Low Self-Perceived Need for PrEP and Behavioral Indications of MSM Who Recently Refused Daily PrEP: A Mixed Methods Study in Three U.S. Cities.

Pre-exposure prophylaxis (PrEP) reduces sexual risk for HIV transmission by 99% when used appropriately, but remains underutilized among gay, bisexual, and other men who have sex with men (MSM). In this mixed-method study, we describe reasons for PrEP refusal associated with low self-perceived need for PrEP among MSM who recently declined daily oral PrEP when offered by a provider. Data are from a quantitative behavioral survey of MSM (N = 93) living in Atlanta, Chicago, and Raleigh-Durham, who also either responded to an in-depth interview (n = 51) or participated in one of 12 focus groups (n = 42). Themes of low self-perceived need for PrEP were: low self-perceived risk for HIV acquisition (33% of respondents); confidence in remaining HIV-negative (35%); using condoms (81%); limiting number of partners and choosing partners carefully (48%); asking partners about their HIV status before having sex (45%); engaging in safer sexual positions or oral sex (28%); being in a monogamous relationship or exclusivity with one partner (26%); and regular HIV testing (18%). Low self-perceived risk for HIV acquisition and high confidence in other prevention strategies were important factors related to low self-perceived need in MSM refusing daily oral PrEP when offered. Providers should continue to discuss the benefits of PrEP as a safe and highly effective option for HIV prevention.

RESUMEN: La profilaxis pre-exposición (PrEP) reduce el riesgo de transmisión sexual por el VIH en un 99% cuando se utiliza apropiadamente, pero sigue siendo subutilizada entre hombres gais, bisexuales y otros hombres que tienen sexo con hombres (HSH). En este estudio de método mixto, describimos los motivos del rechazo de la PrEP asociados a la baja necesidad autopercibida de la PrEP entre los HSH que recientemente rechazaron la PrEP oral diaria, cuando fue ofrecida por un proveedor de salud. Los datos provienen de una encuesta cuantitativa de comportamiento de los HSH (N = 93) que viven en Atlanta, Chicago y Raleigh-Durham, quienes también respondieron a una entrevista en profundidad (n = 51) o participaron en uno de los 12 grupos focales (n = 42). Los temas de baja necesidad autopercibida del uso de la PrEP fueron: el bajo riesgo auto percibido de contraer el VIH (33% de los encuestados); la confianza en seguir siendo VIH negativo (35%); utilizar condones (81%); limitar el número de parejas sexuales y elegir las parejas cuidadosamente (48%); preguntar a sus parejas sobre su estado de VIH antes de tener relaciones sexuales (45%); participar en posiciones sexuales más seguras o sexo oral (28%); estar en relación monógama o de exclusividad con una sola pareja (26%); y hacerse pruebas del VIH regularmente (18%). El bajo riesgo autopercibido de contraer el VIH y la alta confianza en otras estrategias de prevención fueron factores importantes relacionados con la baja necesidad autopercibida en los HSH que rechazaron la PrEP oral diaria cuando se les ofreció. Los proveedores de salud deben continuar el diálogo sobre los beneficios de la PrEP como una opción segura y altamente eficaz para la prevención del VIH.

Progress Toward Equitable Mpox Vaccination Coverage: A Shortfall Analysis - United States, May 2022-April 2023.

More than 30,000 monkeypox (mpox) cases were reported in the United States during the 2022 multinational outbreak; cases disproportionately affected gay, bisexual, and other men who have sex with men (MSM). Substantial racial and ethnic disparities in incidence were also reported (1). The national mpox vaccination strategy* emphasizes that efforts to administer the JYNNEOS mpox vaccine should be focused among the populations at elevated risk for exposure to mpox (2). During May 2022-April 2023, a total of 748,329 first JYNNEOS vaccine doses (of the two recommended) were administered in the United States.† During the initial months of the outbreak, lower vaccination coverage rates among racial and ethnic minority groups were reported (1,3); however, after implementation of initiatives developed to expand access to mpox vaccination,§ coverage among racial and ethnic minority groups increased (1,4). A shortfall analysis was conducted to examine whether the increase in mpox vaccination coverage was equitable across all racial and ethnic groups (5). Shortfall was defined as the percentage of the vaccine-eligible population that did not receive the vaccine (i.e., 100% minus the percentage of the eligible population that did receive a first dose). Monthly mpox vaccination shortfalls were calculated and were stratified by race and ethnicity; monthly percent reductions in shortfall were also calculated compared with the preceding month's shortfall (6). The mpox vaccination shortfall decreased among all racial and ethnic groups during May 2022-April 2023; however, based on analysis of vaccine administration data with race and ethnicity reported, 66.0% of vaccine-eligible persons remained unvaccinated at the end of this period. The shortfall was largest among non-Hispanic Black or African American (Black) (77.9%) and non-Hispanic American Indian or Alaska Native (AI/AN) (74.5%) persons, followed by non-Hispanic White (White) (66.6%) and Hispanic or Latino (Hispanic) (63.0%) persons, and was lowest among non-Hispanic Asian (Asian) (38.5%) and non-Hispanic Native Hawaiian and other Pacific Islander (NH/OPI) (43.7%) persons. The largest percentage decreases in the shortfall were achieved during August (17.7%) and September (8.5%). However, during these months, smaller percentage decreases were achieved among Black persons (12.2% and 4.9%, respectively), highlighting the need for a focus on equity for the entirety of a public health response. Achieving equitable progress in JYNNEOS vaccination coverage will require substantial decreases in shortfalls among Black and AI/AN persons.

Racial and Ethnic Disparities in Mpox Cases and Vaccination Among Adult Males - United States, May-December 2022.

As of December 31, 2022, a total of 29,939 monkeypox (mpox) cases* had been reported in the United States, 93.3% of which occurred in adult males. During May 10-December 31, 2022, 723,112 persons in the United States received the first dose in a 2-dose mpox (JYNNEOS)† vaccination series; 89.7% of these doses were administered to males (1). The current mpox outbreak has disproportionately affected gay, bisexual, and other men who have sex with men (MSM) and racial and ethnic minority groups (1,2). To examine racial and ethnic disparities in mpox incidence and vaccination rates, rate ratios (RRs) for incidence and vaccination rates and vaccination-to-case ratios were calculated, and trends in these measures were assessed among males aged ≥18 years (males) (3). Incidence in males in all racial and ethnic minority groups except non-Hispanic Asian (Asian) males was higher than that among non-Hispanic White (White) males. At the peak of the outbreak in August 2022, incidences among non-Hispanic Black or African American (Black) and Hispanic or Latino (Hispanic) males were higher than incidence among White males (RR = 6.9 and 4.1, respectively). Overall, vaccination rates were higher among males in racial and ethnic minority groups than among White males. However, the vaccination-to-case ratio was lower among Black (8.8) and Hispanic (16.2) males than among White males (42.5) during the full analytic period, indicating that vaccination rates among Black and Hispanic males were not proportionate to the elevated incidence rates (i.e., these groups had a higher unmet vaccination need). Efforts to increase vaccination among Black and Hispanic males might have resulted in the observed relative increased rates of vaccination; however, these increases were only partially successful in reducing overall incidence disparities. Continued implementation of equity-based vaccination strategies is needed to further increase vaccination rates and reduce the incidence of mpox among all racial and ethnic groups. Recent modeling data (4) showing that, based on current vaccination coverage levels, many U.S. jurisdictions are vulnerable to resurgent mpox outbreaks, underscore the need for continued vaccination efforts, particularly among racial and ethnic minority groups.

Modification of N-hydroxycytidine yields a novel lead compound exhibiting activity against the Venezuelan equine encephalitis virus.

Nucleoside and nucleobase analogs capable of interfering with nucleic acid synthesis have played essential roles in fighting infectious diseases. However, many of these agents are associated with important and potentially lethal off-target intracellular effects that limit their use. Based on the previous discovery of base-modified 2'-deoxyuridines, which showed high anticancer activity while exhibiting lower toxicity toward rapidly dividing normal human cells compared to antimetabolite chemotherapeutics, we hypothesized that a similar modification of the N4-hydroxycytidine (NHC) molecule would provide novel antiviral compounds with diminished side effects. This presumption is due to the substantial structural difference with natural cytidine leading to less recognizability by host cell enzymes. Among the 42 antimetabolite species that have been synthesized and screened against VEEV, one hit compound was identified. The structural features of the modifying moiety were similar to those of the anticancer lead 2'-deoxyuridine derivative reported previously, providing an opportunity to pursue further structure-activity relationship (SAR) studies directed to lead improvement, and obtain insight into the mechanism of action, which can lead to identifying drug candidates against a broad spectrum of RNA viral infections.

Intersectional Discrimination in HIV Healthcare Settings Among Persons with Diagnosed HIV in the United States, Medical Monitoring Project, 2018-2019.

Experiences with stigma and discrimination in healthcare settings are associated with negative health outcome for persons with HIV (PWH). PWH may experience discrimination due to the intersection of multiple marginalized social identities. Describing these experiences is important for informing interventions and strategies to reduce stigma and discrimination. We report experiences with discrimination in HIV healthcare settings attributed to multiple characteristics, e.g., sexual orientation, race/ethnicity, income, or social class, and/or injection drug use, among a nationally representative sample of persons with diagnosed HIV in the United States using data from the Medical Monitoring Project (MMP). We calculated weighted prevalences and associated 95% confidence intervals for any discrimination and discrimination attributed to multiple characteristics (intersectional discrimination). Among those experiencing discrimination, nearly 1 in 4 persons reported intersectional discrimination, with a higher burden among key populations of focus for HIV prevention and treatment. Discrimination was attributed to HIV status (62.5%), sexual orientation (60.4%), and race/ethnicity (54.3%). Persons who experienced intersectional discrimination were less likely to have a regular HIV care provider, have trust in HIV care or treatment information from healthcare providers, and be antiretroviral treatment or HIV care visit adherent. Future studies should explore methods to operationalize and assess experiences with intersectional stigma and discrimination and use the outcomes to inform qualitative research that provides more context and a deeper understanding of experiences with intersectional discrimination among PWH.

Substance use and deaths by suicide: A latent class analysis of the National Violent Death Reporting System.

Substance use is strongly associated with suicide completions. However, little is known about the patterns of substances used in suicide deaths. The purpose of this analysis is to determine latent classes of toxicology-reported substances among individuals who completed suicide. The sample consists of suicide victims in the National Violent Death Reporting System (NVDRS) during years 2003-2017 (n = 202,838). Toxicology reports were used to construct latent class analyses of substance use among suicide victims. Correlates for latent class membership included sex, race/ethnicity, previous experiences of child abuse, homelessness, and intimate partner violence (IPV) victimization. The majority of suicide victims were male (77.7%), straight/heterosexual (99.5%) and white (88.3%). The final unconditional model yielded a four-class model, including a "No substance/single substance use" class, an "Alcohol and other substance" class, a "Marijuana and other substance" class, and an "Opiate use" class. Compared to the reference class of "No substance/single substance," females were more likely than males to be classified in the "Alcohol and other substance" class, the "Multi-substance use" class, and the "Opiate use" class. Homelessness was associated with classification in the "Marijuana and other substance" class and the "Opiate use" class compared to the "No substance/single substance" class. IPV was associated with both polysubstance use classes ("Alcohol plus other substance" and "Marijuana plus other substance") along with the "Opiate use" class compared to the "No substance/single substance" class. These classes highlight profiles of suicide descendants and emphasize the importance of polysubstance use prevention among females, homeless individuals, and those who experience IPV.

Psychosocial mediators of perceived stigma and suicidal ideation among transgender women.

BACKGROUND: Transgender women (TGW) in the U.S. experience high rates of stigma, depression, and elevated rates of suicide. This study examined correlates of suicidal ideation and estimated the conditional indirect effects of perceived stigma and psychosocial mediators on suicidal ideation. METHODS: Using a cross-sectional study design, TGW (N = 92) were recruited through snowball sampling in Atlanta, Georgia. Structured interviews were conducted. Suicidal ideation was assessed by combining two variables that measured suicidal thoughts. Logistic regression models were performed to identify the potential risk and protective factors for suicidal ideation. We examined hypothesized psychosocial factors, including anxiety, depression, psychosocial impact of gender minority status, and substance use behaviors as potential mediators for the relationship between perceived stigma and suicidal ideation. All models were controlled for age, race, education, and homelessness. RESULTS: Suicidal ideation was reported by 33% (N = 30) of the study participants. In multivariable analysis, suicidal ideation was associated with sexual abuse (AOR = 3.17, 95% CI = 1.10-9.30), anxiety (AOR = 1.74, 95% CI = 1.10-2.73), family verbal abuse (AOR = 2.99, 95% CI = 1.10-8.40), stranger verbal abuse (AOR = 3.21, 95% CI = 1.02-10.08), and psychosocial impact of gender minority status (AOR = 3.42, 95% CI = 1.81-6.46). Partner support was found to be the protective factor for suicidal ideation (AOR = 0.34, 95% CI = 0.13-0.90). In the mediation analysis, the psychosocial impact of gender minority status mediated the relationship between perceived stigma and suicidal ideation. The estimated conditional indirect effect was 0.46, (95% CI = 0.12-1.11). CONCLUSION: Interventions that aim to reduce suicidal behaviors among TGW should address stigma, psychosocial impact of gender minority status, and different forms of violence and abuse.

Sorafenib Impedes Rift Valley Fever Virus Egress by Inhibiting Valosin-Containing Protein Function in the Cellular Secretory Pathway.

There is an urgent need for therapeutic development to combat infections caused by Rift Valley fever virus (RVFV), which causes devastating disease in both humans and animals. In an effort to repurpose drugs for RVFV treatment, our previous studies screened a library of FDA-approved drugs. The most promising candidate identified was the hepatocellular and renal cell carcinoma drug sorafenib. Mechanism-of-action studies indicated that sorafenib targeted a late stage in virus infection and caused a buildup of virions within cells. In addition, small interfering RNA (siRNA) knockdown studies suggested that nonclassical targets of sorafenib are important for the propagation of RVFV. Here we extend our previous findings to identify the mechanism by which sorafenib inhibits the release of RVFV virions from the cell. Confocal microscopy imaging revealed that glycoprotein Gn colocalizes and accumulates within the endoplasmic reticulum (ER) and the transport of Gn from the Golgi complex to the host cell membrane is reduced. Transmission electron microscopy demonstrated that sorafenib caused virions to be present inside large vacuoles inside the cells. p97/valosin-containing protein (VCP), which is involved in membrane remodeling in the secretory pathway and a known target of sorafenib, was found to be important for RVFV egress. Knockdown of VCP resulted in decreased RVFV replication, reduced Gn Golgi complex localization, and increased Gn ER accumulation. The intracellular accumulation of RVFV virions was also observed in cells transfected with siRNA targeting VCP. Collectively, these data indicate that sorafenib causes a disruption in viral egress by targeting VCP and the secretory pathway, resulting in a buildup of virions within dilated ER vesicles.IMPORTANCE In humans, symptoms of RVFV infection mainly include a self-limiting febrile illness. However, in some cases, infected individuals can also experience hemorrhagic fever, neurological disorders, liver failure, and blindness, which could collectively be lethal. The ability of RVFV to expand geographically outside sub-Saharan Africa is of concern, particularly to the Americas, where native mosquito species are capable of virus transmission. Currently, there are no FDA-approved therapeutics to treat RVFV infection, and thus, there is an urgent need to understand the mechanisms by which the virus hijacks the host cell machinery to replicate. The significance of our research is in identifying the cellular target of sorafenib that inhibits RVFV propagation, so that this information can be used as a tool for the further development of therapeutics used to treat RVFV infection.

