Clinical features and viral load variations of Mpox: a retrospective study in Chongqing, China.

PURPOSE: Since May 2022, Mpox has spread extensively outside of Africa, posing a serious threat to the health of people globally, and particularly to the men who have sex with men (MSM) population. Chongqing, a province in Southwest China, has relatively large MSM and people living with HIV (PLWH) populations, presenting conditions conducive to the wide dissemination of Mpox. In this study, we investigated the clinical characteristics of Mpox patients among MSM and PLWH in Chongqing, aiming to inform the development of targeted prevention, control, and treatment strategies for Mpox. METHOD: We evaluated the clinical characteristics, travel history, time of onset, distribution and number of skin lesions of Mpox patients admitted to the Chongqing Public Health Medical Center between September 2022 and October 2023. Meanwhile, a series of clinical samples were collected and the pathogen of interest was identified as Mpox virus using quantitative polymerase chain reaction (qPCR). The results were presented in the form of cycle thresholds (Ct), which help to approximate the quantification of viral load. RESULTS: As of October 11, 2023, the Chongqing Public Health Medical Center reported a total of nine Mpox virus infections. All the patients identified were male and belonged to the MSM population, among whom seven (77.8%) were living with HIV, and maintained a preserved immune system while achieving viral suppression via effective ART. We observed no discernible clinical differences between MSM with Mpox with or without HIV, and no fatalities were recorded. Viral loads were observed to be higher in samples taken from the skin than those from the throat, nasopharynx, blood, or semen. CONCLUSION: In this retrospective study, the clinical manifestations of MPXV infection appeared consistent among MSM patients, regardless of HIV status. Elevated MPXV viral loads in the skin and mucosal tissues, particularly at genital and anal sites, indicate that transmission is more likely to occur via direct physical contact as opposed to respiratory pathways or through exposure to bodily fluids.

The role of pyroptosis in incomplete immune reconstitution among people living with HIV：Potential therapeutic targets.

Globally, HIV infection causes significant morbidity and mortality, and is a major public health problem. Despite the fact that widespread use of antiretroviral therapy (ART) has substantially altered the natural history of HIV infection from originally being a universally lethal disease to now being a chronic medical condition for those taking appropriate treatment, approximately 10-40% of people living with HIV (PLWH) who take effective ART and maintain long-term viral suppression fail to achieve normalization of CD4 + T-cell counts. This phenomenon is referred to as incomplete immune reconstitution or immunological non-response. Although the precise mechanisms underlying this outcome have not been elucidated, recent evidence indicates that excessive pyroptosis may play a crucial role in the development of incomplete immune reconstitution. Pyroptosis is characterized by the formation of pores in the cell membrane, cell rupture, and secretion of intracellular contents and pro-inflammatory cytokines, including IL-1ß and IL-18. This excessive inflammation-induced programmed cell death leads to a massive loss of CD4 + T-cells, and inflammatory consequences that may promote and sustain incomplete immune reconstitution. Herein, we review the possible pathways activated in HIV infection by inflammasomes that act as switches of pyroptosis, and the role of pyroptosis in HIV, as well as the relevance of CD4 + T-cells in incomplete immune reconstitution. We also highlight the possible mechanisms of pyroptosis involved in incomplete immune reconstitution, thus paving the way for the development of potential targets for the treatment of incomplete immune reconstitution.

Severe anemia, severe leukopenia, and severe thrombocytopenia of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated talaromycosis: a subgroup analysis of a prospective multicenter cohort study.

BACKGROUND: This study's objective was to investigate the predictors for severe anemia, severe leukopenia, and severe thrombocytopenia when amphotericin B deoxycholate-based induction therapy is used in HIV-infected patients with talaromycosis. METHODS: A total of 170 HIV-infected patients with talaromycosis were enrolled from January 1st, 2019, to September 30th, 2020. RESULTS: Approximately 42.9%, 20.6%, and 10.6% of the enrolled patients developed severe anemia, severe leukopenia, and severe thrombocytopenia, respectively. Baseline hemoglobin level < 100 g/L (OR = 5.846, 95% CI: 2.765 ~ 12.363), serum creatinine level > 73.4 µmol/L (OR = 2.573, 95% CI: 1.157 ~ 5.723), AST/ALT ratio > 1.6 (OR = 2.479, 95% CI: 1.167 ~ 5.266), sodium level ≤ 136 mmol/liter (OR = 4.342, 95% CI: 1.747 ~ 10.789), and a dose of amphotericin B deoxycholate > 0.58 mg/kg/d (OR = 2.504, 95% CI:1.066 ~ 5.882) were observed to be independent risk factors associated with the development of severe anemia. Co-infection with tuberculosis (OR = 3.307, 95% CI: 1.050 ~ 10.420), and platelet level (per 10 × 109 /L) (OR = 0.952, 95% CI: 0.911 ~ 0.996) were shown to be independent risk factors associated with the development of severe leukopenia. Platelet level < 100 × 109 /L (OR = 2.935, 95% CI: 1.075 ~ 8.016) was identified as the independent risk factor associated with the development of severe thrombocytopenia. There was no difference in progression to severe anemia, severe leukopenia, and severe thrombocytopenia between the patients with or without fungal clearance at 2 weeks. 10 mg on the first day of amphotericin B deoxycholate was calculated to be independent risk factors associated with the development of severe anemia (OR = 2.621, 95% CI: 1.107 ~ 6.206). The group receiving a starting amphotericin B dose (10 mg, 20 mg, daily) exhibited the highest fungal clearance rate at 96.3%, which was significantly better than the group receiving a starting amphotericin B dose (5 mg, 10 mg, 20 mg, daily) (60.9%) and the group receiving a starting amphotericin B dose (5 mg, 15 mg, and 25 mg, daily) (62.9%). CONCLUSION: The preceding findings reveal risk factors for severe anemia, severe leukopenia, and severe thrombocytopenia. After treatment with Amphotericin B, these severe adverse events are likely unrelated to fungal clearance at 2 weeks. Starting amphotericin B deoxycholate at a dose of 10 mg on the first day may increase the risk of severe anemia but can lead to earlier fungal clearance. TRIAL REGISTRATION: ChiCTR1900021195. Registered 1 February 2019.

Pretreatment drug resistance in people living with HIV: A large retrospective cohort study in Chongqing, China.

OBJECTIVES: The emergence of pretreatment drug resistance (PDR) caused by increased usage of antiretroviral therapy (ART) represents a significant challenge to HIV management. In this study, we evaluated the prevalence of PDR in people living with HIV (PLWH) in Chongqing, China. METHODS: We retrospectively collected the data of 1110 ART-naïve PLWH in Chongqing from January 1, 2018 to June 30, 2021. HIV-1 genotypes and drug resistance were analyzed using the HIV-1 pol sequence. Risk factors associated with PDR were evaluated via the logistic regression model. RESULTS: Nine genotypes were detected among 1110 participants, with CRF07_BC (55.68%) being the dominant genotype, followed by CRF01_AE (21.44%), CRF08_BC (14.14%), and other genotypes (8.74%). Of all the participants, 24.14% exhibited drug resistance mutations (DRMs). The predominant DRMs for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were V179D/E/A/DIN (13.60%) and M184V/I (1.44%), respectively, whereas only two major DRMs (M46L and I54L) were identified for protease inhibitors (PIs). The total prevalence of PDR was 10.54%, with 2.43%, 7.66%, and 1.71% participants exhibiting PDR to NRTIs, NNRTIs, and PIs, respectively. Furthermore, female PLWH, delays in ART initiation, and the CRF08_BC genotype were associated with a higher risk of PDR. CONCLUSIONS: Our study provides the first large cohort data on the prevalence of PDR in Chongqing, China. HIV-1 genotypes are diverse and complex, with a moderate level of PDR, which does not reach the threshold for the initiation of a public health response. Nevertheless, continuous surveillance of PDR is both useful and advisable.

Comparison of amphotericin B deoxycholate in combination with either flucytosine or fluconazole, and voriconazole plus flucytosine for the treatment of HIV-associated cryptococcal meningitis: a prospective multicenter study in China.

BACKGROUND: The most appropriate alternative to induction therapy for HIV-associated cryptococcal meningitis (CM) remains unclear when standard treatment is unavailable, inaccessible, intolerable, or ineffective. METHODS: A prospective, multi-centre cohort study was conducted to analyze the data of 156 HIV-infected patients with CM who were treated with amphotericin B deoxycholate (AmB-D) + flucytosine (5FC), voriconazole (VCZ) + 5FC, or AmB-D + Fluconazole (Flu) as induction regimens. Clinical efficacy, cumulative mortality, and adverse effects were compared among the three treatment groups. RESULTS: Fewer deaths occurred by week 4 and week 10 among patients receiving AmB-D + 5FC than among those receiving AmB-D + Flu [4 (5.1%) vs. 8 (16.0%) deaths by week 4; hazard ratio, 1.8; 95% confidence interval [CI], 1.0 to 3.3; p = 0.039; and 8 (10.3%) vs. 14 (28.0%) deaths by week 10; hazard ratio, 1.8; 95% CI, 1.1 to 2.7; p = 0.008, respectively]. AmB-D plus 5FC was found to result in significantly higher rates of cerebrospinal fluid (CSF) culture sterility (57.6% vs. 34% by week 2; 87.9% vs. 70% by week 10; p < 0.05 for both comparisons). However, the differences in CSF culture sterility and mortality between the VCZ + 5FC group and the AmB-D + 5FC group were not statistically significant. VCZ plus 5FC had a significantly advantageous effect on the incidence of new AIDS-defining illness and length of hospital stay, compared with AmB-D plus 5FC. Laboratory adverse events (grade 3 or 4), such as severe anemia, were less frequent with VCZ + 5FC use than with AmB-D combined with 5FC or Flu use. CONCLUSION: Our results suggest that AmB-D combined with 5FC remains the more efficacious induction regimen compared to AmB-D plus Flu, and that VCZ + 5FC might be a potential alternative when the standard regimen is not readily available, accessible, tolerated, or effective. CLINICAL TRIALS: Registration number, ChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Initiating antiretroviral therapy within 2 weeks of anti-Pneumocystis treatment does not increase mortality or AIDS-defining events in patients with HIV-associated moderate to severe Pneumocystis pneumonia: results of a prospective observational multicenter study.

BACKGROUND: The mortality rate remains high among patients with coinfection with Pneumocystis pneumonia (PCP) and HIV. The timing for initiation of antiretroviral therapy (ART) after a diagnosis of moderate to severe PCP remains controversial, however. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS-associated PCP (AIDS/PCP) patients. METHODS: This was a multicenter, observational, prospective clinical trial. Eligible participants were recruited from 14 hospitals in mainland China, and assigned to an Early ART arm (initiation of ART ≤ 14 days after PCP diagnosis) and a Deferred ART arm (initiation of ART > 14 days after PCP diagnosis). The primary outcomes were death and the incidence of AIDS-defining events at week 48. The secondary outcomes were the changes in CD4+ T-cell counts from baseline values at weeks 12, 24, and 48, the virological suppression rate at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (PCP/IRIS), and the rate of adverse events over 48 weeks. RESULTS: The present study was performed using the data of 363 participants, with 169 participants in the Early ART arm, and 194 participants in the Deferred ART arm. Immunological and virological outcomes were found to be similar in both treatment arms. At week 48, there were no significant differences for the incidence of mortality (20 vs. 26, p = 0.860), and AIDS-defining events (17 vs. 26, p = 0.412). Over 48 weeks, the rates of PCP/IRIS (2 vs. 3, p = 1.000), adverse events (70 vs. 72, p = 0.465), and grade 3 or 4 adverse events (28 vs. 34, p = 0.919) did not reach statistical significance. A significant difference observed between two study arms was that 11 participants (55.0%) in the Early ART arm compared to 23 participants (88.5%) in the Deferred ART arm (p = 0.026) succumbed before ART had ever been started. CONCLUSIONS: Early ART initiation results in no increase in mortality, AIDS-defining events, IRIS, adverse events, and immunological or virological outcomes. These results support the early initiation of ART in patients with moderate to severe AIDS/PCP. Clinical trial registration The present trial was registered at Chinese Clinical Trial Registry (ChiCTR1900021195). Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

The development and validation of a diagnostic scoring system to differentiate pulmonary tuberculosis from non-tuberculosis pulmonary infections in HIV-infected patients with severe immune suppression.

