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January 2006 - present
Publications
Publications (71)
The co-expression of inhibitory receptors (IRs) is a hallmark of CD8+ T-cell exhaustion (Tex) in people living with HIV-1 (PLWH). Understanding alterations of IRs expression in PLWH on long-term antiretroviral treatment (ART) remains elusive but is critical to overcoming CD8+ Tex and designing novel HIV-1 cure immunotherapies. To address this, we c...
Background
Persistence of viral reservoirs has been observed in people with HIV (PWH), despite long-term ART, and likely contributes to chronic immune activation and inflammation. Obefazimod is a novel drug that inhibits HIV-1 replication and reduces inflammation. Here we assess whether obefazimod is safe and might impact HIV-1 persistence, chronic...
The expression of inhibitory receptors (IRs) is a hallmark of CD8+ T-cell exhaustion (Tex) in people living with HIV-1 (PLWH). Understanding the dynamics of IRs expression in PLWH on long-term antiretroviral treatment (ART) is critical to overcoming CD8+ Tex and designing broadly applicable HIV-1 immunotherapies for cure. To address this, we combin...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection became a pandemic in 2020 and by March 2022 had caused more than 479 million infections and 6 million deaths worldwide. Several acute and long-term symptoms have been reported in infected adults, but it remains unclear whether children/adolescents also experience persistent...
Background:
HIV cure strategies aim to eliminate viral reservoirs that persist despite successful antiretroviral therapy (ART). We have previously described that 9% of HIV-infected individuals who receive ART harbor low levels of provirus (LoViReTs).
Methods:
We selected 22 LoViReTs matched with 22 controls ART suppressed for more than 3 years w...
HIV-1 viremic nonprogressors (VNPs) represent a very rare HIV-1 extreme phenotype. VNPs are characterized by persistent high plasma viremia and maintenance of CD4+ T cell counts in the absence of treatment. However, the causes of nonpathogenic HIV-1 infection in VNPs remain elusive. Here, we identified for the first time two VNPs who experienced th...
The identification of individuals with null alleles enables studying how the loss of gene function affects infection. We previously described a non‐functional variant in SIGLEC1, which encodes the myeloid‐cell receptor Siglec‐1/CD169 implicated in HIV‐1 cell‐to‐cell transmission. Here we report a significant association between the SIGLEC1 null var...
Relative control of HIV-1 infection has been linked to genetic and immune host factors. In this study, we analyzed 96 plasma proteome arrays from chronic untreated HIV-1-infected individuals using the classificatory random forest approach to discriminate between uncontrolled disease (plasma viral load [pVL] >50,000 RNA copies/ml; CD4 counts 283 cel...
Background:
Human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in progression of HIV infection. However, it is also known that viral infections can modify cellular DNA methylation patterns. Therefore, changes in the methylation of CpG islands might modulate progression of HIV infection.
Methods:
85 samples...
Background
Small viral reservoirs are found predominantly in HIV-1 controllers and individuals treated during acute/early HIV-1 infection. However, other HIV⁺ individuals could naturally also harbour low viral reservoirs.
Methods
We screened 451 HIV-1-infected treated-individuals with suppressed plasma viremia for at least 3 years and stored cryop...
Introduction: Treatment with anti PD-1/PD-L1 antibodies has demonstrated clinical activity in different types of solid tumors, but only 20 to 30% of patients (pts) respond to these immune checkpoint inhibitors (ICIs). Therefore, predictive biomarkers of response that can assist in pt selection are urgently needed. Single biomarker expression, like...
HIV-1 persists in cellular reservoirs that can reignite viremia if antiretroviral therapy (ART) is interrupted. Therefore, insight into the nature of those reservoirs may be revealed from the composition of recrudescing viremia following treatment cessation. A minor population of macrophage-tropic (M-tropic) viruses was identified in a library of r...
Importance
Therapies targeting the programmed cell death 1 (PD-1) receptor or its ligand (PD-L1), such as the humanized monoclonal antibody durvalumab, have shown durable clinical responses in several tumor types. However, concerns about the safety and feasibility of PD-1/PD-L1 blockade in HIV-1–infected individuals have led to the exclusion of the...
Background:
Pembrolizumab is an immune checkpoint inhibitor against programmed cell death protein-1 (PD-1) approved for therapy in metastatic melanoma. PD-1 expression is associated with a diminished functionality in HIV-1 specific-CD8+ T cells. It is thought that PD-1 blockade could contribute to reinvigorate antiviral immunity and reduce the HIV...
2501
Background: Durvalumab (MEDI4736), a programmed cell death-ligand 1 (PD-L1) blocking antibody, is currently approved for treatment of several cancer types. As HIV-1-infected (HIV+) patients have been excluded from cancer clinical trials, there are no data on the safety of durvalumab in this population. Methods: DURVAST (NCT03094286) is a multi...
Background:
Epstein-Barr virus (EBV) has been implicated in lymphomagenesis and can be found infecting tumor cells and in plasma at lymphoma diagnosis, especially in HIV-infected patients. Our aim was to evaluate the usefulness of plasma EBV-load as biomarker and prognostic factor in HIV-related lymphomas.
Methods:
EBV-load was measured by polym...
Viremic nonprogressors (VNPs) constitute a very scarce group of untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain stable CD4⁺ T cell counts despite high levels of HIV-1 replication. The specific factors associated with this atypical control of the HIV infection have been poorly described. Since specific T cell...
The well-characterized association between HLA-B*27:05 and protection against HIV disease progression has been linked to immunodominant HLA-B*27:05- restricted CD8⁺ T-cell responses toward the conserved Gag KK10 (residues 263 to 272) and polymerase (Pol) KY9 (residues 901 to 909) epitopes. We studied the impact of the 3 amino acid differences betwe...
Siglec-1/CD169 is a myeloid-cell surface receptor critical for HIV-1 capture and infection of bystander target cells. To dissect the role of SIGLEC1 in natura, we scan a large population genetic database and identify a loss-of-function variant (Glu88Ter) that is found in ∼1% of healthy people. Exome analysis and direct genotyping of 4,233 HIV-1-inf...
Significance
A proportion of the variation in HIV-1 viral load in the infected population is influenced by host genetics. Using a large sample of infected individuals ( n = 6,315) with genome-wide genotype data, we sought to map genomic regions that influence HIV viral load and quantify their impact. We identified amino acid positions located in th...
Objective:
This article compares trends in CD4 T-cell recovery and proportions achieving optimal restoration (≥500 cells/μl) after viral suppression following combination antiretroviral therapy (cART) initiation between rapid and nonrapid progressors.
Methods:
We included HIV-1 seroconverters achieving viral suppression within 6 months of cART....
http://www.retrovirology.com/content/12/1/37
Background
Myeloid cells are key players in the recognition and response of the host against invading viruses. Paradoxically, upon HIV-1 infection, myeloid cells might also promote viral pathogenesis through trans-infection, a mechanism that promotes HIV-1 transmission to target cells via viral capture...
Unlabelled:
Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therap...
OBJECTIVE::
The study of HIV-1 rapid progressors has been limited to specific case reports. Nevertheless, identification and characterization of the viral and host factors involved in rapid progression are crucial when attempting to uncover the correlates of rapid disease outcome.
DESIGN::
We carried out comparative functional analyses in rapid pro...
BACKGROUND: Technically, HIV-1 tropism can be evaluated in plasma or peripheral blood mononuclear cells (PBMCs). However, only tropism testing of plasma HIV-1 has been validated as a tool to predict virological response to CCR5 antagonists in clinical trials. The preferable tropism testing strategy in subjects with undetectable HIV-1 viremia, in wh...
Phylogenetic relatedness of V3 forms before treatment initiation and after 2 years in each subject. Maximum-likelihood phylogenetic trees including V3-loop haplotypes present at a frequency ≥0.6% in the virus population in plasma (triangles), PBMCs before therapy initiation (circles) and PBMCs after persistent viremia suppression (squares). One tre...
Includes Note S1: the cohorts and individuals contributing to the International Consortium for the Genomics of HIV, Tables S1, S2, S3, Figures S1, S2, S3, S4, S5 and supplementary references.
(DOC)
Increased lymphocyte death is a hallmark of human immunodeficiency virus (HIV) infection. Although virological factors have been linked to this phenomenon, increased cell death rates are still observed in treated individuals in which viral replication is halted. To understand the nature of this remaining altered cell death, we have developed a simp...
Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the In...
Background
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study in hemophilia patients highly exposed to potentially contaminated factor VIII infusions.Methods
Individuals with hemophilia A and a documented history of factor...
Combination antiretroviral therapy (cART) greatly improves survival and quality of life of HIV-1-infected patients; however, cART must be continued indefinitely to prevent viral rebound and associated disease progression. Inducing HIV-1-specific immune responses with a therapeutic immunization has been proposed to control viral replication after di...
The use of in vitro models to unravel the phenotypic characteristics of circulating viral variants is key to understanding HIV-1 pathogenesis but limited by the availability of primary viral isolates from biological samples. However, overall in vivo genetic variability of HIV-1 within a subject may not be reflected in the viable viral population ob...
