Biology subjects

Benko, E.

Publications and source records attributed to Benko, E..

5 recordsLinked to original sources

bioRxiv2023

Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. We followed 68 PWH aged 55 and older and 23 age-matched HIV-negative individuals for 48 weeks from the first vaccine dose, after the total of three doses. All PWH were on antiretroviral therapy (cART) and had different immune status, including immune responders (IR), immune non-responders (INR), and PWH with low-level viremia (LLV). We measured total and neutralizing Ab responses to SARS-CoV-2 spike and RBD in sera, total anti-spike Abs in saliva, frequency of anti-RBD/NTD B cells, changes in frequency of anti-spike, HIV gag/nef-specific T cells, and HIV reservoirs in peripheral CD4+ T cells. The resulting datasets were used to create a mathematical model for within-host immunization. Various regimens of BNT162b2, mRNA-1273, and ChAdOx1 vaccines elicited equally strong anti-spike IgG responses in PWH and HIV- participants in serum and saliva at all timepoints. These responses had similar kinetics in both cohorts and peaked at 4 weeks post-booster (third dose), while half-lives of plasma IgG also dramatically increased post-booster in both groups. Salivary spike IgA responses were low, especially in INRs. PWH had diminished live virus neutralizing titers after two vaccine doses which were rescued after a booster. Anti-spike T cell immunity was enhanced in IRs even in comparison to HIV- participants, suggesting Th1 imprinting from HIV, while in INRs it was the lowest. Increased frequency of viral blips in PWH were seen post-vaccination, but vaccines did not affect the size of the intact HIV reservoir in CD4+ T cells in most PWH, except in LLVs. Thus, older PWH require three doses of COVID-19 vaccine to maximize neutralizing responses against SARS-CoV-2, although vaccines may increase HIV reservoirs in PWH with persistent viremia.

immunology↗

bioRxiv2022

High Coverage Mitogenomes and Y-Chromosomal Typing Reveal Ancient Lineages in the Modern-day Szekely Population in Romania

Here we present 115 whole mitogenomes and 92 Y-chromosomal STR and SNP profiles from a Hungarian ethnic group, the Szekelys (in Romanian: Secuii, in German: Sekler) living in southeast Transylvania (Romania). The Szekelys can be traced back to the 12th century in the region, and numerous scientific theories exist as to their origin. We carefully selected sample providers that had local ancestors inhabiting small villages in the area of Odorheiu Secuiesc/Szekelyudvarhely in Romania. The results of our research and the reported data signify a qualitative leap compared to previous studies, since complete mitochondrial DNA sequences and Y-chromosomal data containing 23 STRs have not been available from the region until now. We evaluated the results with population genetic and phylogenetic methods, in the context of the modern and ancient populations that are either geographically or historically related to the Szekelys. Our results demonstrate a predominantly local uniparental make-up of the population that also indicates limited admixture with neighbouring populations. Phylogenetic analyses confirmed the presumed eastern origin of certain maternal (A, C, D) and paternal (Q, R1a) lineages and, in some cases, they could also be linked to ancient DNA data from Migration Period (5th-9th centuries AD) and Hungarian Conquest Period (10th century AD) populations.

genetics↗

bioRxiv2020

Selective BCL-XLAntagonists Eliminate Infected Cells from a Primary Cell Model of HIV Latency but not from Ex Vivo Reservoirs

HIV persists, despite antiviral immune responses and effective antiretroviral therapy, in viral reservoirs that seed rebound viremia if therapy is interrupted. Previously, we showed that the BCL-2 protein contributes to HIV persistence by conferring a survival advantage to reservoir-harboring cells. Here, we demonstrate that many of the BCL-2 family members are overexpressed in HIV-infected CD4+ T-cells, indicating increased tension between pro-apoptotic and pro-survival family members - as well as raising the possibility that the inhibition of pro-survival members may disproportionately affect the survival of HIV-infected cells. Based on these results, we chose to further study BCL2L1 (encoding the protein BCL-XL), due to its consistent overexpression and the availability of selective antagonists. Infection of primary CD4+ T-cells with either a clinical isolate, a CCR5-tropic strain, or a CXCR4-tropic strain of HIV resulted in increased BCL-XL protein expression; and treatment with two selective BCL-XL antagonists, A-1155463 and A-1551852, led to disproportionate cell death compared to uninfected CD4+ T-cells. In a primary cell model of latency, both BCL-XL antagonists drove significant reductions in total HIV DNA and in infectious cell frequencies both alone and in combination with the latency reversing agent bryostatin-1, with little off-target cytotoxicity. However, these antagonists, with or without bryostatin-1, or in combination with the highly potent latency reversing agent combination PMA + ionomycin, failed to reduce total HIV DNA and infectious reservoirs in ex vivo CD4+ T-cells from ART-suppressed donors. Our results add to growing evidence that bonafide reservoir-harboring cells are resistant to multiple "kick and kill" modalities - relative to latency models - and uncover BCL-XL antagonists as a facile approach to probing mechanistic underpinnings. We also interpret our results as encouraging of further exploration of BCL-XL antagonists for cure, where combination approaches may unlock the ability to eliminate ex vivo reservoirs.

microbiology↗

bioRxiv2020

HIV Diversity Considerations in the Application of the Intact Proviral DNA Assay (IPDA)

Opening Paragraph (serves as abstract for submission) and BodyThe Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a precise and scalable method for intact HIV reservoir quantification1. This duplexed droplet digital PCR (ddPCR) assay simultaneously targets the HIV Packaging Signal ({Psi}) and the Rev Responsive Element (RRE) within Envelope (env) to distinguish genomically intact proviruses against a large background of defective ones2. The IPDA requires less time, resources, and biological material than the gold standard for replication-competent HIV reservoir measurement, the Quantitative Viral Outgrowth Assay (QVOA)3, and is being adopted in research and clinical studies4-7. In our cohort of HIV-1 subtype B-infected individuals from North America however, the IPDA yielded a 28% failure rate due to HIV polymorphism. We further demonstrate that within-host HIV diversity can lead the IPDA to underestimate intact HIV reservoir size, which could negatively impact clinical trial results interpretation. While the IPDA represents an important methodological advance, HIV diversity should be addressed before its widespread adoption.

genetics↗

bioRxiv2018

Susceptibility to Neutralization by Broadly Neutralizing Antibodies Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs

Efforts to HIV cure are obstructed by reservoirs of latently infected CD4+ T-cells that can re-establish viremia. Broadly neutralizing HIV-specific antibodies (bNAbs), defined by unusually high neutralization breadths against globally diverse viruses, may contribute to the elimination of these reservoirs by binding to reactivated cells, targeting them for immune clearance. However, the relationship between neutralization of reservoir isolates and binding to corresponding infected primary CD4+ T-cells has not been determined. Thus, the extent to which neutralization breadths and potencies can be used to infer the corresponding parameters of infected-cell binding is currently unknown. We assessed the breadths and potencies of bNAbs against 36 viruses reactivated from peripheral blood CD4+ T-cells of ARV-treated HIV-infected individuals, using paired neutralization and infected-cell binding assays. Single antibody breadths ranged from 0-64% for neutralization (IC80[≤]10g/ml) and 0-89% for binding, with two-antibody combinations reaching 0-83% and 50-100%, respectively. Infected-cell binding correlated with virus neutralization for 10 out of 14 antibodies (e.g. 3BNC117, r=0.87, p<0.0001). Heterogeneity was observed, however, with a lack of significant correlations for 2G12, CAP256.VRC26.25, 2F5, and 4E10. Our results provide guidance on the selection of bNAbs for interventional cure studies; both by providing a direct assessment of intra-and inter-individual variability in neutralization and infected cell binding in a novel cohort, and by defining the relationships between these parameters for a panel of bNAbs.\n\nImportanceAlthough anti-retroviral therapies have improved the lives of people who are living with HIV, they do not cure infection. Efforts are being directed towards harnessing the immune system to eliminate the virus that persists, potentially resulting in virus-free remission without medication. HIV-specific antibodies hold promise for such therapies owing to their abilities to both prevent the infection of new cells (neutralization), and also to direct the killing of infected cells. We isolated 36 HIV strains from individuals whose virus was suppressed by medication, and tested 14 different antibodies for neutralization of these viruses and for binding to cells infected with the same viruses (critical for engaging natural killer cells). For both neutralization and infected-cell binding, we observed variation both between individuals, and amongst different viruses within an individual. For most antibodies, neutralization activity correlated with infected cell binding. These data provide guidance on the selection of antibodies for clinical trials.

immunology↗