BACKGROUND: It remains challenging to differentiate tuberculosis (TB) from non-TB pulmonary infections in HIV-infected patients. Herein, we developed a scoring system aimed to rapidly determine the likelihood of TB or non-TB pathology in HIV-infected patients presenting with pulmonary infections. METHODS: We collected and collated data of hospitalized HIV-infected patients with pulmonary infections, followed by univariate and multivariate data analyses to determine risk variables that were significantly different between HIV/TB patients and HIV/non-TB patients. Subsequently, a regression coefficient was calculated for each variable, and a score was assigned to each variable in line with its regression coefficient. The sum of the scores for each variable in our scoring model was used to predict the likelihood of TB or non-TB pulmonary infection in each patient. Finally, we tested the diagnostic accuracy of the scoring system in our retrospective cohort, as well as in a prospective cohort. RESULTS: A total of 598 HIV-infected patients were enrolled in our retrospective cohort, among whom 288 had TB and 310 had non-TB pulmonary infections. Eight variables, including fever, highest body temperature, erythrocyte sedimentation rate (ESR), cervical lymphadenopathy, hilar and/or mediastinum lymphadenopathy, pulmonary cavitation, pleural effusion, and miliary nodules, were found to be mathematically significantly different via univariate analysis and multivariate logistic regression analysis. After regression coefficient calculation followed by score assignment, a receiver operating characteristic (ROC) curve was plotted, and the area under the curve (AUC) was calculated to be 0.902. When the total score for a patient is > 12, the sensitivity and specificity for TB prediction using our scoring system were 76.4% and 87.7% respectively in the retrospective cohort, and its diagnostic accuracy was 82.7% in the prospective cohort. CONCLUSIONS: Our results demonstrate that our proposed diagnostic scoring system could be helpful in differentiating pulmonary TB from non-TB pulmonary infections in HIV-infected patients.

Establishment of a novel scoring model for mortality risk prediction in HIV-infected patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) remains a leading cause of death in HIV-infected patients, despite advances in CM diagnostic and therapeutic strategies. This study was performed with the aim to develop and validate a novel scoring model to predict mortality risk in HIV-infected patients with CM (HIV/CM). METHODS: Data on HIV/CM inpatients were obtained from a Multicenter Cohort study in China. Independent risk factors associated with mortality were identified based on data from 2013 to 2017, and a novel scoring model for mortality risk prediction was established. The bootstrapping statistical method was used for internal validation. External validation was performed using data from 2018 to 2020. RESULTS: We found that six predictors, including age, stiff neck, impaired consciousness, intracranial pressure, CD4+ T-cell count, and urea levels, were associated with poor prognosis in HIV/CM patients. The novel scoring model could effectively identify HIV/CM patients at high risk of death on admission (area under curve 0.876; p<0.001). When the cut-off value of 5.5 points or more was applied, the sensitivity and specificity was 74.1 and 83.8%, respectively. Our scoring model showed a good discriminatory ability, with an area under the curve of 0.879 for internal validation via bootstrapping, and an area under the curve of 0.886 for external validation. CONCLUSIONS: Our developed scoring model of six variables is simple, convenient, and accurate for screening high-risk patients with HIV/CM, which may be a useful tool for physicians to assess prognosis in HIV/CM inpatients.

Multicentre derivation and validation of a prognostic scoring system for mortality assessment in HIV-infected patients with talaromycosis.

BACKGROUND: Although the widespread use of modern antiretroviral therapy (ART) has reduced the incidence of talaromycosis in people living with HIV, mortality remains as high as 20% in this population, even after appropriate antifungal treatment. OBJECTIVES: The objective of our study was to develop a risk assessment system for HIV-infected patients with comorbid talaromycosis, in order to provide these patients with appropriate, effective and potentially life-saving interventions at an early stage of their illness. PATIENTS/METHODS: This was a multicentre, retrospective cohort study conducted in China. We built a predictive model based on data from 11 hospitals, and a validated model using the data of 1 hospital located in an endemic area. RESULTS: Forward stepwise multivariate statistical calculations indicated that age, aspartate aminotransferase/alanine transaminase ratio and albumin levels, and BUN levels were valid, independent predictors of the risk of death in HIV-infected patients with talaromycosis. Our developed and validated risk scoring system is effective for the identification of HIV-infected patients with talaromycosis at high risk of death at hospital admission (p < .001; AUC = 0.860). In our study, our risk prediction model provided functional and robust discrimination in the validation cohort (p < .001; AUC = 0.793). CONCLUSION: The prognostic scoring system for mortality assessment developed in the present study is an easy-to-use clinical tool designed to accurately assist clinicians in identifying high-risk patients with talaromycosis.

The Optimal Timing of Antiretroviral Therapy Initiation in HIV-Infected Patients with Cryptococcal Meningitis: A Multicenter Prospective Randomized Controlled Trial.

The optimal timing of antiretroviral therapy (ART) initiation in human immunodeficiency virus (HIV)-infected patients with cryptococcal meningitis (HIV/CM) is controversial. We designed a clinical trial to inves-tigate the optimal timing for ART initiation in HIV/CM patients. This will be a multicenter, prospective, and randomized clinical trial. Each enrolled patient will be randomized into either the early ART arm or the deferred ART arm. We will compare the mortality and incident rates of immune reconstitution inflammatory syndrome between the two arms. We hope to elucidate the optimal timing for ART initiation in HIV/CM patients.

JC Polyomavirus, progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome: a review.

The human neurotropic virus JC Polyomavirus, a member of the Polyomaviridae family, is the opportunistic infectious agent causing progressive multifocal leukoencephalopathy, typically in immunocompromised individuals. The spectrum of underlying reasons for the systemic immunosuppression that permits JCV infection in the central nervous system has evolved over the past 2 decades, and therapeutic immunosuppression arousing JCV infection in the brain has become increasingly prominent as a trigger for PML. Effective immune restoration subsequent to human immunodeficiency virus-related suppression is now recognized as a cause for unexpected deterioration of symptoms in patients with PML, secondary to a rebound inflammatory phenomenon called immune reconstitution inflammatory syndrome, resulting in significantly increased morbidity and mortality in a disease already infamous for its lethality. This review addresses current knowledge regarding JC Polyomavirus, progressive multifocal leukoencephalopathy, progressive multifocal leukoencephalopathy-related immune reconstitution inflammatory syndrome, and the immunocompromised states that incite JC Polyomavirus central nervous system infection, and discusses prospects for the future management of these conditions.

Transcriptomic crosstalk between viral and host factors drives aberrant homeostasis of T-cell proliferation and cell death in HIV-infected immunological non-responders.

BACKGROUND: Immunological non-responders (INRs) among people living with HIV have inherently higher mortality and morbidity rates. The underlying immunological mechanisms whereby failure of immune reconstitution occurs in INRs require elucidation. METHOD: HIV-1 DNA and HIV-1 cell-associated RNA (CA-HIV RNA) quantifications were conducted via RT-qPCR. Transcriptome sequencing (RNA-seq), bioinformatics, and biological verifications were performed to discern the crosstalk between host and viral factors. Flow cytometry was employed to analyze cellular activation, proliferation, and death. RESULTS: HIV-1 DNA and CA-HIV RNA levels were observed to be significantly higher in INRs compared to immunological responders (IRs). Evaluation of CD4/CD8 ratios showed a significantly negative correlation with HIV-1 DNA in IRs, but not in INRs. Bioinformatics analyses and biological verifications showed IRF7/INF-α regulated antiviral response was intensified in INRs. PBMCs of INRs expressed significantly more HIV integrase-mRNA (p31) than IRs. Resting (CD4+CD69- T-cells) and activated (CD4+CD69+ T-cells) HIV-1 reservoir harboring cells were significantly higher in INRs, with the co-occurrence of significantly higher cellular proliferation and cell death in CD4+ T-cells of INRs. CONCLUSION: In INRs, the systematic crosstalk between the HIV-1 reservoir and host cells tends to maintain a persistent antiviral response-associated inflammatory environment, which drives aberrant cellular activation, proliferation, and death of CD4+ T-cells.

