Search Results (384)

Human immunodeficiency virus (HIV) is an enveloped virus with a remarkable capacity for genetic diversification, enabling rapid escape from host immune responses and therapeutic interventions. Despite extensive global efforts, the development of an effective vaccine has remained elusive owing to the virus’s high genetic variability and antigenic diversity. Consequently, considerable effort has been directed toward the development of therapeutic agents targeting viral entry, reverse transcriptase, integrase, protease, and more recently, capsid. Although antiretroviral therapy (ART) remains the cornerstone of HIV treatment, it is associated with challenges including drug resistance, adverse side effects, and limitations in access and affordability. Targeting viral entry offers distinct advantages by blocking infection at the earliest stage of the viral life cycle and enabling the neutralization of free virions, as well as Fc-mediated elimination of HIV-infected cells in some cases. This review highlights promising protein-based HIV entry inhibitors that have demonstrated efficacy in preclinical studies, and discusses ongoing efforts to optimize their valency, avidity, specificity, serum half-life, effector functions, and production platforms to improve their therapeutic potential and economic feasibility. Full article

Curcumin derivatives (curcuminoids) exhibit considerable antiparasitic and antiviral activities. In this study, EF24-like bis-2-fluorobenzylidene piperidone derivatives were synthesized and evaluated for antiprotozoal activity and inhibition of the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT)-associated RNase H (HIV-1 RNase H). A series of bis-arylidene piperidones and tetrahydro(thio)pyranones bearing halogen or nitro substituents were tested against Leishmania major (promastigotes and amastigotes) and Toxoplasma gondii. L. major promastigotes were the most sensitive parasitic model, with several compounds exhibiting low-nanomolar IC₅₀ values, while ortho- or para-halogenated analogues demonstrated submicromolar activity against T. gondii. Among them, 3,4-dichlorophenyl (HPip-DC) and 4-bromophenyl (HPip-4Br) derivatives showed potent activity against L. major and HIV-1 RNase H. The entropy-uncorrected MM-GBSA effective binding energy estimates were −33.41, −9.29, −8.37, and −4.27 kcal/mol for the predicted L. major squalene monooxygenase–HPip-DC, bovine cytochrome bc₁–DiFiD (2,4-difluorophenyl derivative), RNase H–HPip-4NO (4-nitrophenyl derivative), and RNase H–HPip-DC complexes, respectively. During 300 ns simulations, the ligands remained associated with their binding pockets. The Arg557 residue was crucial for HPip-4NO-mediated RNase H inhibition while the inhibitory activity of HPip-DC was much less dependent on this amino acid. These findings identify EF24-like curcuminoids with potent in vitro antiprotozoal activity and biochemical inhibition of HIV-1 RNase H. Antiviral activity was observed but confounded by host cell toxicity. Full article

