Person: Pereyra, F
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Pereyra
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Pereyra, F
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Publication Blunted Response to Combination Antiretroviral Therapy in HIV Elite Controllers: An International HIV Controller Collaboration(Public Library of Science, 2014) Boufassa, Faroudy; Lechenadec, Jérome; Meyer, Laurence; Costagliola, Dominique; Hunt, Peter W.; Pereyra, F; Deeks, Steve; Pancino, Gianfranco; Taulera, Olivier; Lichterfeld, Mathias; Delobel, Pierre; Saez-Cirion, Asier; Lambotte, OlivierObjective: HIV “elite controllers” (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs). Methods: ECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (<1 year) ART-naïve HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models. Results: After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63/month), followed by +0.19/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm3, the estimated mean CD4 T-cell gain during the first 12 months was 139/mm3 in VIRs and 80/mm3 in ECs (p = 0.048). Conclusions: cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients.Publication Temporal effect of HLA-B*57 on viral control during primary HIV-1 infection(BioMed Central, 2013) Vaidya, Sagar A; Streeck, Hendrik; Beckwith, Noor; Ghebremichael, Musie; Pereyra, F; Kwon, Douglas; Addo, Marylyn M; Rychert, Jenna; Routy, Jean-Pierre; Jessen, Heiko; Kelleher, Anthony D; Hecht, Frederick; Sekaly, Rafick-Pierre; Carrington, Mary; Walker, Bruce; Allen, Todd; Rosenberg, Eric; Altfeld, MarcusBackground: HLA-B alleles are associated with viral control in chronic HIV-1 infection, however, their role in primary HIV-1 disease is unclear. This study sought to determine the role of HLA-B alleles in viral control during the acute phase of HIV-1 infection and establishment of the early viral load set point (VLSP). Findings: Individuals identified during primary HIV-1 infection were HLA class I typed and followed longitudinally. Associations between HLA-B alleles and HIV-1 viral replication during acute infection and VLSP were analyzed in untreated subjects. The results showed that neither HLA-B*57 nor HLA-B*27 were significantly associated with viral control during acute HIV-1 infection (Fiebig stage I-IV, n=171). HLA-B*57 was however significantly associated with a subsequent lower VLSP (p<0.001, n=135) with nearly 1 log10 less median viral load. Analysis of a known polymorphism at position 97 of HLA-B showed significant associations with both lower initial viral load (p<0.01) and lower VLSP (p<0.05). However, this association was dependent on different amino acids at this position for each endpoint. Conclusions: The effect of HLA-B*57 on viral control is more pronounced during the later stages of primary HIV-1 infection, which suggests the underlying mechanism of control occurs at a critical period in the first several months after HIV-1 acquisition. The risk profile of polymorphisms at position 97 of HLA-B are more broadly associated with HIV-1 viral load during primary infection and may serve as a focal point in further studies of HLA-B function.Publication Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls(Public Library of Science, 2013) McLaren, Paul J.; Coulonges, Cédric; Ripke, Stephan; van den Berg, Leonard; Buchbinder, Susan; Carrington, Mary; Cossarizza, Andrea; Dalmau, Judith; Deeks, Steven G.; Delaneau, Olivier; De Luca, Andrea; Goedert, James J.; Haas, David; Herbeck, Joshua T.; Kathiresan, Sekar; Kirk, Gregory D.; Lambotte, Olivier; Luo, Ma; Mallal, Simon; van Manen, Daniëlle; Martinez-Picado, Javier; Meyer, Laurence; Miro, José M.; Mullins, James I.; Obel, Niels; O'Brien, Stephen J.; Pereyra, F; Plummer, Francis A.; Poli, Guido; Qi, Ying; Rucart, Pierre; Sandhu, Manj S.; Shea, Patrick R.; Schuitemaker, Hanneke; Theodorou, Ioannis; Vannberg, Fredrik; Veldink, Jan; Walker, Bruce; Weintrob, Amy; Winkler, Cheryl A.; Wolinsky, Steven; Telenti, Amalio; Goldstein, David B.; de Bakker, Paul I. W.; Zagury, Jean-François; Fellay, JacquesMultiple 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 International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.Publication HIV-1 persistence in CD4+ T cells with stem cell-like properties(2014) Buzon, Maria J.; Sun, Hong; Li, Chun; Shaw, Amy; Seiss, Katherine; Ouyang, Zhengyu; Martin-Gayo, Enrique; Leng, Jin; Henrich, Timothy J.; Li, Jonathan; Pereyra, F; Zurakowski, Ryan; Walker, Bruce; Rosenberg, Eric; Yu, Xu G.; Lichterfeld, MathiasCellular HIV-1 reservoirs that persist despite antiretroviral treatment are incompletely defined. We show that during suppressive antiretroviral therapy, CD4+ T memory stem cells (TSCM) harbor high per-cell levels of HIV-1 DNA, and make increasing contributions to the total viral CD4+ T cell reservoir over time. Moreover, phylogenetic studies suggested long-term persistence of viral quasispecies in CD4+ TSCM cells. Thus, HIV-1 may exploit stem cell characteristics of cellular immune memory to promote long-term viral persistence.Publication Differential Levels of Soluble Inflammatory Markers by Human Immunodeficiency Virus Controller Status and Demographics(Oxford University Press, 2014) Li, Jonathan; Arnold, Kelly B.; Lo, Janet; Dugast, Anne-Sophie; Plants, Jill; Ribaudo, Heather; Cesa, Kevin; Heisey, Andrea; Kuritzkes, Daniel; Lauffenburger, Douglas A.; Alter, Galit; Landay, Alan; Grinspoon, Steven; Pereyra, FBackground. Human immunodeficiency virus (HIV)-1 elite controllers (ECs) represent an ideal population to study the effects of HIV persistence on chronic inflammation in the absence of antiretroviral therapy (ART). Methods. Twenty inflammatory markers measured in cohorts of ECs, HIV suppressed noncontrollers, and HIV-uninfected controls were compared using rank-based tests and partial least squares discriminant analysis (PLSDA). Spearman correlations were determined among the inflammatory markers, residual viremia by the single-copy assay, and CD4+ T cell slope. Results. Significant differences were seen between cohorts in 15 of the soluble inflammatory markers. Human immunodeficiency virus-1 ECs were found to have the highest levels for all of the markers with the exception of RANTES. In particular, median levels of 7 inflammatory markers (soluble CD14 [sCD14], interferon [IFN]-γ, IFN-γ-inducible protein [IP]-10, interleukin [IL]-4, IL-10, sCD40L, and granulocyte-macrophage colony-stimulating factor) were twice as high in the HIV-1 ECs compared with either of the HIV-suppressed or uninfected groups. Multivariate PLSDA analysis of inflammatory markers improved differentiation between the patient cohorts, discerning gender differences in inflammatory profile amongst individuals on suppressive ART. Soluble markers of inflammation in ECs were not associated with either levels of residual HIV-1 viremia or CD4+ T cell decline. Conclusions. Despite maintaining relatively low levels of viremia, HIV-1 ECs had elevated levels of a set of key inflammatory markers. Additional studies are needed to determine whether ECs may benefit from ART and to further evaluate the observed gender differences.Publication Systemic Inhibition of Myeloid Dendritic Cells by Circulating HLA Class I Molecules in HIV-1 Infection(BioMed Central, 2012) Huang, Jinghe; Al-Mozaini, Maha Ahmed; Rogich, Jerome; Carrington, Mary F.; Seiss, Katherine; Pereyra, F; Lichterfeld, Mathias; Yu, XuBackground: HIV-1 infection is associated with profound dysfunction of myeloid dendritic cells, for reasons that remain ill-defined. Soluble HLA class I molecules can have important inhibitory effects on T cells and NK cells, but may also contribute to reduced functional properties of professional antigen-presenting cells. Here, we investigated the expression of soluble HLA class I isoforms during HIV-1 infection and assessed their functional impact on antigen-presenting characteristics of dendritic cells. Results: Soluble HLA class I molecules were highly upregulated in progressive HIV-1 infection as determined by quantitative Western blots. This was associated with strong increases of intracellular expression of HLA class I isoforms in dendritic cells and monocytes. Using mixed lymphocyte reactions, we found that soluble HLA class I molecules effectively inhibited the antigen-presenting properties of dendritic cells, however, there was no significant influence of HLA class I molecules on the cytokine-secretion properties of these cells. The immunomodulatory effects of soluble HLA class I molecules were mediated by interactions with inhibitory myelomonocytic MHC class I receptors from the Leukocyte Immunoglobulin Like Receptor (LILR) family. Conclusions: During progressive HIV-1 infection, soluble HLA class I molecules can contribute to systemic immune dysfunction by inhibiting the antigen-presenting properties of myeloid dendritic cells through interactions with inhibitory myelomonocytic HLA class I receptors.Publication CTL Responses of High Functional Avidity and Broad Variant Cross-Reactivity Are Associated with HIV Control(Public Library of Science, 2012) Mothe, Beatriz; Llano, Anuska; Ibarrondo, Javier; Zamarreño, Jennifer; Schiaulini, Mattia; Miranda, Cristina; Ruiz-Riol, Marta; Berger, Christoph T.; Herrero, M. José; Palou, Eduard; Plana, Montse; Rolland, Morgane; Heckerman, David; Weiner, David; Paredes, Roger; Clotet, Bonaventura; Felber, Barbara K.; Pavlakis, George N.; Mullins, James I.; Brander, Christian; Khatri, Ashok; Pereyra, F; Walker, BruceCytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication \(in\) \(vivo\). However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct \(ex-vivo\) samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control.Publication Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection(Public Library of Science, 2012) Henn, Matthew R.; Charlebois, Patrick; Lennon, Niall J.; Power, Karen A.; Macalalad, Alexander R.; Berlin, Aaron M.; Malboeuf, Christine M.; Gnerre, Sante; Erlich, Rachel L.; Green, Lisa M.; Berical, Andrew; Wang, Yaoyu; Newman, Ruchi; Axten, Karen L.; Gladden, Adrianne D.; Battis, Laura; Kemper, Michael; Zeng, Qiandong; Shea, Terrance P.; Gujja, Sharvari; Zedlack, Carmen; Gasser, Olivier; Brander, Christian; Günthard, Huldrych F.; Brumme, Zabrina L.; Brumme, Chanson J.; Bazner, Suzane; Rychert, Jenna; Tinsley, Jake P.; Levin, Joshua Z.; Jessen, Heiko; Birren, Bruce W.; Boutwell, C; Ryan, Elizabeth M.; Zody, M; Casali, Monica; Streeck, Hendrik; Bloom, Allyson; Dudek, Timothy E; Tully, Damien C; Hess, Christoph; Mayer, Kenneth; Rosenberg, Eric; Pereyra, F; Young, Sarah K.; Altfeld, Marcus; Walker, Bruce; Allen, ToddDeep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more highly constrained regions of the virus in order to ensure the maintenance of immunodominant CD8 responses and the sustained decline of early viremia.Publication Attenuation of Multiple Nef Functions in HIV-1 Elite Controllers(BioMed Central, 2013) Mwimanzi, Philip; Markle, Tristan J; Martin, Eric; Ogata, Yoko; Kuang, Xiaomei T; Tokunaga, Michiyo; Mahiti, Macdonald; Pereyra, F; Miura, Toshiyuki; Walker, Bruce; Brumme, Zabrina L; Brockman, Mark A; Ueno, TakamasaBackground: Impaired HIV-1 Gag, Pol, and Env function has been described in elite controllers (EC) who spontaneously suppress plasma viremia to < 50 RNA copies/mL; however, activity of the accessory protein Nef remains incompletely characterized. We examined the ability of 91 Nef clones, isolated from plasma of 45 EC and 46 chronic progressors (CP), to down-regulate HLA class I and CD4, up-regulate HLA class II invariant chain (CD74), enhance viral infectivity, and stimulate viral replication in PBMC. Results: In general, EC Nef clones were functional; however, all five activities were significantly lower in EC compared to CP. Nef clones from HLA-B*57-expressing EC exhibited poorer CD4 down-regulation function compared to those from non-B*57 EC, and the number of EC-specific B*57-associated Nef polymorphisms correlated inversely with 4 of 5 Nef functions in these individuals. Conclusion: Results indicate that decreased HIV-1 Nef function, due in part to host immune selection pressures, may be a hallmark of the EC phenotype.Publication Interactions between HLA-B and Leukocyte Immunoglobulin like Receptors B2 (LILRB2) Correlate with HIV-1 Disease Outcomes(BioMed Central, 2012) Martin Gayo, Enrique; Jones, D.; Pereyra, F; Lichterfeld, Mathias; Allen, R. L.; Yu, X. G.