BACKGROUND. People living with HIV (PLHIV) on antiretroviral therapy (ART) exhibit persistent immune dysregulation and microbial dysbiosis, leading to the development of cardiovascular diseases (CVD). We initially compared plasma proteomic profiles between 205 PLHIV and 120 healthy controls (HCs) and validated the results in an independent cohort of 639 PLHIV and 99 HCs. Differentially expressed proteins (DEPs) were then associated to microbiome data. Finally, we assessed which proteins were linked with CVD development in PLHIV. METHOD. Proximity extension assay technology was utilized to measure 1472 plasma proteins. Markers of systemic inflammation (CRP, D-Dimer, IL6, sCD14, and sCD163) and microbial translocation (IFABP) were measured by ELISA, and gut bacterial species were identified using shotgun metagenomic sequencing. Baseline CVD data were available for all PLHIV, and 205 PLHIV were recorded for the development of CVD during a 5-year follow-up. RESULTS. PLHIV on ART displayed systemic dysregulation of protein concentrations compared to HCs. Most of the DEPs originated from the intestine and lymphoid tissues, while they enriched in immune- and lipid metabolism-related pathways. Furthermore, we observed that DEPs originating from the intestine were associated with specific gut bacterial species. Finally, we identified upregulated proteins in PLHIV (GDF15, PLAUR, RELT, NEFL, COL6A3, and EDA2R), unlike most markers of systemic inflammation, associated with the presence and risk of developing CVD in 5-year follow-up. CONCLUSIONS. Our findings suggest a systemic dysregulation of protein concentrations in PLHIV, of which some proteins were associated with CVD development. Most of DEPs originated from the gut and were related to specific gut bacterial species. TRIAL REGISTRATION. Cohorts included in this study are part of the Human Functional Genomics Project (HFGP) (www.humanfunctionalgenomics.org). The 2000HIV Human Functional Genomics Partnership Program is registered at ClinicalTrials.gov: (ID: NCT03994835). FUNDING. The 200HIV and 2000HIV studies are supported by the AIDS-fonds (#P-29001, Netherlands) and a ViiV healthcare grant (A18-1052), respectively; The ViiV healthcare grant was awarded to A.V., M.G.N., L.A.B.J., and Q.d.M; The Spinoza Prize (NWO SPI94-212) and ERC Advanced grant (no. 833247) were awarded to M.G.N; The Indonesia Endowment Fund for Education (LPDP) given by the Ministry of Finance of the Republic of Indonesia was awarded to N.V.
Nadira Vadaq, Yue Zhang, Wilhelm A.J.W. Vos, Albert L. Groenendijk, Martinus J.T. Blaauw, Louise E. van Eekeren, Maartje C.P. Jacobs-Cleophas, Lisa Van de Wijer, Jéssica Cristina dos Santos, Muhammad Hussein Gasem, Leo A.B. Joosten, Mihai G. Netea, Quirijn de Mast, Jingyuan Fu, André J.A.M. van der Ven, Vasiliki Matzaraki
Intestinal epithelial barrier dysfunction, a hallmark of HIV/SIV infection, persists despite viral suppression by combination antiretroviral therapy (cART). Emerging evidence suggests a critical role for long noncoding RNAs (lncRNAs) in maintaining epithelial homeostasis. We simultaneously profiled lncRNA/mRNA expression exclusively in colonic epithelium (CE) of SIV-infected rhesus macaques (RMs) administered vehicle (VEH) or Δ-9-tetrahydrocannabinol (THC). Relative to controls, fewer lncRNAs were up- or downregulated in CE of THC/SIV compared with VEH/SIV RMs. Importantly, reciprocal expression of the natural antisense lncRNA MMP25-AS1 (up 2.3-fold) and its associated protein-coding gene MMP25 (attracts neutrophils by inactivating alpha-1 anti-trypsin/SERPINA1) (down 2.2-fold) was detected in CE of THC/SIV RMs. Computational analysis verified 2 perfectly matched complementary regions and an energetically stable (normalized binding free energy = –0.2626) MMP25-AS1/MMP25 duplex structure. MMP25-AS1 overexpression blocked IFN-γ–induced MMP25 mRNA and protein expression in vitro. Elevated MMP25 protein expression in CE of VEH/SIV but not THC/SIV RMs was associated with increased infiltration by myeloperoxidase/CD11b++ neutrophils (transendothelial migration) and epithelial CD47 (transepithelial migration) expression. Interestingly, THC administered in combination with cART increased MMP25-AS1 and reduced MMP25 mRNA/protein expression in jejunal epithelium of SIV-infected RMs. Our findings demonstrate that MMP25-AS1 is a potentially unique epigenetic regulator of MMP25 and that low-dose THC can reduce neutrophil infiltration and intestinal epithelial injury potentially by downregulating MMP25 expression through modulation of MMP25-AS1.
Lakmini S. Premadasa, Eunhee Lee, Marina McDew-White, Xavier Alvarez, Sahana Jayakumar, Binhua Ling, Chioma M. Okeoma, Siddappa N. Byrareddy, Smita Kulkarni, Mahesh Mohan
HIV-1 usually utilize CCR5 as the co-receptor and rarely switches to CXCR4-tropic until late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in viremic patients as well as SIV-infected non-human primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL15, which increases during acute HIV-1 infection. Here, we report that CCR5 is expressed by CD4+ T cells exhibiting effector or effector memory phenotype with high expression levels of the IL2/IL15 receptor common beta and gamma chains. IL15 but not IL7 improves the survival of CCR5+CD4+ T cells, drives their expansion, and facilitates HIV-1 infection in vitro and in humanized mice. Our study suggests that IL15 plays confounding roles in HIV-1 infection, and future studies on the IL15-based boosting of anti-HIV-1 immunity should carefully exam the potential effects on the expansion of HIV-1 reservoirs in CCR5+CD4+ T cells.
Yuhao Li, Hongbo Gao, Kolin M. Clark, Liang Shan
People with HIV (PWH) appear at higher risk for suboptimal pathogen responses and worse COVID-19 outcomes, but the effects of host factors and COVID-19 on the humoral repertoire remain unclear. We assessed the antibody isotype/subclass and Fc-receptor binding Luminex arrays of non-SARS-CoV-2 and SARS-CoV-2 humoral responses among ART-treated PWH. Among the entire cohort, COVID-19 infection was associated with higher CMV responses (vs COVID-negative), potentially signifying increased susceptibility or a consequence of persistent inflammation. Among the COVID-positive, 1) higher BMI was associated with a striking amplification of SARS-CoV-2 responses, suggesting exaggerated inflammatory responses, and 2) lower nadir CD4 was associated with higher SARS-CoV-2 IgM and FcgRIIB binding capacity, indicating poorly functional extrafollicular and inhibitory responses. Among the COVID-negative, female sex, older age, and lower nadir CD4 were associated with unique repertoire shifts. In this first comprehensive assessment of the humoral repertoire in a global cohort of PWH, we identify distinct SARS-CoV-2-specific humoral immune profiles among PWH with obesity or lower nadir CD4+ T-cell count, underlining plausible mechanisms associated with worse COVID-19-related outcomes in this setting. Host factors associated with the humoral repertoire in the COVID-negative cohort enhance our understanding of these important shifts among PWH.
Samuel R. Schnittman, Wonyeong Jung, Kathleen V. Fitch, Markella V. Zanni, Sara McCallum, Jessica Shih-Lu Lee, Sally Shin, Brandon J. Davis, Evelynne S. Fulda, Marissa R. Diggs, Francoise Giguel, Romina Chinchay, Anandi N. Sheth, Carl J. Fichtenbaum, Carlos D. Malvestutto, Judith A. Aberg, Judith Currier, Douglas A. Lauffenburger, Pamela S. Douglas, Heather J. Ribaudo, Galit Alter, Steven K. Grinspoon
Rhesus cytomegalovirus (RhCMV)-based vaccine vectors induce immune responses that protect ~60% of rhesus macaques (RMs) from SIVmac239 challenge. This efficacy depends on induction of effector memory (EM)-biased CD8+ T cells recognizing SIV peptides presented by major histocompatibility complex (MHC)-E instead of MHC-Ia. The phenotype, durability, and efficacy of RhCMV/SIV-elicited cellular immune responses were maintained when vector spread was severely reduced by deleting the anti-host intrinsic immunity factor pp71. Here, we examined the impact of an even more stringent attenuation strategy on vector-induced immune protection against SIV. Fusion of the FK506-binding protein (FKBP) degradation domain to Rh108, the orthologue of the essential human CMV (HCMV) late gene transcription factor UL79, generated RhCMV/SIV vectors that conditionally replicate only when the FK506-analog Shield-1 is present. Despite lacking in vivo dissemination and reduced innate and B cell responses to vaccination, Rh108-deficient 68-1 RhCMV/SIV vectors elicited high frequency, durable, EM-biased, SIV-specific T cell responses in RhCMV-seropositive RM at doses of ≥106 PFU. Strikingly, elicited CD8+ T cells exclusively targeted MHC-Ia-restricted epitopes and failed to protect against SIVmac239 challenge. Thus, Rh108-dependent late gene expression is required for both induction of MHC-E-restricted T cells and protection against SIV.
Scott G. Hansen, Jennie L. Womack, Wilma Perez, Kimberli A. Schmidt, Emily Marshall, Ravi F. Iyer, Hillary Cleveland-Rubeor, Claire E. Otero, Husam Taher, Nathan H. Vande Burgt, Richard Barfield, Kurt T. Randall, David Morrow, Colette M. Hughes, Andrea N. Selseth, Roxanne M. Gilbride, Julia C. Ford, Patrizia Caposio, Alice Tarantal, Cliburn Chan, Daniel Malouli, Peter A. Barry, Sallie R. Permar, Louis J. Picker, Klaus Frueh
HIV non-progression despite persistent viraemia is rare among antiretroviral therapy (ART)-naïve adults, but relatively common among ART-naïve children. Previous studies indicate that ART-naïve paediatric slow-progressors (PSPs) adopt immune evasion strategies similar to those described in the SIV natural hosts. However, the mechanisms underlying this immunophenotype are not well understood. In a cohort of early-treated infants who underwent analytical treatment interruption (ATI) after 12 months of ART, expression of PD-1 on CD8+ T-cells immediately prior to ATI was the main predictor of slow progression during ATI (r=0.77, p=0.002). PD-1+ CD8+ T-cell frequency was also negatively correlated with CCR5 (r=-0.74, p=0.005) and HLA-DR (r=-0.63, p=0.02) expression on CD4+ T-cells and predicted stronger HIV-specific T-lymphocyte responses. In the CD8+ T-cell compartment of PSPs, we identified an enrichment of stem-like TCF-1+PD-1+ memory cells, whereas paediatric progressors and viraemic adults were populated with a terminally exhausted PD-1+CD39+ population. TCF-1+PD-1+ expression on CD8+ T-cells was associated with higher proliferative activity (r=0.41, p=0.03) and stronger Gag-specific effector functionality. These data prompt the hypothesis that the proliferative burst potential of stem-like HIV-specific cytotoxic cells could be exploited in therapeutic strategies to boost the antiviral response and facilitate remission in early-ART-treated infants with a preserved and non-exhausted T-cell compartment.
Vinicius Adriano Vieira, Nicholas Lim, Alveera Singh, Ellen Leitman, Reena R. D'Souza, Emily Adland, Maximilian Muenchhoff, Julia Roider, Miguel Á. Marín Lopez, Julieta Carabelli, Jennifer Giandhari, Andreas Groll, Pieter Jooste, Julia G. Prado, Christina Thobakgale, Krista Dong, Photini Kiepiela, Andrew J. Prendergast, Gareth Tudor-Williams, John Frater, Bruce D. Walker, Thumbi Ndung'u, Veron Ramsuran, Alasdair Leslie, Henrik N. Kløverpris, Philip Goulder
In spite of the rollout of oral pre-exposure prophylaxis (PrEP), the rate of new HIV infections remains a major health crisis. In the United States, new infections occur predominantly in men having sex with men (MSM) in rural settings where access to PrEP can be limited. As an alternative congruent with MSM sexual behavior, we have optimized and tested tenofovir (TFV) and analog-based iso-osmolar and hypo-osmolar (HOsm) rectal douches for efficacy against rectal simian/human immunodeficiency virus (SHIV) infection of macaques. Single TFV HOsm high-dose douches achieved peak plasma TFV levels similar to daily oral PrEP, while other formulations yielded lower concentrations. Rectal tissue TFV-diphosphate (TFV-DP) concentrations at the portal of virus entry, however, were markedly higher after HOsm douching than daily oral PrEP. Repeated douches led to significantly higher plasma TFV and higher TFV-DP concentrations in rectal tissue at 24 hours compared with single douches, without detectable mucosal or systemic toxicity. Using stringent repeated intrarectal SHIV exposures, single HOsm high-dose douches delivered greater protection from virus acquisition for more than 24 hours compared with oral PrEP. Our results demonstrate a rapid delivery of protective TFV doses to the rectal portal of virus entry as a potential low-cost and safe PrEP alternative.
Peng Xiao, Sanjeev Gumber, Mark A. Marzinke, Thuy Hoang, Rohan Myers, Abhijit A. Date, Justin Hanes, Laura M. Ensign, Lin Wang, Lisa C. Rohan, Richard Cone, Edward J. Fuchs, Craig W. Hendrix, Francois Villinger
A hallmark of HIV-1 infection is chronic inflammation, even in patients treated with antiretroviral therapy (ART). Chronic inflammation drives HIV-1 pathogenesis, leading to loss of CD4+ T cells and exhaustion of antiviral immunity. Therefore, strategies to safely reduce systematic inflammation are needed to halt disease progression and restore defective immune responses. Autophagy is a cellular mechanism for disposal of damaged organelles and elimination of intracellular pathogens. Autophagy is pivotal for energy homeostasis and plays critical roles in regulating immunity. However, how it regulates inflammation and antiviral T cell responses during HIV infection is unclear. Here, we demonstrate that autophagy is directly linked to IFN-I signaling, which is a key driver of immune activation and T cell exhaustion during chronic HIV infection. Impairment of autophagy leads to spontaneous IFN-I signaling, and autophagy induction reduces IFN-I signaling in monocytic cells. Importantly, in HIV-1–infected humanized mice, autophagy inducer rapamycin treatment significantly reduced persistent IFN-I–mediated inflammation and improved antiviral T cell responses. Cotreatment of rapamycin with ART led to significantly reduced viral rebound after ART withdrawal. Taken together, our data suggest that therapeutically targeting autophagy is a promising approach to treat persistent inflammation and improve immune control of HIV replication.