Influence of HIV infection on cognition and overall intelligence in HIV-infected individuals: advances and perspectives.

It is now well understood that HIV-positive individuals, even those under effective ART, tend to develop a spectrum of cognitive, motor, and/or mood conditions which are contemporarily referred to as HIV-associated neurocognitive disorder (HAND), and which is directly related to HIV-1 infection and HIV-1 replication in the central nervous system (CNS). As HAND is known to induce difficulties associated with attention, concentration, and memory, it is thus legitimate and pertinent to speculate upon the possibility that HIV infection may well influence human cognition and intelligence. We therefore propose herein to review the concept of intelligence, the concept of cells of intelligence, the influence of HIV on these particular cells, and the evidence pointing to differences in observed intelligence quotient (IQ) scores between HIV-positive and HIV-negative individuals. Additionally, cumulative research evidence continues to draw attention to the influence of the gut on human intelligence. Up to now, although it is known that HIV infection profoundly alters both the composition and diversity of the gut microbiota and the structural integrity of the gut, the influence of the gut on intelligence in the context of HIV infection remains poorly described. As such, we also provide herein a review of the different ways in which HIV may influence human intelligence via the gut-brain axis. Finally, we provide a discourse on perspectives related to HIV and human intelligence which may assist in generating more robust evidence with respect to this issue in future studies. Our aim is to provide insightful knowledge for the identification of novel areas of investigation, in order to reveal and explain some of the enigmas related to HIV infection.

Candida albicans can foster gut dysbiosis and systemic inflammation during HIV infection.

Candida albicans (C. albicans) is a ubiquitous fungal commensal component of the human microbiota, and under certain circumstances, such as during an immunocompromised state, it may initiate different types of infection. Moreover, C. albicans continuously and reciprocally interacts with the host immune system as well as with other elements of the gut microbiota, thus contributing significantly to both gut homeostasis and host immunity. People living with HIV (PLWH), including those receiving antiretroviral therapy, are characterized by a depletion of CD4 + T-cells and dysbiosis in their gut. C. albicans colonization is frequent in PLWH, causing both a high prevalence and high morbidity. Gut barrier damage and elevated levels of microbial translocation are also fairly common in this population. Herein, we take a closer look at the reciprocity among C. albicans, gut microbiota, HIV, and the host immune system, thus throwing some light on this complex interplay.

Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV.

The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3α (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-ß-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH.

Single-Cell Sequencing Facilitates Elucidation of HIV Immunopathogenesis: A Review of Current Literature.

Knowledge gaps remain in the understanding of HIV disease establishment and progression. Scientists continue to strive in their endeavor to elucidate the precise underlying immunopathogenic mechanisms of HIV-related disease, in order to identify possible preventive and therapeutic targets. A useful tool in the quest to reveal some of the enigmas related to HIV infection and disease is the single-cell sequencing (scRNA-seq) technique. With its proven capacity to elucidate critical processes in cell formation and differentiation, to decipher critical hematopoietic pathways, and to understand the regulatory gene networks that predict immune function, scRNA-seq is further considered to be a potentially useful tool to explore HIV immunopathogenesis. In this article, we provide an overview of single-cell sequencing platforms, before delving into research findings gleaned from the use of single cell sequencing in HIV research, as published in recent literature. Finally, we describe two important avenues of research that we believe should be further investigated using the single-cell sequencing technique.

A Dual Role of Heme Oxygenase-1 in Tuberculosis.