The molecular epidemiology and antiretroviral (ARV) drug resistance of human immunodeficiency virus type 1 (HIV-1) remain incompletely outlined in the Middle East and North Africa (MENA). The aim of this retrospective molecular epidemiology study was to analyze MENA HIV-1 sequences for phylogenetic clustering and to delineate surveillance drug-resistance mutations (SDRMs) for nucleoside reverse-transcriptase inhibitors (NRTIs), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) across various periods, locations, and subtypes/circulating recombinant forms (CRFs). Viral sequences were retrieved from the Los Alamos HIV Sequence Database as of 15 April 2026. Analyses were done using multiple sub-gene regions (two env regions (n = 224 and n = 60) and PR (n = 2413) and RT (n = 2103) of the pol gene). Phylogeny construction was conducted using maximum-likelihood estimation, while ARV drug resistance analysis was conducted using the Stanford HIVdb algorithm. The HIV-1 MENA sequences showed a remarkable genetic diversity, with co-circulation of multiple subtypes/CRFs, including subtype B in the Maghreb, Levant, and Egypt sub-regions, subtypes A1, G, CRF01_AE, and CRF02_AG in the Gulf Cooperation Council (GCC) and Yemen sub-region, and subtypes C and D in the Horn of Africa and Sudan sub-region. The percentage of MENA HIV-1 sequences in clusters was 10.3% for env1, 8.3% for env2, 22.0% for PR and 37.2% for RT. Phylogenetic reconstruction hinted at a structured epidemic dominated by small transmission units, with most clusters comprising dyads (n = 260) or networks (n = 142) and a limited number of large clusters (n = 8) that were largely confined within national boundaries, with only occasional cross-border linkages (n = 8). Overall SDRM prevalence was 3.2% in the PR region and 14.9% in the RT region, with a higher percentage of NNRTI-associated mutations (10.0%) than NRTI-associated mutations (9.1%) and dual-class resistance observed in 4.1% of sequences. Phylogenetic clustering was not associated with the probability of harboring SDRMs; however, negative binomial models showed that non-clustered sequences had a greater burden of NRTI-associated mutations, whereas no such association was observed for NNRTI- or PI-associated mutations. The findings showed predominantly localized and fragmented MENA HIV-1 transmission dynamics. Heterogeneous ARV drug resistance dynamics indicated that resistance emergence might be shaped by broader epidemiologic and treatment-related factors rather than ongoing clustered transmission. There is a need for coordinated molecular surveillance and optimized ART strategies across the MENA countries. Full article

Background/Objectives: Predicting the bioactivity of HIV-related compounds is essential for early-stage drug discovery. However, most existing machine learning (ML) studies emphasize predictive performance while overlooking the predicted pharmacokinetic and drug-likeness properties of prioritized compounds. This study presents a comparative framework integrating classical ML, deep learning, graph-based models, and complementary ADME-based pharmacokinetic assessment. Methods: Twelve predictive models were evaluated using stratified five-fold cross-validation on the MoleculeNet HIV dataset under a unified experimental protocol. Model performance was assessed using multiple classification metrics together with statistical analysis. The highest-ranked compounds from the independent test set were further characterized using predicted ADME and drug-likeness properties. A representative compound (GDL1), prioritized by the GDL model, was subsequently evaluated by molecular docking against HIV-1 protease, HIV-1 integrase, and HIV-1 reverse transcriptase. Results: The graph-based GDL model achieved the highest ROC–AUC ($0.956\pm 0.015$), followed by GRU ($0.930\pm 0.017$) and RF ($0.927\pm 0.023$). Statistical analysis indicated overall differences among model performances (Friedman test, $p<0.001$). However, Holm-corrected pairwise comparisons did not demonstrate statistically significant differences between the highest-performing models. Comparative ADME analysis showed that high predictive performance did not necessarily correspond to favorable predicted pharmacokinetic properties. Molecular docking suggested potential predicted binding interactions of the prioritized GDL1 compound with all three HIV-1 targets, with the most favorable predicted binding affinity observed for HIV-1 reverse transcriptase. Conclusions: The proposed framework enables a comprehensive comparison of diverse molecular learning approaches by integrating predictive performance with complementary predicted ADME, drug-likeness, and molecular docking analyses. Full article

As critical geopolitical and migratory hubs in Eastern Europe, the Azov and Donbas regions represent an epidemiological melting pot for HIV-1 trafficking, exacerbating the global trend of rising dolutegravir (DTG) resistance through the cross-border dissemination of drug-resistant strains. This study presents a comprehensive molecular epidemiological analysis of HIV-1 in these regions in 2025 (N = 1666), focusing on drug resistance and cross-border transmission networks using phylogenetic and molecular network approaches. The study cohort was predominantly female (53.33%) and had heterosexual transmission (78.77%). Most patients (87.64%) received antiretroviral therapy (ART). Sub-subtype A6 predominated, with the radiation’s origin traced to September 1994. Molecular network analysis identified the study area as a significant node, demonstrating viral exports towards the Russian Federation and Belarus, alongside multiple imports from Ukraine, Poland, and Russia. The overall resistance prevalence was 4.49% to integrase strand transfer inhibitors (INSTIs), 2.49% to protease inhibitors (PIs), 12.19% to nucleoside reverse transcriptase inhibitors (NRTIs), and 16.07% to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Surveillance drug resistance mutations in treatment-naive individuals stood at 0.89% (INSTIs), 4.90% (PIs), 4.90% (NRTIs), and 8.82% (NNRTIs). Crucially, intermediate or high-level DTG resistance and key mutations (G118R, R263K, and Y143R) were detected in individuals without prior DTG exposure. This 4.49% integrase inhibitor resistance cannot be considered low; combined with intense cross-border viral dissemination, it may indicate the formation of a stable pool of resistant variants, potentially posing a risk of dolutegravir-based regimen failure and highlighting the need for enhanced regional molecular surveillance. Full article

Background: Doravirine (DOR) is a new-generation non-nucleoside reverse transcriptase inhibitor, which has emerged as an option for people living with HIV (PLWH) owing to its favorable efficacy and safety profile, unique resistance pathway and limited potential for drug-drug interactions. Methods: This retrospective chart review study aimed to better understand DOR-based treatment use in Greece, PLWH characteristics, and drivers of treatment switch. Eligible individuals were adult PLWH who were switched to a DOR-based regimen based on the physician’s decision. Individuals exposed to DOR at any time prior to switching to the DOR-based regimen were excluded. Results: From 12 July 2023 to 31 October 2023, 110 PLWH were consecutively enrolled across 6 public hospital clinics. At baseline (closest prior to or on the date of first DOR prescription), the mean age of PLWH was 49.3 years, 90.9% were males, 88.2% were asymptomatic, 86.5% were virologically suppressed, 33.6% were suffering from multimorbidity (excluding infections/infestations), 45.5% were receiving comedications for their comorbidities, and 5.5% were co-infected with Hepatitis C virus. Most PLWH (98.2%) were prescribed DOR plus two nucleoside reverse transcriptase inhibitors; 87.3% were prescribed DOR/Lamivudine/Tenofovir Disoproxil Fumarate fixed-dose combination. PLWH started DOR a median of 11.7 years after first-ever antiretroviral therapy initiation, corresponding to 2nd/3rd/≥4th antiretroviral line in 33.6%/33.6%/32.7% of participants, respectively; 60.9% of them were proactively switched to a DOR-based regimen. The most common reasons for switching were ‘regimen simplification’ (42.7%), ‘tolerability’ (26.4%) and ‘prevention of toxicities’ (18.2%). Conclusions: This study highlights the patterns of DOR use in real-life clinical practice in Greece among treatment-experienced PLWH. Physicians switch HIV-1-infected individuals from prior ART to DOR-based regimens to offer a simplified regimen or to avoid or prevent toxicity. Full article

Background and Clinical Significance: Tenofovir disoproxil fumarate (TDF) is a widely prescribed nucleotide reverse transcriptase inhibitor (NtRTI) for HIV-1 infection. Though generally well-tolerated, proximal renal tubulopathy resulting in full-blown Fanconi syndrome remains a rare but severe complication (<0.1%). Case Presentation: We present the case of a 52-year-old female living with HIV-1 (diagnosed in 1999, CDC stage A3) who had been treated with a TDF-based antiretroviral regimen for 12 years. Upon admission, she complained of progressive bone pain and polyuria over the preceding six months. Laboratory investigations revealed profound hypokalemia, severe hypophosphatemia, hypouricemia, elevated alkaline phosphatase (ALP) and a decline in renal function (creatinine 1.3 mg/dL from a baseline of 0.7 mg/dL). Arterial blood gas (ABG) analysis showed a normal anion gap hyperchloremic metabolic acidosis alongside respiratory acidosis. Urinalysis demonstrated profound glycosuria in the setting of normal blood glucose levels, coupled with increased 24 h urinary excretion of potassium and phosphorus. A bone scintigraphy demonstrated a “super scan” pattern of metabolic etiology, establishing secondary osteomalacia driven by renal phosphate wasting. Secondary hyperparathyroidism and severe vitamin D3 deficiency were also recorded. The diagnosis of TDF-induced Fanconi syndrome was established. TDF was discontinued, and her antiretroviral regimen was modified to tenofovir alafenamide fumarate (TAF), emtricitabine (FTC), darunavir, and ritonavir, combined with vitamin D supplementation. Over a 6-month follow-up period, renal function normalized, electrolyte wasting resolved, and metabolic acidosis completely reversed. Conclusions: This case highlights that TDF-induced proximal tubulopathy can manifest even after a decade of uneventful therapy, particularly when co-administered with a boosted protease inhibitor. Full article

Background: Transmitted drug resistance (TDR) remains a critical challenge in HIV-1 management, particularly in treatment-naïve populations. Baseline genotypic resistance testing is recommended to optimize antiretroviral therapy (ART), yet data from Saudi Arabia remain limited. This study aimed to characterize HIV-1 genetic diversity and baseline resistance-associated mutations among newly diagnosed, ART-naïve individuals. Methods: We conducted a multi-centre, retrospective cross-sectional study across three hospitals in Saudi Arabia between January 2023 and December 2024. Adult, treatment-naïve patients with confirmed HIV infection who underwent genotyping using Sanger sequencing were included. Mutations in reverse transcriptase (RT), protease (PI), and integrase (INSTI) genes were analyzed using the Stanford HIV Drug Resistance Database. Demographic, clinical, and virological data were collected, and comparative analyses between regions were performed. Results: A total of 614 patients were included, predominantly male (85.5%) and aged 25–44 years. Most patients presented with high viral loads (≥10,000 copies/mL, 89.7%), and 25.3% had CD4 counts <200 cells/mm³. HIV-1 subtype distribution was highly diverse, with subtype C (19.5%), CRF02_AG (15.6%), and subtype G (12.7%) predominating. Although mutations were frequently detected (RT: 85.2%, PI: 94.7%, INSTI: 36.4%), the majority were subtype-associated polymorphisms rather than major drug resistance mutations. Clinically significant mutations including M184V/I (1.17%), K103N (0.83%), and K65R (0.17%) were observed at low frequencies. No major INSTI resistance mutations were detected. Multi-class mutation patterns were common but largely driven by accessory variants. Conclusions: Despite the high prevalence of detected mutations, clinically significant TDR remained low, occurring in approximately 2.8% of patients. Most detected variants were polymorphic or accessory mutations, while susceptibility to INSTIs remained largely preserved. Continued baseline genotyping and molecular surveillance remain important to monitor emerging resistance patterns. Full article

To predict the anti-HIV-1 activity of biphenyl-DAPY-based non-nucleoside reverse transcriptase inhibitors (NNRTIs), a quantitative structure–activity relationship (QSAR) analysis was conducted. Using the heuristic method (HM) for descriptor selection, four predictive models were established: support vector regression (SVR), kernel ridge regression, linear mixed-kernel SVR, and Linear Residual Network (LRNet). Rigorous validations, including leave-one-out cross-validation, fivefold cross-validation, and Y-randomization tests, confirmed their reliability. The LRNet model exhibited the best performance, achieving an average training set $R^2$ of $0.8838\pm 0.0090$ and an average test set $R^2$ of $0.9026\pm 0.0187$ over 50 random train–test splits, with $Q_{5-fold}^2$ and $Q_{LOO}^2$ being 0.8533 and 0.8541, respectively. To further verify the robustness and generalizability of LRNet, independent validation was performed using an external dataset, where LRNet also achieved better generalization performance. The HM and LRNet models were employed to guide the design of novel compounds. Their favorable binding modes with the 1RT2 protein and pharmacokinetic properties were verified via molecular docking and in silico ADMET profiling, respectively. Furthermore, 100 ns molecular dynamics simulations demonstrated the robust dynamic stability, structural compactness, and thermodynamic convergence of the designed candidate within the 1RT2 binding pocket. This study provides a useful computational framework for the rational design and activity prediction of biphenyl-DAPY-based NNRTIs. Full article

Next-generation sequencing (NGS) has improved HIV-1 genotypic resistance testing (GRT) by enabling the detection of minority drug-resistance variants, although interpretation of low-frequency mutations remains challenging because of sequencing artifacts. This study compared the analytical performance and workflow efficiency of two Ion Torrent platforms, GeneStudio S5 (S5) and Genexus (GX), for routine HIV-1 GRT. A total of 134 plasma samples from people with HIV were prospectively collected, and 100 samples successfully sequenced on both platforms were included in the comparative analysis. Overall concordance for resistance-associated mutations was 88.0%, with agreement rates of 97.0% for protease, 90.0% for reverse transcriptase, and 100% for integrase. Both platforms generated clinically interpretable resistance profiles; however, 13 discordant mutations were identified. Application of a standardized confirmation algorithm, integrating Stanford HIVdb analysis with manual read-level inspection in Geneious software (version 2025.2.2), reclassified several discordant mutations as low-confidence or non-confirmed variants. Operationally, GX provided a fully automated workflow with approximately 24 h turnaround time and minimal hands-on processing, whereas S5 required approximately 72 h and substantially greater operator involvement. These findings support both platforms for routine HIV-1 GRT while emphasizing the importance of standardized bioinformatic review for reliable variant interpretation. Full article

Human immunodeficiency virus type 1 exhibits extensive genetic diversity, which has important implications for molecular epidemiology, recombinant-pattern assessment, and antiretroviral resistance surveillance. In Mexico, HIV-1 molecular surveillance has historically relied mainly on partial pol gene sequencing, limiting the ability to compare lineage assignments across gag, pol, and env regions. We analyzed plasma samples from 40 treatment-naïve adults receiving care at a tertiary-care hospital in Mexico using a commercial amplicon-based multiregion HIV-1 genomic sequencing workflow. DeepChek^® was used as the primary workflow for read processing, mutation calling, region-level subtype assignment, and antiretroviral resistance interpretation. Resistance interpretation was restricted to antiretroviral target regions with sufficient coverage, mainly reverse transcriptase, protease, integrase, and capsid, when available. Drug resistance mutations were identified in 6/40 participants (15.0%) when mutation-level resistance findings in RT, PR, and IN were considered; one additional sample showed a capsid inhibitor-nonsusceptible NGS call. NNRTI-associated findings were identified in 2/40 patients (5.0%), whereas NRTI- and PI-associated findings were identified in 1/40 patients (2.5%). Accessory or secondary INSTI-associated substitutions were detected in 2/40 patients (5.0%). Region-level subtype analysis revealed frequent discordant assignments across amplified segments, which is consistent with complex mosaic profiles; however, these findings are interpreted as region-level subtypes and recombinant-pattern assignments rather than continuous whole-genome recombination maps. One sample had insufficient RT/PROT/INT coverage for drug resistance interpretation in the complete DeepChek report and was retained only for regions meeting quality thresholds. These findings support the value of multiregion HIV-1 sequencing for local molecular surveillance while emphasizing the need for transparent region-level coverage reporting, cautious interpretation of recombinant-pattern calls, and transparent repository reporting. Full article

Background: Virological suppression is a key outcome of antiretroviral therapy. Despite progress in HIV treatment in Kazakhstan, virological non-suppression remains a relevant clinical and public health issue requiring further analysis. This study aimed to assess the prevalence of virological suppression (VS) and to identify factors associated with the absence of VS among people living with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy (ART) in Kazakhstan. Methods: A retrospective cross-sectional analytical study was conducted using secondary analysis of a de-identified national registry database of people living with HIV (PLHIV) receiving ART in the Republic of Kazakhstan as of 30 September 2025. The primary outcome was virological non-suppression (VNS), defined as the last viral load (VL) value of at least 200 copies per milliliter. The analysis included sex, age, presumed route of HIV transmission, the first available cluster of differentiation 4 (CD4) cell count recorded in the registry, the last recorded percentage category of adherence to ART, and the aggregated category of ART regimen. The main descriptive, bivariate, and multivariable analyses were performed using a complete-case approach. Independent associations were assessed using multivariable logistic regression, and the results were presented as adjusted odds ratios (aORs) with 95 percent confidence intervals (CIs). Results: The initial registry extraction included 33,614 records, of which 32,130 patients were included in the final analytical sample. VS was achieved in 29,454 (91.7%) patients, whereas VNS was observed in 2676 (8.3%) patients. In the multivariable model, higher adjusted odds of VNS were observed among men compared with women (aOR 1.14; 95% CI 1.02–1.26), as well as among patients with a first CD4 count < 200 cells/μL compared with those with a first CD4 count of ≥500 cells/μL (aOR 1.25; 95% CI 1.09–1.44). The strongest association was found for reduced adherence to therapy. Compared with adherence of at least 95%, the adjusted odds of VNS were markedly higher among patients with adherence of 85–94% (aOR 28.66; 95% CI 25.85–31.77) and among those with adherence below 85% (aOR 61.05; 95% CI 50.50–73.81). In all age groups older than 25 years, the adjusted odds of VNS were lower than among patients younger than 25 years. Lower adjusted odds of VNS were also observed among patients with homosexual transmission, vertical transmission, and other or unspecified transmission routes compared with heterosexual transmission. Among ART regimens, regimens containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) were associated with lower adjusted odds of VNS than dolutegravir-containing regimens (DTG-containing regimens) (aOR 0.68; 95% CI 0.52–0.88), whereas no statistically significant differences were identified for regimens containing protease inhibitors (PIs). Conclusions: Despite the high overall level of VS among PLHIV receiving ART in Kazakhstan, VNS remains concentrated in clinically and programmatically important subgroups. It was most strongly associated with reduced adherence and was also associated with younger age, marked baseline immunosuppression, and male sex in the primary model. These findings support the need for targeted interventions focused on adherence support, early diagnosis, and differentiated long-term follow-up of patients. Full article

Background: Concomitant HIV/HBV infection results in worse health outcomes, with HBV reactivations being observed in immunocompromised individuals. However, data on HBV infection in people with advanced HIV disease (AHD) remains sparse in Botswana. We aimed to determine the prevalence and molecular characteristics of HBV in people living with HIV (PLHIV) with CD4+ T-cell counts ≤100 cells/µL in Botswana. Methods: Plasma samples (n = 1097) of PLHIV with CD4+ T-cell count ≤100 cells/uL collected between 2014 and 2016 were screened for hepatitis B surface antigen (HBsAg) and HBV core antibodies (anti-HBc). A 415bp region of the HBV surface gene was amplified and sequenced using Sanger sequencing. Genotypic and mutational analysis was performed using Geno2pheno. Adjusted prevalence ratios (aPRs) were estimated from a modified Poisson regression model to explore factors associated with HBV infection. p-values < 0.05 indicated statistical significance. Results: The median age was 37 years (IQR: 32–43), and 565/1097 (51.5%) were male. HBsAg prevalence was 10.6% (95%CI: 8.8–12.5%) and anti-HBc prevalence was 50.0% (95%CI:46.9–52.9%). Factors associated with HBV infection were male sex [aPR: 1.6 (p < 0.01)] and those that were ART-experienced [aPR: 1.43 (p = 0.04). Eighteen samples were successfully genotyped. The prevalence of genotype A was (12/18, 66.7%) and D (6/18, 33.3%). Sixty-three mutations were identified as associated with drug resistance and immune and diagnostic escape. Highly prevalent immune escape mutations in the surface region were S207N (12/63, 19%) and A194V (9/63, 14.3%). V163I (12/63, 19%) and M129L (12/63, 19%) were highly prevalent in the reverse transcriptase region. Two classical lamivudine-associated drug resistance mutations were observed, each occurring in one participant (L180M and V173L). Conclusions: The prevalence of HBV in people with AHD is high, highlighting the importance of HBV screening and HIV/HBV co-management in this population. Full article

The international spread of HIV-1 sub-subtype A6 raises concerns due to its association with contraindications for long-acting injectable formulations of cabotegravir (LA-CAB) and rilpivirine (LA-RPV). This study investigated its increasing proportion in Belgium, assessing transmission dynamics and potential migration links. Additionally, genotypic drug resistance in the Belgian HIV-1 sub-subtype A6 population were analyzed and four automatic subtyping tools were compared. A dataset of 4764 HIV-1 protease and reverse transcriptase (RT) sequences from newly diagnosed, treatment-naïve individuals in Belgium (2013–2022) was analyzed. A combination of phylogenetic analysis and online subtyping tools identified 136 sub-subtype A6 sequences. The increase in the proportion of HIV-1 sub-subtype A6 observed in Belgium since 2020 reflects changing transmission patterns, especially among Belgium-born men having sex with men, and cannot be solely linked to the recent influx of Ukrainian migrants. Of these sub-subtype A6 sequences, less than 10% showed LA-CAB + LA-RPV resistance, mainly due to E138A within RT. HIVdb and ANRS reliably assessed resistance in this therapy-naïve cohort, and HIVdb, COMET, and SmartGene^® produced concordant subtyping results. While algorithm choice has little impact at low resistance prevalence, further research is necessary and HIVdb and ANRS remain more suitable for ongoing clinical and research use. Full article

Background: People living with HIV (PLWH) constitute a vulnerable population during the COVID-19 pandemic; however, it remains uncertain whether long-term suppressive antiretroviral therapy (ART) restores sufficient immune competence to support robust hybrid immunity. While vaccination followed by breakthrough infection—termed hybrid immunity—typically elicits potent humoral responses in immunocompetent individuals, the functional quality and breadth of these responses against evolving Omicron subvariants remain poorly characterized in PLWH. This study aimed to assess functional antibody responses, including neutralizing activity and Fc effector functions, in vaccinated and unvaccinated PLWH who experienced breakthrough infection with Omicron subvariants BA.4/5 or BF.7. Methods: We enrolled three cohorts between December 5 and December 20, 2022: 25 HIV-negative individuals with breakthrough infection (BTI-HC), 20 ART-experienced PLWH with breakthrough infection following three-dose COVID-19 vaccination (BTI-HIV), and 10 ART-experienced PLWH with primary infection without prior vaccination (PI-HIV). All HIV-positive participants were receiving suppressive ART with regimens based on non-nucleoside reverse transcriptase inhibitors or integrase strand transfer inhibitors for a median of 3.4 years. We measured receptor-binding domain (RBD)-specific IgG, neutralizing antibody titers against ancestral D614G, Delta, BA.1, BA.4/5, BF.7, XDV, KP.2, and KP.3 variants, and antibody-dependent cellular cytotoxicity (ADCC) responses. Results: Despite lower absolute CD4⁺ T cell counts, BTI-HIV participants mounted RBD-binding IgG, neutralizing antibody, and ADCC responses that were comparable to BTI-HC and significantly exceeded PI-HIV across all tested variants. Both breakthrough infection cohorts exhibited immunological imprinting, with higher neutralizing titers against ancestral D614G than infecting BA.4/5 or BF.7 variants. Emerging variants XDV, KP.2, and KP.3 demonstrated substantial neutralization escape in all groups. PI-HIV showed markedly diminished neutralization breadth and failed to generate enough responses against all tested Omicron strains. Conclusions: Suppressive ART enables PLWH to mount hybrid immunity—conferred by vaccination followed by BF.7 or BA.4/5 breakthrough infection—with neutralizing and ADCC responses comparable to HIV-negative individuals, and significantly exceeding those of unvaccinated PLWH with primary infection. This underscores the critical role of vaccination in establishing effective hybrid immunity in this population. However, we observed immunological imprinting, with higher titers against ancestral strains than against infecting variants, and substantial escape by emerging sublineages XDV, KP.2, and KP.3 across all groups. These findings support prioritizing updated variant-containing vaccines for HIV-positive populations and reinforce the essential role of vaccination in this vulnerable group. Full article