Wenli Mu, Valerie Rezek, Heather Martin, Mayra A. Carrillo, Shallu Tomer, Philip Hamid, Miguel A. Lizarraga, Tristan D. Tibbe, Otto O. Yang, Beth D. Jamieson, Scott G. Kitchen, Anjie Zhen
The HIV latent viral reservoir (LVR) remains a major challenge in the effort to find a cure for HIV. There is interest in lymphocyte-depleting agents, used in solid organ and bone marrow transplantation to reduce the LVR. This study evaluated the LVR and T cell receptor repertoire in HIV-infected kidney transplant recipients using intact proviral DNA assay and T cell receptor sequencing in patients receiving lymphocyte-depleting or lymphocyte-nondepleting immunosuppression induction therapy. CD4+ T cells and intact and defective provirus frequencies decreased following lymphocyte-depleting induction therapy but rebounded to near baseline levels within 1 year after induction. In contrast, these biomarkers were relatively stable over time in the lymphocyte-nondepleting group. The lymphocyte-depleting group had early TCRβ repertoire turnover and newly detected and expanded clones compared with the lymphocyte-nondepleting group. No differences were observed in TCRβ clonality and repertoire richness between groups. These findings suggest that, even with significant decreases in the overall size of the circulating LVR, the reservoir can be reconstituted in a relatively short period of time. These results, while from a relatively unique population, suggest that curative strategies aimed at depleting the HIV LVR will need to achieve specific and durable levels of HIV-infected T cell depletion.
Sarah E. Benner, Yolanda Eby, Xianming Zhu, Reinaldo E. Fernandez, Eshan U. Patel, Jessica E. Ruff, Feben Habtehyimer, Haley A. Schmidt, Charles S. Kirby, Sarah Hussain, Darin Ostrander, Niraj M. Desai, Sander Florman, Meenakshi M. Rana, Rachel Friedman-Moraco, Marcus R. Pereira, Shikha Mehta, Peter Stock, Alexander Gilbert, Michele I. Morris, Valentina Stosor, Sapna A. Mehta, Catherine B. Small, Karthik Ranganna, Carlos A.Q. Santos, Saima Aslam, Jennifer Husson, Maricar Malinis, Nahel Elias, Emily A. Blumberg, Brianna L. Doby, Allan B. Massie, Melissa L. Smith, Jonah Odim, Thomas C. Quinn, Gregory M. Laird, Robert F. Siliciano, Dorry L. Segev, Andrew D. Redd, Christine M. Durand, Aaron A.R. Tobian
HIV-specific chimeric antigen receptor–T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. Paramount to translating such therapeutic candidates successfully into the clinic will require anti-HIV CAR T cells to localize to lymphoid tissues in the body and eliminate reactivated HIV-infected cells such as CD4+ T cells and monocytes/macrophages. Here we show that i.v. injected anti-HIV duoCAR T cells, generated using a clinical-grade anti-HIV duoCAR lentiviral vector, localized to the site of active HIV infection in the spleen of humanized mice and eliminated HIV-infected PBMCs. CyTOF analysis of preinfusion duoCAR T cells revealed an early memory phenotype composed predominantly of CCR7+ stem cell–like/central memory T cells (TSCM/TCM) with expression of some effector-like molecules. In addition, we show that anti-HIV duoCAR T cells effectively sense and kill HIV-infected CD4+ T cells and monocytes/macrophages. Furthermore, we demonstrate efficient genetic modification of T cells from PWH on suppressive ART into anti-HIV duoCAR T cells that subsequently kill autologous PBMCs superinfected with HIV. These studies support the safety and efficacy of anti-HIV duoCAR T cell therapy in our presently open phase I/IIa clinical trial (NCT04648046).
Kim Anthony-Gonda, Alex Ray, Hang Su, Yuge Wang, Ying Xiong, Danica Lee, Ariele Block, Vanessa Chilunda, Jessica Weiselberg, Lily Zemelko, Yen Y. Wang, Sarah Kleinsorge-Block, Jane S. Reese, Marcos de Lima, Christina Ochsenbauer, John C. Kappes, Dimiter S. Dimitrov, Rimas Orentas, Steven G. Deeks, Rachel L. Rutishauser, Joan W. Berman, Harris Goldstein, Boro Dropulić
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