Iron metabolism is vital for the survival of both humans and microorganisms. Heme oxygenase-1 (HO-1) is an essential stress-response enzyme highly expressed in the lungs, and catabolizes heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV)/bilirubin (BR), especially in pathological conditions which cause oxidative stress and inflammation. Ferrous iron (Fe2+) is an important raw material for the synthesis of hemoglobin in red blood cells, and patients with iron deficiency are often associated with decreased cellular immunity. CO and BR can inhibit oxidative stress and inflammation. Thus, HO-1 is regarded as a cytoprotective molecule during the infection process. However, recent study has unveiled new information regarding HO-1. Being a highly infectious pathogenic bacterium, Mycobacterium tuberculosis (MTB) infection causes acute oxidative stress, and increases the expression of HO-1, which may in turn facilitate MTB survival and growth due to increased iron availability. Moreover, in severe cases of MTB infection, excessive reactive oxygen species (ROS) and free iron (Fe2+) due to high levels of HO-1 can lead to lipid peroxidation and ferroptosis, which may promote further MTB dissemination from cells undergoing ferroptosis. Therefore, it is important to understand and illustrate the dual role of HO-1 in tuberculosis. Herein, we critically review the interplay among HO-1, tuberculosis, and the host, thus paving the way for development of potential strategies for modulating HO-1 and iron metabolism.

SARS-CoV-2 pre-exposure prophylaxis: A potential COVID-19 preventive strategy for high-risk populations, including healthcare workers, immunodeficient individuals, and poor vaccine responders.

The unprecedented worldwide spread of SARS-CoV-2 has imposed severe challenges on global health care systems. The roll-out and widespread administration of COVID-19 vaccines has been deemed a major milestone in the race to restrict the severity of the infection. Vaccines have as yet not entirely suppressed the relentless progression of the pandemic, due mainly to the emergence of new virus variants, and also secondary to the waning of protective antibody titers over time. Encouragingly, an increasing number of antiviral drugs, such as remdesivir and the newly developed drug combination, Paxlovid® (nirmatrelvir/ritonavir), as well as molnupiravir, have shown significant benefits for COVID-19 patient outcomes. Pre-exposure prophylaxis (PrEP) has been proven to be an effective preventive strategy in high-risk uninfected people exposed to HIV. Building on knowledge from what is already known about the use of PrEP for HIV disease, and from recently gleaned knowledge of antivirals used against COVID-19, we propose that SARS-CoV-2 PrEP, using specific antiviral and adjuvant drugs against SARS-CoV-2, may represent a novel preventive strategy for high-risk populations, including healthcare workers, immunodeficient individuals, and poor vaccine responders. Herein, we critically review the risk factors for severe COVID-19 and discuss PrEP strategies against SARS-CoV-2. In addition, we outline details of candidate anti-SARS-CoV-2 PrEP drugs, thus creating a framework with respect to the development of alternative and/or complementary strategies to prevent COVID-19, and contributing to the global armamentarium that has been developed to limit SARS-CoV-2 infection, severity, and transmission.

Changes of human immunodeficiency virus (HIV) burden globally and in China over three decades: a secondary analysis of global HIV statistics.

