Anti-PD-L1 antibody ASC22 in combination with a histone deacetylase inhibitor chidamide as a "shock and kill" strategy for ART-free virological control: a phase II single-arm study.

The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.

Prevalence and associated factors of low bone mineral density in people living with HIV: a cross-sectional study.

This study examined low bone mineral density (BMD) prevalence and associated factors among Chinese people living with HIV (PLWH), uncovering a persistent high BMD risk in older individuals, even after adjusting for age and body mass index (BMI). Notably, lopinavir/ritonavir (LPV/r) therapy was linked to reduced BMD, highlighting the imperative need for regular BMD monitoring and interventions in older PLWH. PURPOSE: HIV infection and antiretroviral therapy (ART) have been shown to contribute to lower BMD, resulting in an increased susceptibility to osteopenia and osteoporosis. However, there is limited knowledge about the prevalence of reduced BMD and its associated factors among Chinese PLWH. In this cross-sectional study, we aimed to investigate the prevalence and factors associated with low BMD among PLWH in China. METHODS: We retrospectively enrolled PLWH and non-HIV volunteers who underwent dual-energy X-ray absorptiometry (DXA) scans to measure bone density. Demographic information, laboratory test results, ART regimens, and treatment duration were collected. Univariate and multiple regression analyses were performed to identify factors influencing abnormal bone mass in PLWH. RESULTS: A total of 829 individuals were included in this study, comprising the HIV group (n = 706) and the non-HIV group (n = 123). The prevalence of low BMD among all PLWH was found to be 13.88% (98 out of 706). However, among PLWH aged 50 years and above, the prevalence increased to 65.32% (81 out of 124). In contrast, control subjects in the same age group had a prevalence of 38.21% (47 out of 123). After adjusting for age and BMI, older PLWH still demonstrated a higher prevalence of low BMD compared to the non-HIV group (68.24% vs 34.94%, P < 0.001). Multivariate analysis revealed that older age was strongly associated with a higher risk of low BMD among PLWH, with an odds ratio (OR) of 6.28 for every 10-year increase in age in the ART-naïve population (95% confidence intervals [CIs], 3.12-12.65; P < 0.001) and OR of 4.83 in the ART-experienced population (3.20-7.29, P < 0.001). Within the ART-experienced group, current LPV/r treatment was associated with an increased risk of low BMD (OR = 3.55, 1.24-10.14, P < 0.05), along with lower BMI (OR = 0.84, 0.75-0.95, P < 0.05), and elevated alkaline phosphatase (OR = 1.02, 1.01-1.03, P < 0.01). CONCLUSION: The prevalence of low BMD is higher among PLWH aged 50 years and above compared to non-HIV individuals. The use of LPV/r for ART is associated with reduced BMD. These findings emphasize the importance of regular monitoring of BMD in older PLWH and the need for appropriate interventions to mitigate the risks of osteopenia and osteoporosis in this population.

Hospital-treated infectious diseases, infection burden and risk of Parkinson disease: An observational and Mendelian randomization study.

BACKGROUND: Experimental and cross-sectional evidence has suggested a potential role of infection in the ethology of Parkinson's disease (PD). We aim to examine the longitudinal association of infections with the incidence of PD and to explore whether the increased risk is limited to specific infection type rather than infection burden. METHODS: Based on the UK Biobank, hospital-treated infectious diseases and incident PD were ascertained through record linkage to national hospital inpatient registers. Infection burden was defined as the sum of the number of infection episodes over time and the number of co-occurring infections. The polygenic risk score (PRS) for PD was calculated. The genome-wide association studies (GWAS) used in two-sample Mendelian Randomization (MR) were obtained from observational cohort participants of mostly European ancestry. RESULTS: Hospital-treated infectious diseases were associated with an increased risk of PD (adjusted HR [aHR] 1.35 [95 % CI 1.20-1.52]). This relationship persisted when analyzing new PD cases occurring more than 10 years post-infection (aHR 1.22 [95 % CI 1.04-1.43]). The greatest PD risk was observed in neurological/eye infection (aHR 1.72 [95 % CI 1.32-2.34]), with lower respiratory tract infection (aHR 1.43 [95 % CI 1.02-1.99]) ranked the second. A dose-response association was observed between infection burden and PD risk within each PD-PRS tertile (p-trend < 0.001). Multivariable MR showed that bacterial and viral infections increase the PD risk. CONCLUSIONS: Both observational and genetic analysis suggested a causal association between infections and the risk of developing PD. A dose-response relationship between infection burden and incident PD was revealed.

Comprehensive risk factor predictions for 3-year survival among HIV-associated and disseminated cryptococcosis involving lungs and central nervous system.

BACKGROUND: The global mortality rate resulting from HIV-associated cryptococcal disease is remarkably elevated, particularly in severe cases with dissemination to the lungs and central nervous system (CNS). Regrettably, there is a dearth of predictive analysis regarding long-term survival, and few studies have conducted longitudinal follow-up assessments for comparing anti-HIV and antifungal treatments. METHODS: A cohort of 83 patients with HIV-related disseminated cryptococcosis involving the lung and CNS was studied for 3 years to examine survival. Comparative analysis of clinical and immunological parameters was performed between deceased and surviving individuals. Subsequently, multivariate Cox regression models were utilized to validate mortality predictions at 12, 24, and 36 months. RESULTS: Observed plasma cytokine levels before treatment were significantly lower for IL-1RA (p < 0.001) and MCP-1 (p < 0.05) when in the survivor group. Incorporating plasma levels of IL-1RA, IL-6, and high-risk CURB-65 score demonstrated the highest area under curve (AUC) value (0.96) for predicting 1-year mortality. For 1-, 2- and 3-year predictions, the single-factor model with IL-1RA demonstrated superior performance compared to all multiple-variate models (AUC = 0.95/0.78/0.78). CONCLUSIONS: IL-1RA is a biomarker for predicting 3-year survival. Further investigations to explore the pathogenetic role of IL-1RA in HIV-associated disseminated cryptococcosis and as a potential therapeutic target are warranted.

Employing bimodal representations to predict DNA bendability within a self-supervised pre-trained framework.

The bendability of genomic DNA, which measures the DNA looping rate, is crucial for numerous biological processes of DNA. Recently, an advanced high-throughput technique known as 'loop-seq' has made it possible to measure the inherent cyclizability of DNA fragments. However, quantifying the bendability of large-scale DNA is costly, laborious, and time-consuming. To close the gap between rapidly evolving large language models and expanding genomic sequence information, and to elucidate the DNA bendability's impact on critical regulatory sequence motifs such as super-enhancers in the human genome, we introduce an innovative computational model, named MIXBend, to forecast the DNA bendability utilizing both nucleotide sequences and physicochemical properties. In MIXBend, a pre-trained language model DNABERT and convolutional neural network with attention mechanism are utilized to construct both sequence- and physicochemical-based extractors for the sophisticated refinement of DNA sequence representations. These bimodal DNA representations are then fed to a k-mer sequence-physicochemistry matching module to minimize the semantic gap between each modality. Lastly, a self-attention fusion layer is employed for the prediction of DNA bendability. In conclusion, the experimental results validate MIXBend's superior performance relative to other state-of-the-art methods. Additionally, MIXBend reveals both novel and known motifs from the yeast. Moreover, MIXBend discovers significant bendability fluctuations within super-enhancer regions and transcription factors binding sites in the human genome.

Development of a novel ZIKV vaccine comprised of immunodominant CD4+ and CD8+ T cell epitopes identified through comprehensive epitope mapping in Zika virus infected mice.

Zika virus (ZIKV) caused over two million human infections in more than 80 countries around 2015-2016. Current vaccines under development are mostly focused on inducing antibodies that despite capable of inhibiting the virus, may have the potential to trigger antibody dependent enhancement (ADE). T cell vaccines that do not induce antibodies targeting viral surface will unlikely cause ADE, but be capable of potentiating the effectiveness of an antibody-inducing vaccine. To develop such a protective T cell vaccine, we first examined the repertoire of antigen-specific T cells in immunocompetent mice that have been transiently infected by ZIKV. Through epitope mapping using 427 overlapping peptides spanning the entire length of ZIKV polyprotein, we discovered 27 immunodominant epitopes scattered throughout the virus on C, E, NS1-NS5 proteins. Among them, 8 were confirmed as CD4+ T cell epitopes, and 16 as CD8+ T cell epitopes, while 3 for both T cell subsets. From these 27 newly identified epitopes, the top 10 epitopes were selected to formulate three T cell vaccines comprised of either CD4+ T cell epitopes, or CD8+ T cell epitopes, or a mixture of both. Immunization with these T cell epitopes induced T cell-mediated cytotoxicity and cytokine production, and conferred varying degrees of protection against ZIKV challenge. Moreover, these new T cell vaccines also improved the protective efficacy of a neutralizing antibody-inducing recombinant E80 protein vaccine. Together, our results provided additional evidence in support of the protective role of ZIKV-specific CD4+ and CD8+ T cells, and laid foundation for future development of T cell vaccines for ZIKV.

Establishment of Murine Infection Models with Biological Clones of Dengue Viruses Derived from a Single Clinical Viral Isolate.

Dengue virus (DENV) is a single-stranded RNA virus transmitted by mosquitoes in tropical and subtropical regions. It causes dengue fever, dengue hemorrhagic fever and dengue shock syndrome in patients. Each year, 390 million people are estimated to be infected by four serotypes of dengue virus, creating a great burden on global public health and local economy. So far, no antiviral drug is available for dengue disease, and the newly licensed vaccine is far from satisfactory. One large obstacle for dengue vaccine and drug development is the lack of suitable small animal models. Although some DENV infection models have been developed, only a small number of viral strains can infect immunodeficient mice. In this study, with biologically cloned viruses from a single clinical isolate, we have established two mouse models of DENV infection, one is severe lethal infection in immunocompromised mice, and the other resembles self-limited disease manifestations in Balb/c mice with transient blockage of type I IFN responses. This study not only offers new small animal models of dengue viral infection, but also provides new viral variants for further investigations on dengue viral pathogenesis.

Defeat Dengue and Zika Viruses With a One-Two Punch of Vaccine and Vector Blockade.

Dengue virus (DENV) and Zika virus (ZIKV) are two mosquito-borne flaviviruses afflicting nearly half of the world population. Human infection by these viruses can either be asymptomatic or manifest as clinical diseases from mild to severe. Despite more cases are presented as self-limiting febrile illness, severe dengue disease can be manifested as hemorrhagic fever and hemorrhagic shock syndrome, and ZIKV infection has been linked to increased incidence of peripheral neuropathy Guillain-Barre syndrome and central neural disease such as microcephaly. The current prevention and treatment of these infectious diseases are either non-satisfactory or entirely lacking. Because DENV and ZIKV have much similarities in genomic and structural features, almost identical mode of mosquito-mediated transmission, and probably the same pattern of host innate and adaptive immunity toward them, it is reasonable and often desirable to investigate these two viruses side-by-side, and thereby devise common countermeasures against both. Here, we review the existing knowledge on DENV and ZIKV regarding epidemiology, molecular virology, protective immunity and vaccine development, discuss recent new discoveries on the functions of flavivirus NS1 protein in viral pathogenesis and transmission, and propose a one-two punch strategy using vaccine and vector blockade to overcome antibody-dependent enhancement and defeat Dengue and Zika viruses.