Protein Kinase R Degradation Is Essential for Rift Valley Fever Virus Infection and Is Regulated by SKP1-CUL1-F-box (SCF)FBXW11-NSs E3 Ligase.

Activated protein kinase R (PKR) plays a vital role in antiviral defense primarily by inhibiting protein synthesis and augmenting interferon responses. Many viral proteins have adopted unique strategies to counteract the deleterious effects of PKR. The NSs (Non-structural s) protein which is encoded by Rift Valley fever virus (RVFV) promotes early PKR proteasomal degradation through a previously undefined mechanism. In this study, we demonstrate that NSs carries out this activity by assembling the SCF (SKP1-CUL1-F-box)(FBXW11) E3 ligase. NSs binds to the F-box protein, FBXW11, via the six amino acid sequence DDGFVE called the degron sequence and recruits PKR through an alternate binding site to the SCF(FBXW11) E3 ligase. We further show that disrupting the assembly of the SCF(FBXW11-NSs) E3 ligase with MLN4924 (a small molecule inhibitor of SCF E3 ligase activity) or NSs degron viral mutants or siRNA knockdown of FBXW11 can block PKR degradation. Surprisingly, under these conditions when PKR degradation was blocked, NSs was essential and sufficient to activate PKR causing potent inhibition of RVFV infection by suppressing viral protein synthesis. These antiviral effects were antagonized by the loss of PKR expression or with a NSs deleted mutant virus. Therefore, early PKR activation by disassembly of SCF(FBXW11-NSs) E3 ligase is sufficient to inhibit RVFV infection. Furthermore, FBXW11 and BTRC are the two homologues of the ßTrCP (Beta-transducin repeat containing protein) gene that were previously described to be functionally redundant. However, in RVFV infection, among the two homologues of ßTrCP, FBXW11 plays a dominant role in PKR degradation and is the limiting factor in the assembly of the SCF(FBXW11) complex. Thus, FBXW11 serves as a master regulator of RVFV infection by promoting PKR degradation. Overall these findings provide new insights into NSs regulation of PKR activity and offer potential opportunities for therapeutic intervention of RVFV infection.

siRNA Screen Identifies Trafficking Host Factors that Modulate Alphavirus Infection.

Little is known about the repertoire of cellular factors involved in the replication of pathogenic alphaviruses. To uncover molecular regulators of alphavirus infection, and to identify candidate drug targets, we performed a high-content imaging-based siRNA screen. We revealed an actin-remodeling pathway involving Rac1, PIP5K1- α, and Arp3, as essential for infection by pathogenic alphaviruses. Infection causes cellular actin rearrangements into large bundles of actin filaments termed actin foci. Actin foci are generated late in infection concomitantly with alphavirus envelope (E2) expression and are dependent on the activities of Rac1 and Arp3. E2 associates with actin in alphavirus-infected cells and co-localizes with Rac1-PIP5K1-α along actin filaments in the context of actin foci. Finally, Rac1, Arp3, and actin polymerization inhibitors interfere with E2 trafficking from the trans-Golgi network to the cell surface, suggesting a plausible model in which transport of E2 to the cell surface is mediated via Rac1- and Arp3-dependent actin remodeling.

Countering Zika Virus: The USAMRIID Response.

The United States Army Medical Research Institute of Infectious Diseases (USAMRIID) possesses an array of expertise in diverse capabilities for the characterization of emerging infectious diseases from the pathogen itself to human or animal infection models. The recent Zika virus (ZIKV) outbreak was a challenge and an opportunity to put these capabilities to work as a cohesive unit to quickly respond to a rapidly developing threat. Next-generation sequencing was used to characterize virus stocks and to understand the introduction and spread of ZIKV in the United States. High Content Imaging was used to establish a High Content Screening process to evaluate antiviral therapies. Functional genomics was used to identify critical host factors for ZIKV infection. An animal model using the temporal blockade of IFN-I in immunocompetent laboratory mice was investigated in conjunction with Positron Emission Tomography to study ZIKV. Correlative light and electron microscopy was used to examine ZIKV interaction with host cells in culture and infected animals. A quantitative mass spectrometry approach was used to examine the protein and metabolite type or concentration changes that occur during ZIKV infection in blood, cells, and tissues. Multiplex fluorescence in situ hybridization was used to confirm ZIKV replication in mouse and NHP tissues. The integrated rapid response approach developed at USAMRIID presented in this review was successfully applied and provides a new template pathway to follow if a new biological threat emerges. This streamlined approach will increase the likelihood that novel medical countermeasures could be rapidly developed, evaluated, and translated into the clinic.

Prevalence of use and perceptions of risk of novel and other alternative tobacco products among sexual minority adults: Results from an online national survey, 2014-2015.

Sexual minority (lesbian, gay, and bisexual [LGB]) populations experience disparities in cigarette use, but sparse evidence exists about novel and other alternative tobacco product use. In this study, we compared rates of novel and other alternative tobacco product use, risk perceptions, and worldview between LGB and heterosexual (HET) adults. An online survey administered in 2014-2015, using a weighted probability sample of 11,525 U.S. adults, assessed awareness of tobacco products; ever and current use of e-cigarettes, cigars, little cigars and cigarillos, and hookahs; perceptions of e-cigarettes; and worldview (individualism vs. communitarianism). Bivariate and adjusted multivariable analyses were performed to determine differences between LGB and HET groups. In the adjusted analyses, LGB adults were 1.5 times more likely to have ever used e-cigarettes (95% CI 1.2-1.9) and 1.9 times more likely to have ever used hookahs (95% CI 1.5-2.4) as compared to HET adults. A lower percentage of LGB adults, as compared to HET adults (16.7% vs. 19.2%), believed that exposure to vapors from e-cigarettes was "harmful" and reported that they "did not know" of any harm (35.1% vs. 39.8%). LGB were 20% less likely than were HET adults to endorse an individualistic worldview. These results suggest that a disparity exists, whereby LGB adults are more likely to have used e-cigarettes and hookahs. In addition, although vapor from e-cigarettes contains nicotine and other chemicals, LGB adults are less likely to perceive exposure to secondhand vapor as harmful. Tailored awareness campaigns and interventions are needed to convey the risks and curb use of these products.

Coordinated Dynamics of RNA Splicing Speckles in the Nucleus.

Despite being densely packed with chromatin, nuclear bodies and a nucleoskeletal network, the nucleus is a remarkably dynamic organelle. Chromatin loops form and relax, RNA transcripts and transcription factors move diffusively, and nuclear bodies move. We show here that RNA splicing speckled domains (splicing speckles) fluctuate in constrained nuclear volumes and remodel their shapes. Small speckles move in a directed way toward larger speckles with which they fuse. This directed movement is reduced upon decreasing cellular ATP levels or inhibiting RNA polymerase II activity. The random movement of speckles is reduced upon decreasing cellular ATP levels, moderately reduced after inhibition of SWI/SNF chromatin remodeling and modestly increased upon inhibiting RNA polymerase II activity. To define the paths through which speckles can translocate in the nucleus, we generated a pressure gradient to create flows in the nucleus. In response to the pressure gradient, speckles moved along curvilinear paths in the nucleus. Collectively, our results demonstrate a new type of ATP-dependent motion in the nucleus. We present a model where recycling splicing factors return as part of small sub-speckles from distal sites of RNA processing to larger splicing speckles by a directed ATP-driven mechanism through interchromatin spaces.

Strong association between long and heterogeneous telomere length in blood lymphocytes and bladder cancer risk in Egyptian.

Although it is widely recognized that telomere dysfunction plays an important role in cancer, the relationship between telomere function and bladder cancer risk is not well defined. In a case-control study of bladder cancer in Egypt, we examined relationships between two telomere features and bladder cancer risk. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and the risk of urothelial carcinoma of the bladder. High telomere length variation (TLV) across all chromosomal ends was significantly associated with an increased risk of bladder cancer [adjusted odds ratios (OR) = 2.22, 95% confidence interval (CI) = 1.48-3.35], as was long average telomere length (OR = 3.19, 95% CI = 2.07, 4.91). Further, TLV and average telomere length jointly affected bladder cancer risk: when comparing individuals with long telomere length and high TLV to those with short telomere length and low TLV, the adjusted OR was 14.68 (95% CI: 6.74-31.98). These associations were stronger among individuals who are 60 years of age or younger. In summary, long and heterogeneous telomere length in blood lymphocytes was strongly associated with an increased bladder cancer risk in Egyptian and the association was modulated by age.

Characterization of the murine macrophage response to infection with virulent and avirulent Burkholderia species.

BACKGROUND: Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are Gram-negative facultative intracellular pathogens, which are the causative agents of melioidosis and glanders, respectively. Depending on the route of exposure, aerosol or transcutaneous, infection by Bp or Bm can result in an extensive range of disease - from acute to chronic, relapsing illness to fatal septicemia. Both diseases are associated with difficult diagnosis and high fatality rates. About ninety five percent of patients succumb to untreated septicemic infections and the fatality rate is 50 % even when standard antibiotic treatments are administered. RESULTS: The goal of this study is to profile murine macrophage-mediated phenotypic and molecular responses that are characteristic to a collection of Bp, Bm, Burkholderia thailandensis (Bt) and Burkholderia oklahomensis (Bo) strains obtained from humans, animals, environment and geographically diverse locations. Burkholderia spp. (N = 21) were able to invade and replicate in macrophages, albeit to varying degrees. All Bp (N = 9) and four Bm strains were able to induce actin polymerization on the bacterial surface following infection. Several Bp and Bm strains showed reduced ability to induce multinucleated giant cell (MNGC) formation, while Bo and Bp 776 were unable to induce this phenotype. Measurement of host cytokine responses revealed a statistically significant Bm mediated IL-6 and IL-10 production compared to Bp strains. Hierarchical clustering of transcriptional data from 84 mouse cytokines, chemokines and their corresponding receptors identified 29 host genes as indicators of differential responses between the Burkholderia spp. Further validation confirmed Bm mediated Il-1b, Il-10, Tnfrsf1b and Il-36a mRNA expressions were significantly higher when compared to Bp and Bt. CONCLUSIONS: These results characterize the phenotypic and immunological differences in the host innate response to pathogenic and avirulent Burkholderia strains and provide insight into the phenotypic alterations and molecular targets underlying host-Burkholderia interactions.

IFITM-2 and IFITM-3 but not IFITM-1 restrict Rift Valley fever virus.

We show that interferon-induced transmembrane protein 1 (IFITM-1), IFITM-2, and IFITM-3 exhibit a broad spectrum of antiviral activity against several members of the Bunyaviridae family, including Rift Valley fever virus (RVFV), La Crosse virus, Andes virus, and Hantaan virus, all of which can cause severe disease in humans and animals. We found that RVFV was restricted by IFITM-2 and -3 but not by IFITM-1, whereas the remaining viruses were equally restricted by all IFITMs. Indeed, at low doses of alpha interferon (IFN-α), IFITM-2 and -3 mediated more than half of the antiviral activity of IFN-α against RVFV. IFITM-2 and -3 restricted RVFV infection mostly by preventing virus membrane fusion with endosomes, while they had no effect on virion attachment to cells, endocytosis, or viral replication kinetics. We found that large fractions of IFITM-2 and IFITM-3 occupy vesicular compartments that are distinct from the vesicles coated by IFITM-1. In addition, although overexpression of all IFITMs expanded vesicular and acidified compartments within cells, there were marked phenotypic differences among the vesicular compartments occupied by IFITMs. Collectively, our data provide new insights into the possible mechanisms by which the IFITM family members restrict distinct viruses.

Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease.

Although smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.

Brief Report: Refusal of Daily Oral PrEP: Implementation Considerations and Reported Likelihood of Using Various HIV Prophylaxis Products in a Diverse Sample of MSM.

BACKGROUND: An important subgroup of gay, bisexual, and other men who have sex with men (MSM) with behavioral indications refuse daily oral pre-exposure prophylaxis (PrEP) when recommended by a provider. Emerging HIV prophylaxis products (eg, injectable, event-driven) offer more options to MSM who refuse daily PrEP. In this article, we assess reasons for refusal and likelihood to use various products among MSM who refused PrEP. METHODS: MSM who reported anal sex without condoms or PrEP and refused daily oral PrEP in the past 6 months were recruited through clinics, community venues, and online in Atlanta, Chicago, and Raleigh-Durham. Men were asked their main reason for recently refusing daily PrEP and likelihood of using various PrEP options in the future. Bivariate and multivariable regression models were used to estimate associations. RESULTS: MSM (n = 93; 70% Black, 48% age 18-29 years) reported their main reason for refusing daily PrEP were potential side effects (35%), a daily pill regimen (22%), and not having enough information (18%). Reported likelihood of using PrEP products was 58% for penile gel, 54% for event-driven oral, 52% for injectable, and 50% for daily PrEP. MSM who reported daily regimen as the main reason for refusing PrEP had greater odds of likelihood to use an injectable [adjusted odds ratio (AOR) = 5.21, 95% confidence interval (CI): 1.32 to 20.52]. Younger men (18-29 vs 30+ years) had greater odds of likelihood to use condoms (AOR = 3.40, 95% CI: 1.15 to 10.04) and daily PrEP (AOR = 2.76, 95% CI: 1.06 to 7.16); there were no product preference differences by race. CONCLUSION: Most men who refused daily PrEP indicated likelihood of using some form of PrEP in the future.

Racial/ethnic disparities in estimated undiagnosed HIV infection among adolescents and adults in the United States, 2017-2021.

In 2021, there were an estimated 153 500 persons aged at least 13 years with undiagnosed HIV infection. Estimated rates among Black/African American, Hispanic/Latino, and White persons were used to assess disparity trends from 2017 to 2021. Rates decreased across two absolute and relative disparity measures. Despite these declines, Black and Hispanic persons had rates 8.3 and 4.2 times the rate of White persons in 2021. Increased testing and innovative efforts are needed to address HIV-related disparities.

Pre-exposure prophylaxis in the era of emerging methods for men who have sex with men in the USA: the HIV Prevention Cycle of Care model.

Expanding on previous work, we present an HIV Prevention Cycle of Care model to facilitate understanding of the complexity of issues involved in pre-exposure prophylaxis implementation for gay, bisexual, and other men who have sex with men (MSM) in the USA, including individual, client-provider, and overarching issues such as health equity, stigma, and prevention nomenclature. The HIV prevention cycle of care applies to MSM who test negative for HIV. The Prevention Cycle of Care model includes seven steps: prevention knowledge, prevention self-awareness and preferences, prevention motivation, health-care access and cost, provider issues, adherence and persistence, and periodic reassessment and adjustment. HIV prevention is complex in an era of emerging multiple modalities, and more research is needed to successfully implement pre-exposure prophylaxis options over time and across diverse communities of MSM who are sexually active.