BACKGROUND: A more comprehensive understanding of the trends of incidence, prevalence, and mortality in human immunodeficiency virus (HIV), and their complex interrelationships, may provide important evidence for decision-making related to HIV prevention and control. The variances in these indices between different population groups, genders, and ages are critical to decipher evolving patterns of the HIV epidemic in specific populations. METHODS: A secondary analysis of relevant data was conducted using data extracted from the Global Burden of Disease study of 2019. HIV/acquired immune deficiency syndrome (AIDS) incidence, prevalence, AIDS-related mortality, and mortality-to-prevalence ratio (MPR) for annual percentage change, average annual percentage change (AAPC), and corresponding 95% confidence intervals (CIs) were calculated using joinpoint regression statistical analysis. RESULTS: The AAPC of HIV/AIDS incidence, prevalence, AIDS-related mortality rate, and MPR were -1.4 (95% CI: -1.6, -1.2), 4.1 (95% CI: 4.0, 4.3), 2.0 (95% CI: 1.7, 2.3), and -2.1 (95% CI: -2.3, -1.8) between 1990 and 2019 globally, and were 3.5 (95% CI: 2.2, 4.8), 6.9 (95% CI: 6.8, 7.0), 8.1 (95% CI: 7.1, 9.1), and 1.2 (95% CI: 0.1, 2.3) in China during the same period. In terms of differences in the preceding indicators by gender, we observed a similar pattern of trends for male and female genders both globally and in China during the entire study period. Each specific age group exhibits a distinct pattern in terms of incidence, prevalence, mortality rate, and MPR both globally and in China. CONCLUSIONS: Prevalence and mortality rates of HIV/AIDS have increased between 1990 and 2019 globally and in China. While the incidence rate and MPR have declined globally over the past three decades, these two indicators are observed to present an increasing trend in China. There is a high HIV burden among young and middle-aged adults globally; however, the elderly have a high HIV burden in China. HIV screening at older age should be scaled up, and patients with advanced HIV disease should be provided early with additional care and health resources.

Efficacy and Safety of Voriconazole Versus Amphotericin B Deoxycholate Induction Treatment for HIV-Associated Talaromycosis: A Prospective Multicenter Cohort Study in China.

INTRODUCTION: Current guidelines recommend amphotericin B as the preferred drug for induction therapy; however, amphotericin B is not available in certain settings. Induction therapy with amphotericin B deoxycholate or voriconazole has been shown to be an effective treatment for talaromycosis. However, prospective clinical trials comparing these two antifungal drugs are absent from the literature. METHODS: In this open-labeled, multicenter, prospective controlled trial, we enrolled patients at 15 hospitals in China from 2019 to 2020. Participants received induction treatment with either amphotericin B deoxycholate intravenously at a dose of 0.5 to 0.7 mg per kilogram per day or voriconazole at a dose of 6 mg/kg intravenously twice daily for the first day, followed by 4 mg/kg intravenously twice daily for 3 days, and then voriconazole was given either intravenously (4 mg/kg intravenously twice daily) or orally (200 mg twice daily) for the remaining 10 days. The primary outcome was all-cause mortality during 48 weeks after baseline. Secondary outcomes were mortality at week 2 or week 24, clinical resolution of talaromycosis, and fungal clearance at week 2. A propensity score (PS) matching analysis was performed to control confounding factors. RESULTS: We observed no difference in the risk of death at week 2, at week 24, or at week 48 in either the unmatched cohort or the matched cohort. Both in the unmatched and the matched cohorts, logistic regression analysis revealed a significantly lower odds ratio of clinical resolution (OR 0.450, 95% CI 0.291-0.696, p < 0.001; OR 0.443, 95% CI 0.261-0.752, p = 0.003) and fungal clearance (OR 0.514, 95% CI 0.333-0.793, p = 0.003; OR 0.542, 95% CI 0.318-0.923, p = 0.024) in voriconazole users compared to amphotericin B deoxycholate users over the course of 2 weeks. In the induction therapy without ART subgroup patients in the amphotericin B deoxycholate group showed a significantly higher rate of clinical resolution and fungal clearance than those in the voriconazole group (56.1% vs. 30.4%, 95% CI 13.4-36.5, p = 0.000; 63.8% vs. 40.4%, 95% CI 11.1-34.7, p = 0.000), whereas there was no significant difference in clinical resolution and fungal clearance in the induction therapy combined with ART subgroup. CONCLUSIONS: Induction therapy using voriconazole had a similar efficacy, in terms of all-cause mortality rate, to induction therapy using amphotericin B deoxycholate in HIV-infected patients with talaromycosis over a 48-week observation period. Amphotericin B deoxycholate contributed to earlier fungal clearance and earlier clinical resolution of symptoms in the induction therapy without ART subgroup, whereas amphotericin B deoxycholate use did not contribute to a significant difference in clinical resolution and fungal clearance in the induction therapy combination with ART subgroup. TRIAL REGISTRATION: ChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .