Biology subjects

Calmy, A.

Publications and source records attributed to Calmy, A..

5 recordsLinked to original sources

bioRxiv2026

Developmental and molecular features shaping broad and synergistic actions of human autoantibodies targeting interferon-α

Neutralizing autoantibodies against interferon- (IFN) are associated with severe viral infections but may improve outcomes in IFN-driven autoimmunity. How these antibodies emerge, mature, and function at the molecular level remains unclear. Here, we tracked development of plasma neutralizing activity against all 12 IFNs in multiple human donors over years. Plasma neutralization frequently initiates with narrow IFN specificity, often IFN8, but increases in breadth and potency with individual kinetics. Monoclonal antibody analyses reveal that affinity maturation generates epitope-specific antibody classes, highlighting parallel emergence of subtype-restricted and broadly-reactive antibodies. Biophysical and structural characterization of human antibody-IFN complexes uncovers determinants of initial specificity and breadth development. Strikingly, antibodies engaging non-competing, neutralizing epitopes can act co-operatively to block IFN signaling, and some combinations trigger Fc-effector functions via cell surface IFN:IFNAR2 interactions that may eliminate IFN-responsive cells. Our findings reveal features shaping anti-IFN autoantibody repertoires and unappreciated synergistic mechanisms that amplify their potency and pathogenic potential.

immunology↗

bioRxiv2025

Interdependent Dynamics of mRNA Expression and HIV-1 Viral Load: Insights from Transcriptomics and Mendelian Randomization

The interaction between HIV-1 and the host immune system plays a crucial role in the natural control and progression of the infection. Previous studies have identified APOBEC3G, Tetherin, SAMHD1, and SERINC5 as HIV-1 host restriction factors, which are counteracted by the viral proteins Vif, Vpu, and Nef, respectively. The blood expression levels of some of these host proteins are correlated with HIV load, suggesting that interindividual differences in the spontaneous control of HIV infection might lead to the identification of novel HIV restriction factors. Our study enrolled 150 participants from the Swiss HIV Cohort Study with human genome-wide genotyping data, pre-antiretroviral treatment peripheral blood mononuclear cells (PBMC) aliquots and HIV load measurements. Using BrB-seq, we quantified mRNA expression of all protein-coding genes and found significant associations between 792 genes and HIV load. Pathway analysis revealed that higher viral load associated with the upregulation of innate immune response, proteasome complex, mitochondrial and cell-cycle related activity, and with the downregulation of ribosomal transcripts and genes involved in cytokine-cytokine receptor interaction, including IL4R, IL7R, and TCF7. Mendelian Randomization confirmed the viral restriction activity of TRABD2A and identified new candidates as potential restriction factors. These findings provide novel insights into the host-virus interplay and suggest additional genes that may contribute to the natural control of HIV-1 infection.

immunology↗

bioRxiv2024

The XbnAb Cohort: 304 people with broadly neutralizing antibody activity to HIV-1

Broadly neutralizing antibodies (bnAbs) recognizing a diversity of HIV-1 strains are widely thought to be essential for an HIV-1 vaccine. Extensive knowledge on bnAbs has been gained from studying natural HIV infection by following bnAb evolution in individual people with HIV (PWH). However, it remains essential to increase knowledge of bnAb responses in large PWH cohorts to assess the feasibility of inducing bnAb activity by vaccination. To allow systematic analysis, we created the XbnAb cohort, a large bnAb-inducer cohort selected by screening plasma of PWH enrolled in the Swiss HIV Cohort Study (SHCS) and the Zurich Primary HIV Infection Study (ZPHI). The XbnAb cohort represents a retrospective, biobank-based cohort comprising data of 305 PWH who developed bnAb activity during HIV-1 infection. Here, we report on the characteristics of the XbnAb cohort and its potential for HIV vaccine research.

immunology↗

bioRxiv2023

Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity

Infection with Mycobacterium tuberculosis (MTB) remains one of the most important opportunistic infections in people with HIV-1 (PWH). While active Tuberculosis (TB) leads to rapid progression of immunodeficiency in PWH, the interaction between MTB and HIV-1 during the asymptomatic phase of both infections remains poorly understood. In a cohort of individuals with HIV (PWH) with and without suppressed HIV-1 viral load, the transcriptomic profiles of peripheral blood mononuclear cells (PBMC) clustered in individuals infected with Mycobacterium tuberculosis (MTB) compared to carefully matched controls. Subsequent functional annotation analysis disclosed alterations in the IL-6, TNF, and KRAS pathways. Notably, MTB-associated genes demonstrated an inverse correlation with HIV-1 viremia, evident at both on individual gene level and when employed as a gene score. In sum, our data show that MTB infection in PWH is associated with a shift in the activation state of the immune system, displaying an inverse relationship with HIV-1 viral load. These results could provide an explanation for the observed increased antiretroviral control associated with MTB infection in PWH.

immunology↗

bioRxiv2017

Dissecting HIV Virulence: Heritability Of Setpoint Viral Load, CD4+ T Cell Decline And Per-Parasite Pathogenicity

Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as \"per-parasite pathogenicity\". Using viral load and CD4+ T cell measures from 2014 HIV-1 subtype B infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence -- measured as the rate of decline of CD4+ T cells -- and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor-recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4+ T cell declines and per-parasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4+ T cell decline is 17% (5%-30%), and that of the per-parasite pathogenicity is 17% (4%-29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12%-46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4+ T cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genetype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

evolutionary biology↗