Person: Yu, Xu
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Publication Targeted HIV testing at birth supported by low and predictable mother‐to‐child transmission risk in Botswana(John Wiley and Sons Inc., 2018) Ibrahim, Maryanne; Maswabi, Kenneth; Ajibola, Gbolahan; Moyo, Sikhulile; Hughes, Michael; Batlang, Oganne; Sakoi, Maureen; Auletta‐Young, Chloe; Vaughan, Laura; Lockman, Shahin; Jean‐Philippe, Patrick; Yu, Xu; Lichterfeld, Matthias; Kuritzkes, Daniel R; Makhema, Joseph; Shapiro, RogerAbstract Introduction: Most African countries perform infant HIV testing at 6 weeks or later. The addition of targeted testing at birth may improve retention in care, treatment outcomes and survival for HIV‐infected infants. Methods: HIV‐exposed infants were screened as part of the Early Infant Treatment (EIT) study in Botswana. Screened infants were ≥35 weeks gestational age and ≥2000 g at birth. Risk factors for mother‐to‐child transmission (MTCT) were assessed by maternal obstetric card or verbally. Risk factors included <8 weeks ART in pregnancy, last known CD4 <250 cells/mm3, last known HIV RNA >400 copies/mL, poor maternal ART adherence, lack of maternal zidovudine (ZDV) in labour, or lack of infant post‐exposure prophylaxis. Infants underwent dried blood spot testing by Roche Cobas Ampliprep/Cobas Taqman HIV‐1 qualitative PCR. Results: From April 2015 to April 2016, 2303 HIV‐exposed infants were tested for HIV in the EIT study. Of these, 369 (16%) were identified as high risk for HIV infection by information available at birth, and 12 (0.5% overall, 3.25% of high risk) were identified as HIV positive at birth. All 12 positive infants were identified as high risk at the time of screening, and only 2 risk factors were required to identify all positive infants: either <8 weeks of maternal ART in pregnancy (75%) or lack of maternal HIV suppression at last test (25%). Conclusions: In utero MTCT occurred only among infants identified as high risk at delivery, using information available from the mother or obstetric record. Birth testing that targets high‐risk infants based on maternal ART receipt is likely to identify the majority of in utero HIV transmissions, and allows early ART initiation for these infants.Publication A Reproducibility-Based Computational Framework Identifies an Inducible, Enhanced Antiviral State in Dendritic Cells from HIV-1 Elite Controllers(BioMed Central, 2018) Martin-Gayo, Enrique; Cole, Michael B.; Kolb, Kellie E.; Ouyang, Zhengyu; Cronin, Jacqueline; Kazer, Samuel W.; Ordovas-Montanes, Jose; Lichterfeld, Mathias; Walker, Bruce; Yosef, Nir; Shalek, Alex K.; Yu, XuBackground: Human immunity relies on the coordinated responses of many cellular subsets and functional states. Inter-individual variations in cellular composition and communication could thus potentially alter host protection. Here, we explore this hypothesis by applying single-cell RNA-sequencing to examine viral responses among the dendritic cells (DCs) of three elite controllers (ECs) of HIV-1 infection. Results: To overcome the potentially confounding effects of donor-to-donor variability, we present a generally applicable computational framework for identifying reproducible patterns in gene expression across donors who share a unifying classification. Applying it, we discover a highly functional antiviral DC state in ECs whose fractional abundance after in vitro exposure to HIV-1 correlates with higher CD4+ T cell counts and lower HIV-1 viral loads, and that effectively primes polyfunctional T cell responses in vitro. By integrating information from existing genomic databases into our reproducibility-based analysis, we identify and validate select immunomodulators that increase the fractional abundance of this state in primary peripheral blood mononuclear cells from healthy individuals in vitro. Conclusions: Overall, our results demonstrate how single-cell approaches can reveal previously unappreciated, yet important, immune behaviors and empower rational frameworks for modulating systems-level immune responses that may prove therapeutically and prophylactically useful. Electronic supplementary material The online version of this article (10.1186/s13059-017-1385-x) contains supplementary material, which is available to authorized users.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 Functional Characterization of HLA-G+ Regulatory T Cells in HIV-1 Infection(Public Library of Science, 2013) Li, Chun; Toth, Ilona; Schulze zur Wiesch, Julian; Pereyra, Florencia; Rychert, Jennifer Ann; Rosenberg, Eric; van Lunzen, Jan; Lichterfeld, Mathias; Yu, XuRegulatory T cells represent a specialized subpopulation of T lymphocytes that may modulate spontaneous HIV-1 disease progression by suppressing immune activation or inhibiting antiviral T cell immune responses. While the effects of classical CD25hi FoxP3+ Treg during HIV-1 infection have been analyzed in a series of recent investigations, very little is known about the role of non-classical regulatory T cells that can be phenotypically identified by surface expression of HLA-G or the TGF-β latency-associated peptide (LAP). Here, we show that non-classical HLA-G-expressing CD4 Treg are highly susceptible to HIV-1 infection and significantly reduced in persons with progressive HIV-1 disease courses. Moreover, the proportion of HLA-G+ CD4 and CD8 T cells was inversely correlated to markers of HIV-1 associated immune activation. Mechanistically, this corresponded to an increased ability of HLA-G+ Treg to reduce bystander immune activation, while only minimally inhibiting the functional properties of HIV-1-specific T cells. Frequencies of LAP+ CD4 Treg were not significantly reduced in HIV-1 infection, and unrelated to immune activation. These data indicate an important role of HLA-G+ Treg for balancing bystander immune activation and anti-viral immune activity in HIV-1 infection and suggest that the loss of these cells during advanced HIV-1 infection may contribute to immune dysregulation and HIV-1 disease progression.Publication Mutational Escape in HIV-1 CTL Epitopes Leads to Increased Binding to Inhibitory Myelomonocytic MHC Class I Receptors(Public Library of Science, 2010) Yang, Yue; Huang, Jinghe; Toth, Ildiko; Lichterfeld, Mathias; Yu, XuEscape mutations in HIV-1 cytotoxic T cell (CTL) epitopes can abrogate recognition by the TCR of HIV-1-specific CD8+ T cells, but may also change interactions with alternative MHC class I receptors. Here, we show that mutational escape in three HLA-A11-, B8- and B7- restricted immunodominant HIV-1 CTL epitopes consistently enhances binding of the respective peptide/MHC class I complex to Immunoglobulin-like transcript 4 (ILT4), an inhibitory myelomonocytic MHC class I receptor expressed on monocytes and dendritic cells. In contrast, mutational escape in an alternative immunodominant HLA-B57-restricted CTL epitope did not affect ILT4-mediated recognition by myelomonocytic cells. This suggests that in addition to abrogating recognition by HIV-1-specific CD8 T cells, mutational escape in some, but not all CTL epitopes may mediate important immunoregulatory effects by increasing binding properties to ILT4, and augmenting ILT4-mediated inhibitory effects of professional antigen-presenting cells.Publication Human Immunodeficiency Virus Type 1 Specific Cytotoxic T Lymphocyte Responses in Chinese Infected with HIV-1 B'/C Recombinant (CRF07_BC)(BioMed Central, 2007) Chen, Jianping; Hong, Kunxue; Jia, Mingming; Liu, Hongwei; Zhang, Yuanzhi; Zhang, Xiaoqing; Zhao, Hongjing; Peng, Hong; Ma, Pengfei; Xing, Hui; Ruan, Yuhua; Shao, Yiming; Liu, Sha; Altfeld, Marcus; Walker, Bruce; Williams, Katie L.; Yu, XuBackground: The characterization of HIV-1-specific T cell responses in people infected with locally circulating HIV-1 strain will facilitate the development of HIV-1 vaccine. Sixty intravenous drug users infected with HIV-1 circulating recombinant form 07_BC (CRF07_BC), which has been spreading rapidly in western China from north to south, were recruited from Xinjiang, China to assess the HIV-1-specific T cell responses at single peptide level with overlapping peptides (OLP) covering the whole concensus clades B and C proteome. Results: The median of the total magnitude and total number of OLPs recognized by CTL responses were 10925 SFC/million PBMC and 25 OLPs, respectively, when tested by clade C peptides, which was significantly higher than when tested by clade B peptides. The immunodominant regions, which cover 14% (58/413) of the HIV-1 proteome, are widely distributed throughout the HIV-1 proteome except in Tat, Vpu and Pol-PR, with Gag, Pol-RT, Pol-Int and Nef being most frequently targeted. The subdominant epitopes are mostly located in p24, Nef, integrase, Vpr and Vif. Of the responses directed to clade C OLPs, 61.75% (972/1574) can be observed when tested with corresponding clade B OLPs. However, Pol-PR and Vpu tend to be targeted in the clade B sequence rather than the clade C sequence, which is in line with the recombinant pattern of CRF07_BC. Stronger and broader CTL responses in subjects with CD4 cell counts ranging from 200 to \(400/mm^3\) were observed when compared to those with less than \(200/mm^3\) or more than \(400/mm^3\), though there have been no significant correlations identified between the accumulative CTL responses or overall breadth and CD4 cell count or plasma viral load. Conclusion: This is the first study conducted to comprehensively address T cell responses in Chinese subjects infected with HIV-1 CRF07_BC in which subtle differences in cross-reactivity were observed, though similar patterns of overall immune responses were demonstrated with clade B infected populations. The immunodominant regions identified in this population can facilitate future HIV-1 vaccine development in China.Publication HLA-B*35-Px–mediated Acceleration of HIV-1 Infection by Increased Inhibitory Immunoregulatory Impulses(The Rockefeller University Press, 2009) Goedert, James J.; Sundberg, Eric J.; Cung, Thai Duong Hong; Burke, Patrick S.; Preiss, Liliana; Lifson, Jeffrey; Carrington, Mary; Huang, Jinghe; Martin, Maureen P.; Lichterfeld, Mathias; Yu, XuA subset of HLA-B*35 alleles, B*35-Px, are strongly associated with accelerated HIV-1 disease progression for reasons that are not understood. Interestingly, the alternative set of B*35 subtypes, B*35-PY, have no detectable impact on HIV-1 disease outcomes, even though they can present identical HIV-1 epitopes as B*35-Px molecules. Thus, the differential impact of these alleles on HIV-1 disease progression may be unrelated to interactions with HIV-1–specific CD8+ T cells. Here, we show that the B*35-Px molecule B*3503 binds with greater affinity to immunoglobulin-like transcript 4 (ILT4), an inhibitory MHC class I receptor expressed on dendritic cells, than does the B*35-PY molecule B*3501, even though these two B*35 molecules differ by only one amino acid and present identical HIV-1 epitopes. The preferential recognition of B*3503 by ILT4 was associated with significantly stronger dendritic cell dysfunction in in vitro functional assays. Moreover, HIV-1–infected carriers of B*3503 had poor dendritic cell functional properties in ex vivo assessments when compared with carriers of the B*3501 allele. Differential interactions between HLA class I allele subtypes and immunoregulatory MHC class I receptors on dendritic cells thus provide a novel perspective for the understanding of MHC class I associations with HIV-1 disease progression and for the manipulation of host immunity against HIV-1.Publication P16-12. Relative Dominance of Gag-Specific Cytotoxic T Lymphocytes Is Associated with Viral Load Inversely in HIV-1 Clade B' Infected Chinese(BioMed Central, 2009) Jia, M; Chen, J; Hong, K; Liu, S; Zhang, X; Zhao, H; Altfeld, Marcus; Walker, Bruce; Yu, Xu; Shao, YPublication CD8+ T lymphocyte responses target functionally important regions of Protease and Integrase in HIV-1 infected subjects(BioMed Central, 2004) Rodriguez, William Richard; Addo, Marylyn Martina; Rathod, Almas; Fitzpatrick, Cecily A; Yu, Xu; Perkins, Beth; Rosenberg, Eric; Altfeld, Marcus; Walker, BruceBackground: CD8+ T cell responses are known to be important to the control of HIV-1 infection. While responses to reverse transcriptase and most structural and accessory proteins have been extensively studied, CD8 T cell responses specifically directed to the HIV-1 enzymes Protease and Integrase have not been well characterized, and few epitopes have been described in detail. Methods: We assessed comprehensively the CD8 T cell responses to synthetic peptides spanning Protease and Integrase in 56 HIV-1 infected subjects with acute, chronic, or controlled infection using IFN-γ-Elispot assays and intracellular cytokine staining. Fine-characterization of novel CTL epitopes was performed on peptide-specific CTL lines in Elispot and \(^{51}\)Chromium-release assays. Results: Thirteen (23%) and 38 (68%) of the 56 subjects had detectable responses to Protease and Integrase, respectively, and together these targeted most regions within both proteins. Sequence variability analysis confirmed that responses cluster largely around conserved regions of Integrase, but responses against a large, highly conserved region of the N-terminal DNA-binding domain of Integrase were not readily detected. CD8 T cell responses targeted regions of Protease that contain known Protease inhibitor mutation residues, but strong Protease-specific CD8 T cell responses were rare. Fine-mapping of targeted epitopes allowed the identification of three novel, HLA class I-restricted, frequently-targeted optimal epitopes. There were no significant correlations between CD8 T cell responses to Protease and Integrase and clinical disease category in the study subjects, nor was there a correlation with viral load. Conclusions: These findings confirm that CD8 T cell responses directed against HIV-1 include potentially important functional regions of Protease and Integrase, and that pharmacologic targeting of these enzymes will place them under both drug and immune selection pressure.Publication HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8+ T Cell Response against HIV-1(Public Library of Science, 2006) Kalife, Elizabeth T; Qi, Ying; Johnston, Mary N; Burgett, Nicole; Swartz, Martha E; Yang, Amy; Rockstroh, Juergen K; Jessen, Heiko; Carrington, Mary; Altfeld, Marcus; Streeck, Hendrik; Lichterfeld, Mathias; Alter, Galit; Yu, Xu; Meier, Angela; Allen, Todd; Rosenberg, Eric; Walker, BruceBackground: Very little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression. Methods and Findings: In a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8+ T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8+ T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8+ T cell response during primary infection. Conclusions: These data demonstrate consistent immunodominance patterns of HIV-1-specific CD8+ T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression.