Fujie Zhang

Incomplete immune reconstitution (IIR) is a serious complication affecting 10 to 40% of people living with HIV (PLWH) despite effective antiretroviral therapy, leading to increased morbidity and mortality. Current risk prediction models rely on single–time point measurements and lack dynamic assessment capabilities. We developed a dynamic joint prediction system for IIR risk (DJPSIIR) using Bayesian joint modeling to analyze longitudinal data from 21,862 PLWH across 31 Chinese provinces (2003–2024). The system integrates continuous CD4 ⁺ T cell counts and CD4/CD8 ratios with clinical parameters to generate real-time risk predictions. DJPSIIR demonstrated strong discriminatory performance with area under receiver operating characteristic curves of 0.890 to 0.912 for 5- to 7-year predictions, consistently outperforming expert assessments and 19 machine learning algorithms across multiple validation cohorts. Our dynamic prediction system enables precise identification of high-risk individuals and could transform clinical decision-making by facilitating timely interventions to prevent IIR progression in HIV care.

SUMMARY: Despite advancements in antiretroviral therapy, people living with HIV (PLWH) remain at high risk of lymphoma. The persistence of HIV reservoirs and their spatial association with lymphoma highlights the need to clarify their role in lymphomagenesis. HIV reservoirs, which are established early during infection and maintained through clonal expansion, epigenetic silencing, and immune evasion, may contribute to lymphomagenesis through four interconnected mechanisms: provirus integration effects, viral protein-mediated disturbances, microenvironment dysregulation, and reservoir reactivation. Current therapeutic approaches that simultaneously target HIV reservoirs and lymphoma—including allogeneic hematopoietic stem cell transplantation, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors—show promise but face substantial challenges. There is an urgent need to develop accessible strategies that can both eradicate HIV reservoirs and mitigate lymphoma risk. Such efforts may ultimately enable a “double cure” for PLWH with lymphoma, offering new hope against this life-threatening comorbidity. This review summarizes the potential links between HIV reservoirs and HIV-associated lymphoma and outlines emerging therapeutic avenues toward achieving a double cure.

Purpose: HIV drug resistance is increasing globally, especially in resource-limited settings. NNRTIs, commonly used as first-line ART, have a low genetic barrier and are prone to resistance mutations. Lifelong ART contributes to the accumulation of drug resistance mutations (DRMs), compromising treatment efficacy. Genotypic resistance testing is essential before initiating or modifying ART. However, the Sanger sequencing method relies on successful PCR amplification, which is often suboptimal in low viral load (VL) samples, limiting sensitivity and coverage. Patients and Methods: We developed an optimized primer system targeting conserved regions in the protease (PR), reverse transcriptase (RT), and integrase (IN) genes, covering PR aa 1-99, RT aa 1-410 (including NNRTI resistance sites Y318 and N348), and IN aa 1-288. A total of 2,071 HIV-positive plasma samples collected in China (Jan 2023-Dec 2024) were analyzed using a PCR-Sanger sequencing method. Subtyping was performed using BLAST, COMET 2.4, and the HIV-1 Gene Sequences Database (China). Amplification success rates and mutation detection were evaluated across VL levels. Results: The overall amplification success rates were 87.40% (1,810/2,071) for the PR/RT region and 87.06% (1,803/2,071) for the IN region. In samples with VLs of 50-200 copies/mL, the success rates remained above 80% for PR/RT and 78.10% for IN. For samples with VL ≥1000 copies/mL, both regions achieved amplification rates above 99%. Among eight samples harboring Y318 or N348 mutations, all were successfully amplified at 1000, 400, 200, and 100 copies/mL. Three of them consistently yielded detectable mutations across all gradients. Subtyping revealed CRF01_AE and CRF07_BC as the predominant strains, consistent with national epidemiological trends. Conclusion: The optimized system improves amplification sensitivity and mutation coverage, especially in low-VL samples. It enables stable detection of key NNRTI resistance mutations and shows strong subtype compatibility, supporting its utility in clinical resistance surveillance and early detection.

Background: HIV drug resistance is a crucial factor in treatment failure. Sanger sequencing, the current gold standard for resistance testing, cannot detect low-abundance variants constituting <20% of the virus population. Although next-generation sequencing (NGS) offers higher sensitivity, it is susceptible to biases during the amplification stage, further reducing the proportion of low-abundance mutant sequences. This study aimed to evaluate the application of droplet digital polymerase chain reaction (ddPCR) combined with Sanger sequencing and NGS in resistance monitoring, seeking a more efficient method for drug-resistant mutation detection. Methods: Samples from 106 participants with treatment failure were subjected to amplification by ddPCR and bulk polymerase chain reaction (PCR). Amplification was successful with both methods in 103 participants, and Sanger sequencing was subsequently performed on their samples. NGS was performed on 16 of these participants. The success rates of genotyping were compared across viral loads. Additionally, we analyzed the consistency of Sanger sequencing results, explored differences in NGS results, and examined the relationship between low-frequency drug-resistant mutations and patient prognosis. Results: The amplification success rate of ddPCR is 97.2% (103/106) and increases with higher viral loads. The phylogenetic analysis results indicate that the 2 amplification methods exhibit good consistency, with 99% (102/103) of the pol gene sequences from the same sample clustering. The overall prevalence of HIV DRMs was 50.5% (52/103), and both methods yielded the same resistance results. NGS of 16 participants identified low-frequency resistance mutations in 15 individuals. The bulk PCR detected 31 mutations, while ddPCR detected 39 mutations. Conclusions: The combination of ddPCR and NGS detects more low-frequency variants and offers greater accuracy than conventional bulk PCR. Our ddPCR technology provides a more efficient method for HIV drug resistance testing.

The rapid initiation of antiretroviral therapy has become an international trend, necessitating lifelong medication for all HIV patients. Sanger sequencing, as the gold standard for clinically detecting HIV drug resistance, often fails to detect mutations comprising less than 20% of the total viral population. With the advancement of detection technologies, HIV-1 drug-resistant minority variants have garnered increasing attention. Few studies have analyzed the hotspots and trends in this field, which bibliometrics can effectively address. Publications related to HIV-1 DRMinVs from 1999 to 2024 were searched on the Web of Science Core Collection database. Visual knowledge maps and bibliometric analyses were generated using VOSviewer and Bibliometrix. In total, 289 publications concerning HIV-1 drug-resistant minority variants were identified from 1999 to 2024, demonstrating a steady increase in publication output over the years. Although developed countries, led by the United States, are the main contributors, 9.57% and 2.48% of the research from the top five publishing countries focus on populations in Africa and other developing countries, respectively. Most contributing institutions are universities and public health organizations, with the University of Washington having the highest publication output. The Journal of Antimicrobial Chemotherapy holds the highest prominence among journals in this domain. The main hotspots include “drug classes,” “drug resistance surveillance,” “mother-to-child transmission,” “treatment outcomes,” and “targets of HIV-1 drug resistance testing,” And we found several noteworthy shifts in research trends in HIV-1 drug-resistant minority variants studies, including changes in drug resistance testing technologies, the primary study population, and drug classes. This is the first bibliometric analysis of publications related to HIV-1 DRMinVs from 1999 to 2024. We analyzed the key research contributions across countries, institutions and journals. Based on keyword co-occurrence and cluster analysis, we identified several noteworthy shifts in research trends in HIV-1 DRMinVs studies, including changes in drug resistance testing technologies, the primary study population, and drug classes.

Human immunodeficiency virus (HIV), a retrovirus of the Lentivirus genus, targets CD4 ⁺ T cells, causing immune dysfunction and AIDS. Approximately 8% of the human genome consists of human endogenous retroviruses (HERVs), ancient retroviral remnants that may interact with HIV. Despite antiretroviral therapy, challenges such as drug resistance, poor immune reconstitution (PIR), and reservoirs remain. This GEM discusses the impact of HIV on HERVs, the potential roles of HERVs in PIR and reservoirs, and provides insights into future research directions.

Objective: Long-term management of people living with HIV (PLWHs) often relies on CD4⁺ T cell counts for assessing immune recovery, yet a single metric offers limited information. This study aimed to explore the association between the CD4/CD8 ratio and T lymphocyte activities in PLWHs. Methods: 125 PLWHs and 31 HIV-uninfected controls (UCs) were enrolled and categorized into four groups based on their CD4/CD8 ratios: extremely low ratio (ELR) group: 0.4 < CD4/CD8; low ratio (LR) group: 0.4 ≤ CD4/CD8+ T cells and CD8⁺ T cells were measured, and correlations between the CD4/CD8 ratio and T cell functions were analyzed. Results: T cell activation and proliferation were significantly elevated in the ELR group compared to UCs. However, the ELR group had a larger proportion of T cells with lipid peroxidation, mitochondrial lipid reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) abnormalities compared to the other groups. As the CD4/CD8 ratio increased, mitochondrial lipid peroxidation damage decreased and MMP was restored. Additionally, the ELR group had more inflammatory markers in CD4⁺ T cells. Correlation analysis revealed that the CD4/CD8 ratio was associated with multiple T cell functions, and its correlation coefficient with mitochondrial function was higher than that of CD4⁺ T cell count. Conclusion: The CD4/CD8 ratio is closely related to T lymphocyte functions and is significantly superior to the CD4⁺ T cell count in reflecting the mitochondrial lipid peroxidation level and mitochondrial functions within T lymphocytes.