Chikungunya virus release is reduced by TIM-1 receptors through binding of envelope phosphatidylserine.

T-cell immunoglobin and mucin domain protein-1 (TIM-1) mediates entry of chikungunya virus (CHIKV) into some mammalian cells through the interaction with envelope phospholipids. While this interaction enhances entry, TIM-1 has been shown to tether newly formed HIV and Ebola virus particles, limiting their efficient release. In this study, we investigate the ability of surface receptors such as TIM-1 to sequester newly budded virions on the surface of infected cells. We established a luminescence reporter system to produce chikungunya viral particles that integrate nano-luciferase and easily quantify viral particles. We found that TIM-1 on the surface of host cells significantly reduced CHIKV release efficiency in comparison to other entry factors. Removal of cell surface TIM-1 through direct cellular knock-out or altering the cellular lipid distribution enhanced CHIKV release. Over the course of infection, CHIKV was able to counteract the tethering effect by gradually decreasing the surface levels of TIM-1 in a process mediated by the nonstructural protein 2. This study highlights the importance of phosphatidylserine receptors in mediating not only the entry of CHIKV but also its release and could aid in developing cell lines capable of enhanced vaccine production. IMPORTANCE: Chikungunya virus (CHIKV) is an enveloped alphavirus transmitted by the bites of infectious mosquitoes. Infection with CHIKV results in the development of fever, joint pain, and arthralgia that can become chronic and last for months after infection. Prevention of this disease is still highly focused on vector control strategies. In December 2023, a new live attenuated vaccine against CHIKV was approved by the FDA. We aimed to study the cellular factors involved in CHIKV release, to better understand CHIKV's ability to efficiently infect and spread among a wide variety of cell lines. We found that TIM-1 receptors can significantly abrogate CHIKV's ability to efficiently exit infected cells. This information can be beneficial for maximizing viral particle production in laboratory settings and during vaccine manufacturing.

Chikungunya Virus Release is Reduced by TIM-1 Receptors Through Binding of Envelope Phosphatidylserine.

T-cell immunoglobin and mucin domain protein-1 (TIM-1) mediates entry of Chikungunya virus (CHIKV) into some mammalian cells through the interaction with envelope phospholipids. While this interaction enhances entry, TIM has been shown to tether newly formed HIV and Ebola virus particles, limiting their efficient release. In this study, we investigate the ability of surface receptors such as TIM-1 to sequester newly budded virions on the surface of infected cells. We established a luminescence reporter system to produce Chikungunya viral particles that integrate nano-luciferase and easily quantify viral particles. We found that TIM-1 on the surface of host cells significantly reduced CHIKV release efficiency in comparison to other entry factors. Removal of cell surface TIM-1 through direct cellular knock-out or altering the cellular lipid distribution enhanced CHIKV release. Over the course of infection, CHIKV was able to counteract the tethering effect by gradually decreasing the surface levels of TIM-1 in a process that appears to be mediated by the nonstructural protein 2. This study highlights the importance of phosphatidylserine receptors in mediating not only the entry of CHIKV but also its release and could aid in developing cell lines capable of enhanced vaccine production.

N-dihydrogalactochitosan serves as an effective mucosal adjuvant for intranasal vaccine in combination with recombinant viral proteins against respiratory infection.

