locator, and a medication self-monitoring and reminder system. Participants are randomly assigned to the intervention (n=40) or control (Ryan White standard of care; n=40) arm, with follow-up at 3 and 6 months. At each assessment, participants complete an interviewer-administered survey and submit hair samples for the assessment of HIV medication adherence. All research staff and investigators adhere to ethical principles and guidelines for conducting research activities. Data will be analyzed using generalized estimating equations. Final development and testing of the LinkPositively app were completed in July 2021. As of May 2023, we have screened 97 women for eligibility. Of the 97 women screened, 27 (28%) were eligible and have been enrolled in the study. The dissemination of preliminary results will occur in 2024. This trial will advance HIV prevention science by harnessing technology to promote engagement in HIV care while improving social support through peers and social networking-all while being trauma informed for Black women living with HIV with experiences of interpersonal violence. If shown to be feasible and acceptable, LinkPositively has the potential to improve HIV care outcomes among Black women, a marginalized key population. DERR1-10.2196/46325.