Despite successful viral suppression with antiretroviral therapy, individuals infected with human immunodeficiency virus type 1(HIV-1) develop chronic inflammation, which may be related to immune activation due to the persistence of the viral reservoir. However, the mechanisms linking HIV-1 reservoirs to inflammation are not fully understood. Here, we comprehensively analyzed 92 inflammation-related proteins (IRPs) in HIV-1-infected individuals using Olink proteomics, including 16 longitudinal pre- and post-treatment participants, 32 long-term treatments (more than 8 years), and age-matched healthy controls. We identified 16 IRPs whose expression remained elevated after treatment regardless of treatment duration, and finally flow validation revealed that MCP-2, CD8A, and TNFRSF9 were significantly positively correlated with HIV-1 DNA, independently of age and sex, whereas CXCL11 was significantly negatively correlated with immune recovery in HIV-1 individuals. The results indicated that the persistence of HIV-1 reservoirs is closely associated with a unique inflammatory environment, which providing novel insights into HIV-1 reservoirs and inflammation.

Elite controllers (ECs) are rare human immunodeficiency virus (HIV)-infected individuals who manage viral replication without antiretroviral therapy. While their cellular immunity is well characterized, humoral responses remain limited, which provides an uncommon window into antibody responses to HIV-1. Using single-cell functional screening, this study aimed to isolate and characterize HIV-1 envelope (Env)-specific monoclonal antibodies (mAbs) from ECs. The Beacon platform was used for enrichment, activation, and screening of cluster of differentiation 27+ (CD27+) memory B cells. Among 12,000 single B cells, 40 Env-specific IgG-secreting cells were identified. Although 18 mAbs were recovered, six showed high-affinity binding to multiple Env trimers (average EC50 < 100 ng/mL). Notably, one mAb (#2) demonstrated broad reactivity, neutralizing 15 of the 17 pseudoviruses, albeit with limited potency (geometric mean IC50 of 46.53 μg/mL). Sequence analysis revealed predominant usage of IGHV1-69 and varied somatic hypermutation levels. However, the high binding affinity could not consistently predict neutralization potency. This study demonstrated the utility of integrated single-cell screening for rapid discovery of antibodies from rare donors. This study also highlights the need for functional assessment in HIV-1 antibody development and identification of mAb candidates for potential therapeutic applications.

Understanding the evolution of broadly neutralizing antibody (bNAb) activity in people living with HIV is crucial for vaccine design and immunization strategies. It has been proposed that antibody cross-reactive activity is associated with lower CD4+ T cell counts during people living with HIV, but the underlying mechanisms remain unclear. To further explore the correlation between antibody reactivity and CD4+ T cell counts, we recruited people living with HIV with varying CD4+ T cell counts: (i) CD4+ T cell ≤50 cells/μL, (ii) 50 cells/μL < CD4+ T cell ≤200 cells/μL, (iii) 200 cells/μL < CD4+ T cell ≤500 cells/μL, (iv) 500 cells/μL < CD4+ T cell. We assessed the antigen-specific antibodies in serum using SOSIP.664 trimers from four different subtypes. Immune repertoire sequencing was used to characterize the B cell receptor (BCR) repertoire of these individuals. The evaluation of antigen-specific antibodies with different SOSIP.664 trimers showed enhanced reactivity in individuals with low CD4+ T cell counts compared to those with high/normal CD4+ T cell counts. Analysis of antibody gene repertoires through BCR high throughput sequencing revealed an increased proportion of IgG with heavy chain complementarity-determining region 3 (CDRH3) loops exceeding 20 amino acids in individuals with CD4+ T cell counts below 50 cells/μL. Notably, the IGHV1-46 and IGHV4-34 germlines, which are suggestive of most polyreactive B cells, were preferentially used in individuals with low CD4+ T cell counts. These results suggest that limited engagement of CD4+ T cells could facilitate the survival of aberrant B cell repertoire with long CDRH3 regions.

Introduction:The genetic diversity of human immunodeficiency virus-1 (HIV-1) in China is characterized by multiple subtypes, circulating recombinant forms (CRFs) and unique recombinant forms (URFs) across the country. Through timely molecular surveillance, over 65 distinct CRFs have been identified in China to date. In this study, we identified five novel URFs among newly reported HIV-1 infected individuals in Anhui Province, China. Methods:Near-full length HIV genome sequences were obtained using two-half molecule amplification methods from five samples containing potential URFs. The sequences were subsequently subjected to phylogenetic and recombination analyses. Results:Phylogenetic and recombination analyses of the five near-full length genome sequences confirmed their classification as novel URFs. Among these, three sequences were recombinants of CRF01_AE and CRF07_BC, one sequence was a recombinant of CRF01_AE, CRF07_BC and B, and one sequence resulted from CRF07_BC and CRF08_BC recombination. Conclusions:The identification of URFs in newly infected individuals indicates ongoing transmission of multiple HIV-1 clades in Anhui Province, with superinfection occurring at notable frequencies. These findings emphasize the importance of enhancing long-term surveillance of circulating HIV-1 clades using near-full length sequence analysis in Anhui, China.

In people living with human immunodeficiency virus (HIV, PLWH), the coronavirus disease 2019 (COVID-19) vaccine often results in a limited humoral immune response. While a reduced absolute CD4+ T cell count is a known factor, other determinants remain unclear. To investigate variables influencing the differential antibody response to the COVID-19 vaccine in PLWH, 43 HIV-1/AIDS patients receiving antiretroviral therapy (ART) and 2 doses of the COVID-19 vaccine were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G (IgG) levels and neutralizing antibody (NAb) titers. A retrospective analysis was also performed, examining immune reconstitution and epidemiological history, including annual CD4+ T-cell counts and the duration of HIV-1 infection. To further elucidate the role of CD4+ T cells in the antibody response to the COVID-19 vaccine, next-generation sequencing was used to analyze the T cell receptor (TCR) profiles of CD4+ T cells from twelve representative individuals. The results showed that the SARS-CoV-2-specific antibody response in PLWH was not solely determined by the current CD4+ T cell count, the progression of immune reconstitution and the TCR profile of CD4+ T cells also played significant roles. These findings provide critical insights into the multifaceted roles of CD4+ T cells in SARS-CoV-2-specific antibody responses in PLWH following COVID-19 vaccination.

Molecular transmission networks are being used with increasing frequency to study HIV-1 transmission patterns and to develop precise intervention strategies for high-risk populations. Here, we analyzed the molecular transmission networks of newly diagnosed patients with HIV-1 in Hefei City, Anhui Province, from 2017 to 2022. Of the 1,413 newly diagnosed HIV-1 Pol sequences, the major genotypes in Hefei were CRF07_BC (600, 42.5%) and CRF01_AE (530, 37.5%). Molecular transmission network analysis identified 146 clusters and 9 large propagation clusters, including four CRF01_AE clusters, four CRF07_BC clusters, and one CRF55_01B cluster. This study highlights the pattern of local HIV-1 transmission in Hefei City, with notable rapid transmission of CRF55_01B. It suggests that the implementation of focused strategies for the identified key transmission clusters is essential for effective control of the HIV-1 epidemic.

Background National treatment guidelines of China evolving necessitates population-level surveillance of transmitted drug resistance (TDR) to inform or update HIV treatment strategies.Methods We analyzed the demographic, clinical, and virologic data obtained from people with HIV (PWH) residing in 31 provinces of China who were newly diagnosed between 2018 and 2023. Evidence of TDR was defined by the World Health Organization list for surveillance of drug resistance mutations.Results Among the 22 124 PWH with protease and reverse transcriptase sequences, 965 (4.36%; 95% CI, 4.1-4.63) had at least 1 TDR mutation. The most frequent TDR mutations were nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.39%; 95% CI, 2.19%-2.59%), followed by nucleoside reverse transcriptase inhibitor mutations(1.35%; 95% CI, 1.2%-1.5%) and protease inhibitor mutations (1.12%; 95% CI, .98%-1.26%). The overall protease and reverse transcriptase TDR increased significantly from 4.05% (95% CI, 3.61%-4.52%) in 2018 to 5.39% (95% CI, 4.33%-6.57%) in 2023. A low level of integrase strand transfer inhibitor TDR was detected in 9 (0.21%; 95% CI, .1%-.38%) of 4205 PWH.Conclusions Presently, the continued use of NNRTI-based first-line antiretroviral therapy regimen for HIV treatment has been justified. We found a significantly increasing prevalence of overall and nonnucleoside reverse transcriptase inhibitor transmitted drug resistance from 2018 to 2023, whereas integrase strand transfer inhibitor transmitted drug resistance was uncommon. Presently, the continued use of a first-line antiretroviral therapy regimen based on nonnucleoside reverse transcriptase inhibitors for HIV treatment has been justified.

In individuals diagnosed with AIDS, the primary method of sustained suppression of HIV-1 replication is antiretroviral therapy, which systematically increases CD4+ T cell levels and restores immune function. However, there is still a subset of 10-40% of people living with HIV who not only fail to reach normal CD4+ T cell counts but also experience severe immune dysfunction. These individuals are referred to as immunological nonresponders (INRs). INRs have a higher susceptibility to opportunistic infections and non-AIDS-related illnesses, resulting in increased morbidity and mortality rates. Therefore, it is crucial to gain new insights into the primary mechanisms of immune reconstitution failure to enable early and effective treatment for individuals at risk. This review provides an overview of the dynamics of key lymphocyte subpopulations, the main molecular mechanisms of INRs, clinical diagnosis, and intervention strategies during immune reconstitution failure, primarily from a multiomics perspective.

BACKGROUND:In 2016, China has implemented the World Health Organization's "treat all" policy. We aimed to assess the impact of significant improvements in the 95-95-95 targets on population-level human immunodeficiency virus (HIV) transmission dynamics and incidence. METHODS:We focused on 3 steps of the HIV care continuum: diagnosed, on antiretroviral therapy, and achieving viral suppression. The molecular transmission clusters were inferred using HIV-TRACE. New HIV infections were estimated using the incidence method in the European Centre for Disease Prevention and Control HIV Modelling Tool. RESULTS:Between 2004 and 2023, the national HIV epidemiology database recorded 2.99 billion person-times of HIV tests and identified 1 976 878 new diagnoses. We noted a roughly "inverted-V" curve in the clustering frequency, with the peak recorded in 2014 (67.1% [95% confidence interval, 63.7%-70.5%]), concurrent with a significant improvement in the 95-95-95 targets from 10-13-<71 in 2005 to 84-93-97 in 2022. Furthermore, we observed a parabolic curve for a new infection with the vertex occurring in 2010. CONCLUSIONS:In general, it was suggested that the improvements in the 95-95-95 targets were accompanied by a reduction in both the population-level HIV transmission rate and incidence. Thus, China should allocate more effort to the first "95" target to achieve a balanced 95-95-95 target.

While the SARS-CoV-2 vaccine offers 70%-95% protection effectiveness against Coronavirus disease 2019 (COVID-19), a portion of recipients do not produce adequate protective immune responses, particularly, neutralizing antibodies (nAbs). Previous studies of COVID-19 patients have identified several public antibody lineages, such as IGHV3-30, IGHV3-33, IGHV3-53, IGHV1-58, and IGHV1-24. However, it remains unclear how these public antibodies evolve during vaccination or whether there are any special antibody lineages correlated with SARS-CoV-2 vaccination. In this study, through a combination of single B cell sequencing and next-generation sequencing analysis, we systemically studied the dynamic changes of antibody lineages derived from different B cell germlines in their sequence, frequency, and neutralization ability in different vaccinees before and after receiving inactivated SARS-CoV-2 vaccines. Our findings indicate that the frequency of antibodies derived from the IGHV4-34 lineage increased in most individuals after vaccination, and the higher frequency of the antibody usually resulted in stronger binding affinity. Additionally, the ratio of IGHV4-34 derived antibodies, when compared with other public antibodies, more strongly correlated with the neutralization activity of immune sera from vaccinees. Taken together, these results suggest that IGHV4-34 is a novel vaccine-elicited public nAb lineage that plays a crucial role in immune response following inactivated COVID-19 vaccination.

Introduction HIV-1 subtype B, as once one of the earliest strains introduced into mainland China rapidly spread in commercial plasma donors and heterosexuals in 1990s. Here, we aim to investigate the origin and evolutionary history of HIV-1 subtype B in Fuyang city, China. Methods We collected sequences tested from Fuyang in the east of China where higher prevalence of HIV-1 among commercial plasma donors and heterosexuals to construct a phylogenetic tree using the Markov chain Monte Carlo (MCMC) algorithm, infer molecular transmission network using TN93 model and visualize it with Cytoscape software. Results and discussion Our results showed that >99% of subtype B sequences belonged to Thai B. The sequences from Fuyang often cluster closer to those from other its adjacent cities, which clustered together and formed a monophyletic cluster. HIV-1 B circulating in Fuyang dates back to approximately 1990. Among the 1,437 sequences, 166 clustered at a genetic distance of ≤1.2%, resulting in 73 clusters. The degree of clustering with at least one other person was 11.55%. Among the transmission clusters, 50 (80.65%) comprised two individuals. Most clusters consisted of both heterosexual transmission routes and men who have sex with men. Phylogenetic and molecular network analyses revealed a common origin with neighboring regions in mainland China, local onwards transmission after its introduction, and a limited clustering degree. However, at least two co-existing transmission routes in most transmission clusters imply a greater challenge in controlling the spread of HIV-1. Our findings highlight the value on tailoring prevention interventions by combination of molecular surveillance and epidemiology.

HIV subtypes convey important epidemiological information and possibly influence the rate of disease progression. In this study, HIV disease progression in patients infected with CRF01_AE, CRF07_BC, and subtype B was compared in the largest HIV molecular epidemiology study ever done in China. A national data set of HIV pol sequences was assembled by pooling sequences from public databases and the Beijing HIV laboratory network. Logistic regression was used to assess factors associated with the risk of AIDS at diagnosis ([AIDSAD], defined as a CD4 count < 200 cells/µL) in patients with HIV subtype B, CRF01_AE, and CRF07_BC. Of the 20,663 sequences, 9,156 (44.3%) were CRF01_AE. CRF07_BC was responsible for 28.3% of infections, followed by B (13.9%). In multivariable analysis, the risk of AIDSAD differed significantly according to HIV subtype (OR for CRF07_BC vs. B: 0.46, 95% CI 0.39─0.53), age (OR for ≥ 65 years vs. < 18 years: 4.3 95% CI 1.81─11.8), and transmission risk groups (OR for men who have sex with men vs. heterosexuals: 0.67 95% CI 0.6─0.75). These findings suggest that HIV diversity in China is constantly evolving and gaining in complexity. CRF07_BC is less pathogenic than subtype B, while CRF01_AE is as pathogenic as B.

Traditional methods of quantifying epidemic spread are based on surveillance data. The most widely used surveillance data are normally incidence data from case reports and hospital records, which are normally susceptible to human error, and sometimes, they even can be seriously error-prone and incomplete when collected during a destructive epidemic. In this manuscript, we introduce a new method to study the spread of infectious disease. We gave an example of how to use this method to predict the virus spreading using the HIV gene sequences data of China. First, we applied Bayesian inference to gene sequences of two main subtypes of the HIV virus to infer the effective reproduction number (GRe(t)) to trace the history of HIV transmission. Second, a dynamic model was established to forecast the spread of HIV medication resistance in the future and also obtain its effective reproduction number (MRe(t)). Through fitting the two effective reproduction numbers obtained from the two separate ways above, some crucial parameters for the dynamic model were obtained. Simply raising the treatment rate has no impact on lowering the infection rate, according to the dynamics model research, but would instead increase the rate of medication resistance. The negative relationship between the prevalence of HIV and the survivorship of infected individuals following treatment may be to blame for this. Reducing the MSM population's number of sexual partners is a more efficient strategy to reduce transmission per the sensitivity analysis.

Ocular toxoplasmosis (OT) is one of the most common causes of posterior uveitis. However, the pathogenic mechanisms of OT have not been well elucidated. Here, we used C57BL/6 (B6) mice to establish OT by peroral infection with 20 cysts of the TgCtWh6 strain, and severe ocular damage was observed by histopathological analysis in the eyes of infected mice. RNA-sequencing results showed that infection with T. gondii increased the expression of the NK-mediated cytotoxicity gene pathway at Day 30 after ocular T. gondii infection. Both NK-cell and CD49a+ NK-cell subsets are increased in ocular tissues, and the expression levels of LFA-1 in NK cells and ICAM-1 in the OT murine model were upregulated upon infection. Furthermore, inhibition of the interaction between LFA-1 and ICAM-1 with lifitegrast, a novel small molecule integrin antagonist, inhibited the protein expression of LFA-1 and ICAM-1 in murine OT and NK cells, improved the pathology of murine OT and influenced the secretion of cytokines in the OT murine model. In conclusion, the interaction between LFA-1 and ICAM-1 plays a role in the early regulation of the CD49a+ NK-cell proportion in an OT murine model. LFA-1/ ICAM-1 may be a key molecule in the pathogenesis of OT, and may provide new insights for potential immunotherapy.

To study the characteristics of HIV pretreatment drug resistance (PDR) and acquired drug resistance (ADR) in Hefei, a cross-sectional survey was used to collect 816 samples from newly reported HIV infections from 2017 to 2020 and 127 samples from HIV infections with virological failure from 2018 to 2019 in Hefei. HIV drug resistance levels and drug resistance mutations were interpreted using the Stanford Drug Resistance Database. Molecular networks were constructed by HIV-TRACE. Among the newly reported infections in Hefei, the prevalence of PDR was 6.4% (52/816). The drug resistance mutations were mainly V179E/D/T (12.4%), K103N (1.3%), and V106I/M (1.3%). In addition, it was found that the CRF55_01B subtype had a higher drug resistance rate than other subtypes (p < 0.05). Molecular network analysis found that K103N and V179E may be transmitted in the cluster of the CRF55_01B subtype. The prevalence of ADR among HIV infections with virological failure was 38.6% (49/127), and the drug resistance mutations were mainly M184V (24.4%), K103N/S (15.7%), Y181C (11.0%), G190S/A/E (10.2%), and V106M/I (10.2%). The molecular network was constructed by combining HIV infections with virological failure and newly reported infections; M184V and Y181C may be transmitted between them. The chi-square trend test results indicated that the higher the viral load level, the greater the number of newly reported infections linked to the infections with virological failure in the molecular network. In conclusion, interventions should focus on infections of the CRF55_01B subtype to reduce the transmission of drug-resistant strains. However, improving the treatment effect of HIV infections is beneficial for reducing the second-generation transmission of HIV.

Abstract. Although the advent of combination antiretroviral therapy can efficiently suppress human immunodeficiency virus (HIV) replication, a complete cure for HIV infection cannot be achieved due to the existence of latent viral reservoirs. In recent years, investigation of HIV cure strategies has become a hot topic in the field. In this article, we review the major barriers to HIV cure, compare the progress and challenges of non-specific and specific latent reversal agents in curing HIV, and discuss possible solutions to the current problems.

Despite the discovery that the human immunodeficiency virus 1 (HIV-1) is the pathogen of acquired immunodeficiency syndrome (AIDS) in 1983, there is still no effective anti-HIV-1 vaccine. The major obstacle to the development of HIV-1 vaccine is the extreme diversity of viral genome sequences. Nonetheless, a number of broadly neutralizing antibodies (bNAbs) against HIV-1 have been made and identified in this area. Novel strategies based on using these bNAbs as an efficacious preventive and/or therapeutic intervention have been applied in clinical. In this review, we summarize the recent development of bNAbs and its application in HIV-1 acquisition prevention as well as discuss the innovative approaches being used to try to convey protection within individuals at risk and being treated for HIV-1 infection.

HIV subtypes convey important epidemiological information and possibly influence the rate of disease progression. In this study, HIV disease progression in patients infected with CRF01_AE, CRF07_BC, and subtype B was compared in the largest HIV molecular epidemiology study ever done in China. A national data set of HIV pol sequences was assembled by pooling sequences from public databases and the Beijing HIV laboratory network. Logistic regression was used to assess factors associated with the risk of AIDS at diagnosis ([AIDSAD], defined as a CD4 count <200 cells/µL) in patients with HIV subtype B, CRF01_AE, and CRF07_BC. Of the 20,663 sequences, 9,156 (44.3%) were CRF01_AE. CRF07_BC was responsible for 28.3% of infections, followed by B (13.9%). In multivariable analysis, the risk of AIDSAD differed significantly according to HIV subtype (OR for CRF07_BC vs. B: 0.46, 95% CI 0.39─0.53), age (OR for ≥65 years vs. <18 years: 4.3 95% CI 1.81─11.8), and transmission risk groups (OR for man who have sex with man vs. heterosexual: 0.67 95% CI 0.6─0.75). These findings suggest that HIV diversity in China is constantly evolving and gaining complexity. CRF07_BC is less pathogenic than subtype B, while CRF01_AE is as pathogenic as B.

Hefei, Anhui province, is one of the cities in the Yangtze River Delta, where many people migrate to Jiangsu, Zhejiang and Shanghai. High migration also contributes to the HIV epidemic. This study explored the HIV prevalence in Hefei to provide a reference for other provinces and assist in the prevention and control of HIV in China. A total of 816 newly reported people with HIV in Hefei from 2017 to 2020 were recruited as subjects. HIV subtypes were identified by a phylogenetic tree. The most prevalent subtypes were CRF07_BC (41.4%), CRF01_AE (38.1%) and CRF55_01B (6.3%). Molecular networks were inferred using HIV-TRACE. The largest and most active transmission cluster was CRF55_01B in Hefei’s network. A Chinese national database (50,798 sequences) was also subjected to molecular network analysis to study the relationship between patients in Hefei and other provinces. CRF55_01B and CRF07_BC-N had higher clustered and interprovincial transmission rates in the national molecular network. People with HIV in Hefei mainly transmitted the disease within the province. Finally, we displayed the epidemic trend of HIV in Hefei in recent years with the dynamic change of effective reproductive number (Re). The weighted overall Re increased rapidly from 2012 to 2015, with a peak value of 3.20 (95% BCI, 2.18–3.85). After 2015, Re began to decline and remained stable at around 1.80. In addition, the Re of CRF55_01B was calculated to be between 2.0 and 4.0 in 2018 and 2019. More attention needs to be paid to the rapid spread of CRF55_01B and CRF07_BC-N strains among people with HIV and the high Re in Hefei. These data provide necessary support to guide the targeted prevention and control of HIV.

目的 了解滁州市艾滋病抗病毒治疗现状,探析艾滋病抗病毒治疗效果改进措施.方法 选取滁州市2018年在治的HIV感染者和艾滋病病人(HIV/AIDS) 362例,对其进行CD4+T淋巴细胞计数、HIV病毒载量检测和基因型耐药检测,分析HIV/AIDS免疫学和病毒学指标变化情况,评估抗病毒治疗效果.结果 359例HIV/AIDS接受了HIV病毒载量检测,333例病毒载量小于1000 cps/ml,病毒抑制率92.7％.362例HIV/AIDS病例治疗后和治疗前CD4+T淋巴计数差异有统计学意义(Z=-11.759,P＜0.001);治疗后不同病毒载量组的CD4+T淋巴细胞计数差异有统计学意义(F=18.453,P＜0.001),其中＜50 cps/ml组与50～1000 cps/ml组CD4+T淋巴细胞计数明显大于基线值(Z=-11.441,P＜0.001;Z=-3.65,P＜0.001).26例HIV/AIDS病例病毒载量＞1000 cp/ml,8例耐药,耐药率为2.2％ (8/359).结论 HIV/AIDS病例抗病毒治疗,有助于改善患者细胞免疫水平.