Mucosal vaccinations for respiratory pathogens provide effective protection as they stimulate localized cellular and humoral immunities at the site of infection. Currently, the major limitation of intranasal vaccination is using effective adjuvants capable of withstanding the harsh environment imposed by the mucosa. Herein, we describe the efficacy of using a unique biopolymer, N-dihydrogalactochitosan (GC), as a nasal mucosal vaccine adjuvant against respiratory infections. Specifically, we mixed GC with recombinant SARS-CoV-2 trimeric spike (S) and nucleocapsid (NC) proteins to intranasally vaccinate K18-hACE2 transgenic mice, in comparison with Addavax (AV), an MF-59 equivalent. In contrast to AV, intranasal application of GC induces a robust, systemic antigen-specific antibody response and increases the number of T cells in the cervical lymph nodes. Moreover, GC+S+NC-vaccinated animals were largely resistant to the lethal SARS-CoV-2 challenge and experienced drastically reduced morbidity and mortality, with animal weights and behavior returning to normal 22 days post-infection. In contrast, animals intranasally vaccinated with AV+S+NC experienced severe weight loss, mortality, and respiratory distress, with none surviving beyond 6 days post-infection. Our findings demonstrate that GC can serve as a potent mucosal vaccine adjuvant against SARS-CoV-2 and potentially other respiratory viruses. STATEMENT OF SIGNIFICANCE: We demonstrated that a unique biopolymer, N-dihydrogalactochitosan (GC), was an effective nasal mucosal vaccine adjuvant against respiratory infections. Specifically, we mixed GC with recombinant SARS-CoV-2 trimeric spike (S) and nucleocapsid (NC) proteins to intranasally vaccinate K18-hACE2 transgenic mice, in comparison with Addavax (AV). In contrast to AV, GC induces a robust, systemic antigen-specific antibody response and increases the number of T cells in the cervical lymph nodes. About 90 % of the GC+S+NC-vaccinated animals survived the lethal SARS-CoV-2 challenge and remained healthy 22 days post-infection, while the AV+S+NC-vaccinated animals experienced severe weight loss and respiratory distress, and all died within 6 days post-infection. Our findings demonstrate that GC is a potent mucosal vaccine adjuvant against SARS-CoV-2 and potentially other respiratory viruses.

N-dihydrogalactochitosan reduces mortality in a lethal mouse model of SARS-CoV-2.

The rapid emergence and global dissemination of SARS-CoV-2 that causes COVID-19 continues to cause an unprecedented global health burden resulting in nearly 7 million deaths. While multiple vaccine countermeasures have been approved for emergency use, additional treatments are still needed due to sluggish vaccine rollout, vaccine hesitancy, and inefficient vaccine-mediated protection. Immunoadjuvant compounds delivered intranasally can guide non-specific innate immune responses during the critical early stages of viral replication, reducing morbidity and mortality. N-dihydrogalactochitosan (GC) is a novel mucoadhesive immunostimulatory polymer of ß-0-4-linked N-acetylglucosamine that is solubilized by the conjugation of galactose glycans with current applications as a cancer immunotherapeutic. We tested GC as a potential countermeasure for COVID-19. GC was well-tolerated and did not produce histopathologic lesions in the mouse lung. GC administered intranasally before and after SARS-CoV-2 exposure diminished morbidity and mortality in humanized ACE2 receptor expressing mice by up to 75% and reduced infectious virus levels in the upper airway. Fluorescent labeling of GC shows that it is confined to the lumen or superficial mucosa of the nasal cavity, without involvement of adjacent or deeper tissues. Our findings demonstrate a new application for soluble immunoadjuvants such as GC for preventing disease associated with SARS-CoV-2 and may be particularly attractive to persons who are needle-averse.

Single-cell transcriptomics reveals that tumor-infiltrating natural killer cells are activated by localized ablative immunotherapy and share anti-tumor signatures induced by immune checkpoint inhibitors.

Rationale: Natural killer (NK) cells provide protective anti-cancer immunity. However, the cancer therapy induced activation gene signatures and pathways in NK cells remain unclear. Methods: We applied a novel localized ablative immunotherapy (LAIT) by synergizing photothermal therapy (PTT) with intra-tumor delivering of the immunostimulant N-dihydrogalactochitosan (GC), to treat breast cancer using a mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) mouse model. We performed single-cell RNA sequencing (scRNAseq) analysis to unveil the cellular heterogeneity and compare the transcriptional alterations induced by PTT, GC, and LAIT in NK cells within the tumor microenvironment (TME). Results: ScRNAseq showed that NK subtypes, including cycling, activated, interferon-stimulated, and cytotoxic NK cells. Trajectory analysis revealed a route toward activation and cytotoxicity following pseudotime progression. Both GC and LAIT elevated gene expression associated with NK cell activation, cytolytic effectors, activating receptors, IFN pathway components, and cytokines/chemokines in NK subtypes. Single-cell transcriptomics analysis using immune checkpoint inhibitor (ICI)-treated animal and human samples revealed that ICI-induced NK activation and cytotoxicity across several cancer types. Furthermore, ICI-induced NK gene signatures were also induced by LAIT treatment. We also discovered that several types of cancer patients had significantly longer overall survival when they had higher expression of genes in NK cells that were also specifically upregulated by LAIT. Conclusion: Our findings show for the first time that LAIT activates cytotoxicity in NK cells and the upregulated genes positively correlate with beneficial clinical outcomes for cancer patients. More importantly, our results further establish the correlation between the effects of LAIT and ICI on NK cells, hence expanding our understanding of mechanism of LAIT in remodeling TME and shedding light on the potentials of NK cell activation and anti-tumor cytotoxic functions in clinical applications.

Health Care Access and Lived Experience of American Indian/Alaska Native Two Spirit and LGBTQ+ Participants in the Pride and Connectedness Survey, 2020.

OBJECTIVE: To better understand health experiences among Two Spirit and lesbian, gay, bisexual, transgender, and queer and questioning (LGBTQ+) American Indian/Alaska Native (AI/AN) people, we examined experiences with access to health care of 223 AI/AN Two Spirit and LGBTQ+ people. METHODS: Participants of the Pride and Connectedness 2020 survey, conducted through the Northwest Portland Area Indian Health Board, were asked about barriers to seeking and accessing care through a 10-question scale. We compared cisgender and gender-diverse participant demographic and scale responses to explore potential differences based on gender identity using the Pearson χ2 test of independence and ordinal logistic regression, respectively. RESULTS: Both cisgender and gender-diverse participants experienced at least some difficulties accessing health care. Finances, lack of psychologists/other mental health support, and lack of psychological support groups for Two Spirit and LGBTQ+ communities were the top 3 barriers to care experienced by all participants (84%, 82%, and 80%, respectively). Compared with cisgender participants, gender-diverse participants were more likely to report difficulties accessing care for nearly all questions on the 10-question scale and nearly 3 times more likely to report fear of being mistreated within the health care system based on their gender identity (adjusted odds ratio = 2.9; 95% CI, 1.8-4.9; P < .001). CONCLUSIONS: Increased access to mental health services and improved health care provider training that focuses on culturally relevant and gender-affirming practices would benefit the health and well-being of AI/AN people who identify as Two Spirit and LGBTQ+.

Immune modulations of the tumor microenvironment in response to phototherapy.

The tumor microenvironment (TME) promotes pro-tumor and anti-inflammatory metabolisms and suppresses the host immune system. It prevents immune cells from fighting against cancer effectively, resulting in limited efficacy of many current cancer treatment modalities. Different therapies aim to overcome the immunosuppressive TME by combining various approaches to synergize their effects for enhanced anti-tumor activity and augmented stimulation of the immune system. Immunotherapy has become a major therapeutic strategy because it unleashes the power of the immune system by activating, enhancing, and directing immune responses to prevent, control, and eliminate cancer. Phototherapy uses light irradiation to induce tumor cell death through photothermal, photochemical, and photo-immunological interactions. Phototherapy induces tumor immunogenic cell death, which is a precursor and enhancer for anti-tumor immunity. However, phototherapy alone has limited effects on long-term and systemic anti-tumor immune responses. Phototherapy can be combined with immunotherapy to improve the tumoricidal effect by killing target tumor cells, enhancing immune cell infiltration in tumors, and rewiring pathways in the TME from anti-inflammatory to pro-inflammatory. Phototherapy-enhanced immunotherapy triggers effective cooperation between innate and adaptive immunities, specifically targeting the tumor cells, whether they are localized or distant. Herein, the successes and limitations of phototherapy combined with other cancer treatment modalities will be discussed. Specifically, we will review the synergistic effects of phototherapy combined with different cancer therapies on tumor elimination and remodeling of the immunosuppressive TME. Overall, phototherapy, in combination with other therapeutic modalities, can establish anti-tumor pro-inflammatory phenotypes in activated tumor-infiltrating T cells and B cells and activate systemic anti-tumor immune responses.

Localized ablative immunotherapy drives de novo CD8+ T-cell responses to poorly immunogenic tumors.

BACKGROUND: Localized ablative immunotherapies hold great promise in stimulating antitumor immunity to treat metastatic and poorly immunogenic tumors. Tumor ablation is well known to release tumor antigens and danger-associated molecular patterns to stimulate T-cell immunity, but its immune stimulating effect is limited, particularly against metastatic tumors. METHODS: In this study, we combined photothermal therapy with a potent immune stimulant, N-dihydrogalactochitosan, to create a local ablative immunotherapy which we refer to as laser immunotherapy (LIT). Mice bearing B16-F10 tumors were treated with LIT when the tumors reached 0.5 cm3 and were monitored for survival, T-cell activation, and the ability to resist tumor rechallenge. RESULTS: We found that LIT stimulated a stronger and more consistent antitumor T-cell response to the immunologically 'cold' B16-F10 melanoma tumors and conferred a long-term antitumor memory on tumor rechallenge. Furthermore, we discovered that LIT generated de novo CD8+ T-cell responses that strongly correlated with animal survival and tumor rejection. CONCLUSION: In summary, our findings demonstrate that LIT enhances the activation of T cells and drives de novo antitumor T-cell responses. The data presented herein suggests that localized ablative immunotherapies have great potential to synergize with immune checkpoint therapies to enhance its efficacy, resulting in improved antitumor immunity.

Single-cell RNA sequencing reveals localized tumour ablation and intratumoural immunostimulant delivery potentiate T cell mediated tumour killing.

BACKGROUND: Metastatic breast cancer poses great challenge in cancer treatment. N-dihydrogalactochitosan (GC) is a novel immunoadjuvant that stimulates systemic immune responses when administered intratumourally following local tumour ablation. A combination of photothermal therapy (PTT) and GC, referred to as localized ablative immunotherapy (LAIT), extended animal survival and generates an activated B cell phenotype in MMTV-PyMT mouse mammary tumour microenvironment (TME). However, how T cell populations respond to LAIT remains to be elucidated. METHODS: Using depletion antibodies, we studied the contributions of CD8+ and CD4+ T cells to the therapeutic effect of LAIT. Using single-cell RNA-sequencing (scRNAseq), we analysed tumour-infiltrating T cell heterogeneity and dissected their transcriptomes upon treatments of PTT, GC, and LAIT (PTT+GC). RESULTS: Loss of CD8+ T cells after LAIT abrogated the therapeutic benefits of LAIT. Ten days after treatment, proportions of CD8+ and CD4+ T cells in untreated TME were 19.2% and 23.0%, respectively. Upon LAIT, both proportions were increased to 25.5% and 36.2%, respectively. In particular, LAIT increased the proportions of naïve and memory cells from a resting state to an activated state. LAIT consistently induced the expression of co-stimulatory molecules, type I IFN responsive genes, and a series of antitumor cytokines, Ifng, Tnf, Il1, and Il17 in CD8+ and CD4+ T cells. LAIT also induced immune checkpoints Pdcd1, Ctla4, and Lag3 expression, consistent with T cell activation. Relevant to clinical translation, LAIT also upregulated genes in CD8+ and CD4+ T cells that positively correlated with extended survival of breast cancer patients. CONCLUSIONS: Overall, our results reveal that LAIT prompts immunological remodelling of T cells by inducing broad proinflammatory responses and inhibiting suppressive signalling to drive antitumour immunity.

Antigen presentation and interferon signatures in B cells driven by localized ablative cancer immunotherapy correlate with extended survival.

Rationale: B cells have emerged as key regulators in protective cancer immunity. However, the activation pathways induced in B cells during effective immunotherapy are not well understood. Methods: We used a novel localized ablative immunotherapy (LAIT), combining photothermal therapy (PTT) with intra-tumor delivery of the immunostimulant N-dihydrogalactochitosan (GC), to treat mice bearing mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT). We used single-cell RNA sequencing to compare the transcriptional changes induced by PTT, GC and PTT+GC in B cells within the tumor microenvironment (TME). Results: LAIT significantly increased survival in the tumor-bearing mice, compared to the treatment by PTT and GC alone. We found that PTT, GC and PTT+GC increased the proportion of tumor-infiltrating B cells and induced gene expression signatures associated with B cell activation. Both GC and PTT+GC elevated gene expression associated with antigen presentation, whereas GC elevated transcripts that regulate B cell activation and GTPase function and PTT+GC induced interferon response genes. Trajectory analysis, where B cells were organized according to pseudotime progression, revealed that both GC and PTT+GC induced the differentiation of B cells from a resting state towards an effector phenotype. The analyses confirmed upregulated interferon signatures in the differentiated tumor-infiltrating B cells following treatment by PTT+GC but not by GC. We also observed that breast cancer patients had significantly longer survival time if they had elevated expression of genes in B cells that were induced by PTT+GC therapy in the mouse tumors. Conclusion: Our findings show that the combination of local ablation and local application of immunostimulant initiates the activation of interferon signatures and antigen-presentation in B cells which is associated with positive clinical outcomes for breast cancer. These findings broaden our understanding of LAIT's regulatory roles in remodeling TME and shed light on the potentials of B cell activation in clinical applications.

Synergistic interventional photothermal therapy and immunotherapy using an iron oxide nanoplatform for the treatment of pancreatic cancer.

Pancreatic cancer (PC) is the most lethal malignancy due to its high metastatic ability and poor drug permeability. Here, a synergized interventional photothermal-immunotherapy strategy was developed with imaging guidance and temperature monitoring by magnetic resonance imaging (MRI) technique, for the local treatment of metastatic PC. A tumor microenvironment (TME)-responsive nanoplatform was fabricated via coating of DSPE-PEG and indocyanine green (ICG) onto imiquimod (IMQ) loaded amorphous iron oxide nanoparticles (IONs). This unique nanoplatform, IMQ@IONs/ICG, served as a contrast agent for MRI, a drug delivery vehicle for IMQ and ICG, and a catalyst for TME modulation. The biodegradable IMQ@IONs/ICG was also non-toxic, and improved the penetration of the loaded drugs in PC to maximize thermal ablation of the tumor and minimize damage to the surrounding healthy tissue. For the treatment of aggressive, metastatic Panc02-H7 pancreatic tumors in mice, ION-assisted MRI was employed to guide the administration of interventional photothermal therapy (IPTT) and monitor the temperature distribution in target tumor and surrounding tissue during treatment. The local IPTT treatment induced in situ immunogenic cell death (ICD), and, in combination with released IMQ, triggered a strong antitumor immunity, leading to decreased metastases and increased CD8+ in spleen and tumors. With precise local treatment and monitoring, treated primary tumors were completely eradicated, mesentery metastases were dramatically reduced, and the survival time was significantly prolonged, without damage to normal tissue and systemic autoimmunity. Overall, this synergistic strategy represents a promising approach to treat PC with significant potential for clinical applications. STATEMENT OF SIGNIFICANCE: Pancreatic cancer (PC) is one of the most lethal malignancies because it is non-permeable to drugs and highly metastatic. In this study, we designed a tumor microenvironment-responsive amorphous iron oxide nanoplatform (ION) to co-deliver photothermal agent (ICG) and toll-like-receptor-7 agonist (IMQ). This biodegradable nanoplatform IMQ@IONs/ICG improved the penetration of the loaded drugs in pancreatic tumor. With MR imaging guidance and temperature monitoring, the precise interventional photothermal therapy on mouse Panc02-H7 orthotopic tumors releases tumor antigens to initiate tumor-special immune responses, amplified by the released IMQ. Our results demonstrate that IMQ@IONs/ICG overcomes the obstacle of drug delivery to pancreatic tumors, and when combined with photothermal therapy, induces a systemic antitumor immunity to control metastatic tumors.

T cell self-reactivity during thymic development dictates the timing of positive selection.

Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced T cell receptor (TCR) sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity downregulate TCR sensitivity more slowly during positive selection, and associate membrane ion channel expression with thymocyte self-reactivity and progress through positive selection.

Factors that influence the thymic selection of CD8αα intraepithelial lymphocytes.

Thymocytes bearing αß T cell receptors (TCRαß) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8αα-expressing intraepithelial lymphocytes (CD8αα IELs). The factors that influence the choice between negative selection versus CD8αα IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8αα IEL development, we show that the affinity threshold for CD8αα IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.

Immunologically modified MnFe2O4 nanoparticles to synergize photothermal therapy and immunotherapy for cancer treatment.

Immunotherapy has been a promising candidate for cancer treatment. The combination of photothermal therapy (PTT) and immunotherapy have shown to cause tumor ablation and induce host immune response. However, this strategy is often hampered by a limited immune response and undesirable immunosuppression. In this work, we developed an immunologically modified nanoplatform, using ovalbumin (OVA)-coated PEGylated MnFe2O4 nanoparticles (NPs) loaded with R837 immunoadjuvant (R837-OVA-PEG-MnFe2O4 NPs) to synergize PTT and immunotherapy for the treatment of breast cancer. The designed R837-OVA-PEG-MnFe2O4 NPs are able to elicit significant immune responses in vitro and in vivo. MnFe2O4 NPs also allowed for a reduction of systemic immunosuppression through downregulation of M2-associated cytokines. More importantly, the R837-OVA-PEG-MnFe2O4 NPs under laser irradiation effectively inhibited tumor growth and prevented lung metastases, leading to a prolonged survival time and improved survival rate. In addition, the designed multitasking MnFe2O4 NPs showed as a good contrast agent for magnetic resonance (MR) imaging to detect orthotopic breast tumor in vivo. Our work provides a novel strategy for combined PTT and improved immunotherapy in the treatment of breast and other metastatic cancers.

A pipeline for identification and validation of tumor-specific antigens in a mouse model of metastatic breast cancer.

Cancer immunotherapy continues to make headway as a treatment for advanced stage tumors, revealing an urgent need to understand the fundamentals of anti-tumor immune responses. Noteworthy is a scarcity of data pertaining to the breadth and specificity of tumor-specific T cell responses in metastatic breast cancer. Autochthonous transgenic models of breast cancer display spontaneous metastasis in the FVB/NJ mouse strain, yet a lack of knowledge regarding tumor-bound MHC/peptide immune epitopes in this mouse model limits the characterization of tumor-specific T cell responses, and the mechanisms that regulate T cell responses in the metastatic setting. We recently generated the NetH2pan prediction tool for murine class I MHC ligands by building an FVB/NJ H-2q ligand database and combining it with public information from six other murine MHC alleles. Here, we deployed NetH2pan in combination with an advanced proteomics workflow to identify immunogenic T cell epitopes in the MMTV-PyMT transgenic model for metastatic breast cancer. Five unique MHC I/PyMT epitopes were identified. These tumor-specific epitopes were confirmed to be presented by the class I MHC of primary MMTV-PyMT tumors and their T cell immunogenicity was validated. Vaccination using a DNA construct encoding a truncated PyMT protein generated CD8 + T cell responses to these MHC class I/peptide complexes and prevented tumor development. In sum, we have established an MHC-ligand discovery pipeline in FVB/NJ mice, identified and tracked H-2Dq/PyMT neoantigen-specific T cells, and developed a vaccine that prevents tumor development in this metastatic model of breast cancer.

Neural Tube Defects in Pregnancies Among Women With Diagnosed HIV Infection - 15 Jurisdictions, 2013-2017.

In May 2018, a study of birth defects in infants born to women with diagnosed human immunodeficiency virus (HIV) infection in Botswana reported an eightfold increased risk for neural tube defects (NTDs) among births with periconceptional exposure to antiretroviral therapy (ART) that included the integrase inhibitor dolutegravir (DTG) compared with other ART regimens (1). The World Health Organization* (WHO) and the U.S. Department of Health and Human Services† (HHS) promptly issued interim guidance limiting the initiation of DTG during early pregnancy and in women of childbearing age with HIV who desire pregnancy or are sexually active and not using effective contraception. On the basis of additional data, WHO now recommends DTG as a preferred treatment option for all populations, including women of childbearing age and pregnant women. Similarly, the U.S. recommendations currently state that DTG is a preferred antiretroviral drug throughout pregnancy (with provider-patient counseling) and as an alternative antiretroviral drug in women who are trying to conceive.§ Since 1981 and 1994, CDC has supported separate surveillance programs for HIV/acquired immunodeficiency syndrome (AIDS) (2) and birth defects (3) in state health departments. These two surveillance programs can inform public health programs and policy, linkage to care, and research activities. Because birth defects surveillance programs do not collect HIV status, and HIV surveillance programs do not routinely collect data on occurrence of birth defects, the related data have not been used by CDC to characterize birth defects in births to women with HIV. Data from these two programs were linked to estimate overall prevalence of NTDs and prevalence of NTDs in HIV-exposed pregnancies during 2013-2017 for 15 participating jurisdictions. Prevalence of NTDs in pregnancies among women with diagnosed HIV infection was 7.0 per 10,000 live births, similar to that among the general population in these 15 jurisdictions, and the U.S. estimate based on data from 24 states. Successful linking of data from birth defects and HIV/AIDS surveillance programs for pregnancies among women with diagnosed HIV infection suggests that similar data linkages might be used to characterize possible associations between maternal diseases or maternal use of medications, such as integrase strand transfer inhibitors used to manage HIV, and pregnancy outcomes. Although no difference in NTD prevalence in HIV-exposed pregnancies was found, data on the use of integrase strand transfer inhibitors in pregnancy are needed to understand the safety and risks of these drugs during pregnancy.

A role for phagocytosis in inducing cell death during thymocyte negative selection.

Autoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, using a murine thymic slice model in which thymocytes undergo negative selection in situ, we demonstrate that phagocytosis promotes negative selection, and provide evidence for the escape of autoreactive CD8 T cells to the periphery when phagocytosis in the thymus is impaired. We also show that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a model for negative selection in which the death process initiated following strong TCR signaling is facilitated by phagocytosis. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.

NIR-Triggered Phototherapy and Immunotherapy via an Antigen-Capturing Nanoplatform for Metastatic Cancer Treatment.

Combined phototherapy and immunotherapy demonstrates strong potential in the treatment of metastatic cancers. An upconversion nanoparticle (UCNP) based antigen-capturing nanoplatform is designed to synergize phototherapies and immunotherapy. In particular, this nanoplatform is constructed via self-assembly of DSPE-PEG-maleimide and indocyanine green (ICG) onto UCNPs, followed by loading of the photosensitizer rose bengal (RB). ICG significantly enhances the RB-based photodynamic therapy efficiency of UCNP/ICG/RB-mal upon activation by a near-infrared (NIR) laser, simultaneously achieving selective photothermal therapy. Most importantly, tumor-derived protein antigens, arising from phototherapy-treated tumor cells, can be captured and retained in situ, due to the functionality of maleimide, which further enhance the tumor antigen uptake and presentation by antigen-presenting cells. The synergized photothermal, photodynamic, and immunological effects using light-activated UCNP/ICG/RB-mal induces a tumor-specific immune response. In the experiments, intratumoral administration of UCNP/ICG/RB-mal, followed by noninvasive irradiation with an NIR laser, destroys primary tumors and inhibits untreated distant tumors, using a poorly immunogenic, highly metastatic 4T1 mammary tumor model. With the simultaneous use of anti-CTLA-4, about 84% of the treated tumor-bearing mice achieve long-term survival and 34% of mice develop tumor-specific immunity. Overall, this antigen-capturing nanoplatform provides a promising approach for the treatment of metastatic cancers.

MIR205HG Is a Long Noncoding RNA that Regulates Growth Hormone and Prolactin Production in the Anterior Pituitary.

MicroRNAs (miRNAs) are processed from primary miRNA transcripts (pri-miRNAs), many of which are annotated as long noncoding RNAs (lncRNAs). We assessed whether MIR205HG, the host gene for miR-205, has independent functions as an lncRNA. Comparing mice with targeted deletions of MIR205HG and miR-205 revealed a functional role for the lncRNA in the anterior pituitary. Mice lacking MIR205HG had a temporal reduction in Pit1, growth hormone, and prolactin. This was mediated, in part, through the ability of this lncRNA to bind and regulate the transcriptional activity of Pit1 in conjunction with Zbtb20. Knockdown of MIR205HG in lactotropes decreased the expression of Pit1, Zbtb20, prolactin, and growth hormone, while its overexpression enhanced the levels of these transcripts. The effects of MIR205HG on the pituitary were independent of miR-205. The data support a role for MIR205HG as an lncRNA that regulates growth hormone and prolactin production in the anterior pituitary.