Genotipic predicition of co-receptor use in DPS sequences from VC, VP and total plasma RNA. Unique sequences obtained from the DPS of the env-V3 loop region were used to run PSSM and g2p algorithms to infer virus co-receptor use per sample type VC (ligth symbols), VP (dark symbols) and RNA (empty symbols) and subject. For comparative purposes env-V...
In order to design strategies for eradication of HIV-1 from infected individuals, detailed insight into the HIV-1 reservoirs that persist in patients on suppressive antiretroviral therapy (ART) is required. In this regard, most studies have focused on integrated (proviral) HIV-1 DNA forms in cells circulating in blood. However, the majority of prov...
This study provides a detailed description and characterization of the preparation of individualized lots of autologous heat inactivated HIV-1 virions used as immunogen in a clinical trial designed to test an autologous dendritic-cell-based therapeutic HIV-1 vaccine (Clinical Trial DCV-2, NCT00402142). For each participant, ex vivo isolation and ex...
High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4⁺ T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive dise...
Studies on drug interruption have provided new insights on the adaptive evolution of rebounding HIV-1 during antiretroviral pressure. We investigated the origin of new viral variants after discontinuation of protease (PR) inhibitors as a treatment remained exclusively based on reverse transcriptase inhibitors, and whether drug susceptibility, viral...
A double-blinded, controlled study of vaccination of untreated patients with chronic human immunodeficiency virus type 1 (HIV-1)
infection with 3 doses of autologous monocyte-derived dendritic cells (MD-DCs) pulsed with heat inactivated autologous HIV-1
was performed. Therapeutic vaccinations were feasible, safe, and well tolerated. At week 24 afte...
Associations between the SNPs identified in the ZNRD1/RNF39 region and disease progression in individuals with and without HLA-A alleles belonging to the serogroup A10. The rs9261174 minor allele C shows the strongest association with progression in individuals that also have an HLA-A10 (green), but it also associates when HLA-A10 is absent (red)....
Number of SNPs discarded during quality control procedures. (0.03 MB DOC)
Comparison of the strength of the association results for polymorphisms with clear association with HIV outcomes using different definitions of progression in survival analyses. (0.03 MB DOC)
Supplementary text. (0.09 MB DOC)
Distribution of individual eigen values along the first axis identified by principal component analysis of the genotyping data (Eigenstrat). Participants are grouped by country of recruitment. The most important contributor to population stratification in our Caucasian population is a North-to-South European ancestry axis. Participants from the USA...
Top 500 SNPs in the setpoint analysis. (0.74 MB DOC)
Results of the GSEA analysis. (0.04 MB DOC)
QQ-plot of observed versus expected -log(p-values) for all SNPs in the set point association analysis. The plot shows no deviation from the expected line, except for the top 3000 SNPs (0.3%). (0.03 MB DOC)
Associations between HLA-C alleles and HIV-1 set point in the subset of 1204 subjects with complete SNP and HLA typing results. (0.06 MB DOC)
Pairs of HLA-B and HLA-C alleles that are in linkage disequilibrium (with an r2 of at least 0.1) in the subset of 1204 individuals with complete HLA typing results. (0.07 MB DOC)
Associations between 4-digit HLA Class I alleles and HIV-1 set point in the subset of 1204 subjects with complete SNP and HLA typing results. (0.10 MB DOC)
P-value distribution of functional variants. P-value distributions of 12,535 functional genetic variants (red, A) in comparison with 12,535 randomly selected intergenic variants (red, B), both in the background of p-value distributions generated from 10,000 permutations (blue, A and B). The upper figures show the distributions of ranked -log10(P) f...
Top 500 SNPs in the progression analysis. (0.72 MB DOC)
Results of the stepwise forward selection of MHC SNPs. (0.04 MB DOC)
VL setpoint values for groups of individuals with or without a recombination event between HCP5 and HLA-B. (0.03 MB DOC)
Participants included in the study. (0.04 MB DOC)
Author Summary
The ability to spontaneously control HIV-1 upon infection is highly variable between individuals. To evaluate the contribution of variation in human genes to differences in plasma viral load and in disease progression rates, we performed a genome-wide association study in >2,500 HIV–infected individuals. This study achieved two goals...
: Resistance to raltegravir is associated with three genetic pathways defined by the mutations Y143R/C, Q148H/R/K or N155H in integrase, which also infer a viral fitness cost. Additionally, the three major HIV-1 drug-targeted enzymes protease, reverse transcriptase and integrase mature from the same polyprotein, suggesting the potential for interac...
During acute human immunodeficiency virus (HIV) infection, high viral loads and the induction of host immune responses typically coincide with the onset of clinical symptoms. However, clinically severe presentations during acute HIV type 1 (HIV-1) infection, including AIDS-defining symptoms, are unusual.
Virus isolates were tested for clade, drug s...
