AIDS/HIVs
Abstract
HIV-1 infection is characterized by a strong inflammatory environment, tissue disruption, and a progressive decline in CD4+ T cell count. Despite treatment with antiretroviral therapy (ART), the majority of persons living with HIV (PLWH) maintain residual levels of inflammation, low degree of immune activation, and higher sensitivity to cell death in their memory CD4+ T-cell compartment. To date, the mechanisms responsible for this high sensitivity remain elusive. We have identified the transcription factor IRF-5 to be involved in impairing the maintenance of murine CD4+ T cells in a chronic inflammatory environment. Here, we investigate whether IRF-5 also contributes to memory CD4+ T cell loss during HIV-1 infection. We show that TLR7 and IRF-5 were upregulated in memory CD4+ T cells from PLWH, when compared with naturally protected elite controllers and HIVfree participants. TLR7 was upstream of IRF-5, promoting Caspase 8 expression in CD4+ T cells from ART HIV-1+ but not from HIVfree participants. Moreover, IRF-5 and TLR7 expression inversely correlated with CD4+ T cell counts in primary HIV infection. Interestingly, the TLR7-IRF-5 axis acted synergistically with the Fas/FasL pathway, suggesting that TLR7 and IRF-5 expression in ART HIV-1+ memory CD4+ T cells represents an imprint that predisposes cells to Fas-mediated apoptosis. This predisposition could be blocked using IRF-5 inhibitory peptides. Thus, we propose IRF-5 blockade as a possible therapy to prevent memory CD4+ T cell loss in PLWH.
Authors
Liseth Carmona-Perez, Xavier Dagenais-Lussier, Linh Thuy Mai, Tanja Stögerer, Sharada Swaminathan, Stephane Isnard, Matthew R. Rice, Betsy J. Barnes, Jean Pierre Routy, Julien van Grevenynghe, Simona Stager
Abstract
The RV144 phase III vaccine trial demonstrated that ALVAC-HIV and AIDSVAX B/E administration over 6 months resulted in 31% efficacy in preventing HIV acquisition, while administration of AIDSVAX B/E alone in both VAX003 and VAX004 studies failed to show efficacy. In this study, we aimed to understand the impact of ALVAC-HIV on the development of cellular, humoral, and functional immune responses compared to the administration of AIDSVAX B/E alone. ALVAC-HIV in combination with 3 doses of AIDSVAX B/E significantly increased CD4+ HIV-specific T cell responses, polyfunctionality, and proliferation compared with 3 doses of AIDSVAX B/E alone. Additionally, Env-specific plasmablasts and A244-specific memory B cells were identified with a significantly higher magnitude in the group that received ALVAC-HIV. Subsequently, data revealed increased magnitude of plasma IgG binding to and avidity for HIV Env in participants who received ALVAC-HIV compared with 3 doses of AIDSVAX B/E alone. Lastly, levels of the Fc-mediated effector functions antibody-dependent cellular cytotoxicity, NK cell activation, and trogocytosis were significantly increased in participants who received ALVAC-HIV compared with those receiving AIDSVAX B/E alone. Taken together, these results suggest that ALVAC-HIV plays an essential role in developing cellular and humoral immune responses to protein-boosted regimens relative to protein alone.
Authors
Margaret C. Costanzo, Dominic Paquin-Proulx, Alexandra Schuetz, Siriwat Akapirat, Zhanna Shubin, Dohoon Kim, Lindsay Wieczorek, Victoria R. Polonis, Hung V. Trinh, Mangala Rao, Hanna Anenia, Michael D. Barrera, Jacob Boeckelman, Barbara Nails, Pallavi Thapa, Michelle Zemil, Carlo Sacdalan, Eugene Kroon, Boot Kaewboon, Somporn Tipsuk, Surat Jongrakthaitae, Sanjay Gurunathan, Faruk Sinangil, Jerome H. Kim, Merlin L. Robb, Julie A. Ake, Robert J. O’Connell, Punnee Pitisutthithum, Sorachai Nitayaphan, Suwat Chariyalertsak, Michael A. Eller, Nittaya Phanuphak, Sandhya Vasan, the RV306, RV328 study groups
Abstract
Biological sex and host genetics influence HIV pathogenesis. Females have a higher likelihood of spontaneous viral control and lower setpoint viral load (spVL). No prior studies have assessed sex-specific genetics of HIV. To address this, we performed a sex stratified genome-wide association study using data from the International Collaboration for the Genomics of HIV. Although it is the largest collection of genomic data in HIV, this multi-ethnic sample of 9,705 people is 81.3% male. We sought to identify sex-specific genetic variants and genes associated with HIV spVL and control. We confirmed associations in the HLA and CCR5 regions in males, and HLA in females. Gene-based analyses detected associations between HIV spVL and PET100 (Pvalue=8.36x10-07), PCP2 (Pvalue=8.81x10-07), XAB2 (Pvalue=1.32x10-6) and STXBP2 (Pvalue=1.65x10-4) only in males. We detected variants with a significant sex-differential effect on spVL in SDC3 and PUM1 (rs10914268,Pvalue=1.93x10-08) and PSORS1C2 (rs1265159, Pvalue=3.26x10-08) and on HIV control in SUB1 (rs687659, Pvalue=1.02×10-08), AL158151.3, PTPA and IER5L (rs4387067, Pvalue=2.07×10-09). Those variants have epigenetic and genetic interactions with relevant genes with both cis and trans effects. In summary, we identified sex-shared associations at the single variant level, sex-specific associations at the gene-based level, and genetic variants with significant differential effects between the sexes.
Authors
Candelaria Vergara, Jeffrey F. Tuff, International Collaboration for the Genomics of HIV, Jacques Fellay, Priya Duggal, Eileen P. Scully, Paul J. McLaren
Abstract
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.
Authors
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
Abstract
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.
Authors
Lakmini S. Premadasa, Eunhee Lee, Marina McDew-White, Xavier Alvarez, Sahana Jayakumar, Binhua Ling, Chioma M. Okeoma, Siddappa N. Byrareddy, Smita Kulkarni, Mahesh Mohan
Abstract
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.
Authors
Yuhao Li, Hongbo Gao, Kolin M. Clark, Liang Shan
Abstract
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.
Authors
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
Abstract
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.
Authors
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
Abstract
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.
Authors
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
Abstract
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.
Authors
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
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