AIDS/HIV
Abstract
We identified a microRNA (miRNA) profile characterizing HIV lipodystrophy and explored the downstream mechanistic implications with respect to adipocyte biology and the associated clinical phenotype. miRNA profiles were extracted from small extracellular vesicles (sEV) of HIV-infected individuals with and without lipodystrophic changes and individuals without HIV, among whom we previously showed significant reductions in adipose Dicer expression related to HIV. miR-20a-3p was increased and miR-324-5p and miR-186 reduced in sEV from HIV lipodystrophic individuals. Changes in these miRNAs correlated with adipose Dicer expression and clinical markers of lipodystrophy, including fat redistribution, insulin resistance, and hypertriglyceridemia. Human preadipocytes transfected with mimic miR-20a-3p, anti-miR-324-5p or anti-miR-186 induced consistent changes in Ltbp2, Wisp2, and Nebl expression. Knockdown of Ltbp2 (Latent-transforming growth factor beta-binding protein 2) downregulated markers of adipocyte differentiation (Fabp4, Pparg, C/ebpa, Fasn, adiponectin, Glut4, CD36), and Lamin C, and increased expression of genes involved in inflammation (IL1β, IL6, and Ccl20). Our studies suggest a unique sEV miRNA signature related to dysregulation of Dicer in adipose in HIV. Enhanced miR-20a-3p or depletion of miR-186 and miR-324-5p may downregulate Ltbp2 in HIV leading to dysregulation in adipose differentiation and inflammation, which could contribute to acquired HIV lipodystrophy and associated metabolic and inflammatory perturbations.
Authors
Suman Srinivasa, Ruben Garcia-Martin, Martin Torriani, Kathleen V. Fitch, Anna R. Carlson, C. Ronald Kahn, Steven K. Grinspoon
Abstract
Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infects epithelial cells of the human gastrointestinal (GI) tract and causes related symptoms. HIV infection impairs gut homeostasis and is associated with an increased risk of COVID-19 fatality. To investigate the potential link between these observations, we analysed single cell transcriptional profiles and SARS-CoV-2 entry receptor expression across lymphoid and mucosal human tissue from chronically HIV infected individuals and uninfected controls. Absorptive gut enterocytes displayed the highest co-expression of SARS-CoV-2 receptors ACE2, TMPRSS2 and TMPRSS4, of which ACE2 expression was associated with canonical interferon response and antiviral genes. Chronic treated HIV infection was associated with a clear antiviral response in gut enterocytes and, unexpectedly, with a significant reduction of ACE2 and TMPRSS2 target cells. Gut tissue from SARS-CoV-2 infected individuals, however, showed abundant SARS-CoV-2 nucleocapsid protein in both the large and small intestine, including an HIV co-infected individual. Thus, upregulation of antiviral response genes and downregulation of ACE2 and TMPRSS2 in the GI tract of HIV infected individuals, does not prevent SARS-CoV-2 infection in this compartment. The impact of these HIV-associated intestinal mucosal changes on SARS-CoV-2 infection dynamics, disease severity and vaccine responses remains unclear and require further investigation.
Authors
Rabiah Fardoos, Osaretin E. Asowata, Nicholas Herbert, Sarah K. Nyquist, Yenzekile Zungu, Alveera Singh, Abigail Ngoepe, Ian M. Mbano, Ntombifuthi Mthabela, Dirhona Ramjit, Farina Karim, Warren Kuhn, Fusi G. Madela, Vukani T. Manzini, Frank Anderson, Bonnie Berger, Tune H. Pers, Alex K. Shalek, Alasdair Leslie, Henrik Kløverpris
Abstract
Historically, naive cells have been considered inconsequential to HIV persistence. Here, we compared the contribution of naive and memory cells to the reservoir of individuals with a spectrum of reservoir sizes and variable immunological control. We performed proviral sequencing of approximately 6000 proviruses from cellular subsets of 5 elite controllers (ECs) off antiretroviral therapy (ART) and 5 chronic progressors (CPs) on ART.The levels of naive infection were barely detectable in ECs and approximately 300-fold lower compared to CPs. Moreover, the ratio of infected naive to memory cells was significantly lower in ECs. Overall naive infection level increased as reservoir size increased such that naive cells were a major contributor to the intact reservoir of CPs, whose reservoirs were generally very diverse. In contrast, the reservoirs of ECs were dominated by proviral clones. Critically, the fraction of proviral clones increased with cell differentiation, with naive infection predicting reservoir diversity. Longitudinal sequencing revealed that the reservoir of ECs was less dynamic compared to CPs. Naive cells play a critical role in HIV persistence. Their infection level predicts reservoir size and diversity. Moreover, the diminishing diversity of the reservoir as cellular subsets mature suggests that naive T cells repopulate the memory compartment and that direct infection of naive T cells occurs in vivo.
Authors
Marilia Rita Pinzone, Sam Weissman, Alexander O. Pasternak, Ryan Zurakowski, Stephen Migueles, Una O'Doherty
Abstract
While antiretroviral therapy suppresses HIV replication, it does not eliminate viral reservoirs or restore damaged lymphoid tissue, posing obstacles to HIV eradication. Using the simian immunodeficiency virus (SIV) model of AIDS, we investigated the effect of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, anti-viral immunity, viral suppression and determined associated molecular/metabolic signatures. MSC administration to SIV-infected macaques resulted in viral reduction and heightened virus-specific responses. Marked clearance of SIV-positive cells from gut mucosal effector sites was correlated with robust regeneration of germinal centers (GC), restoration of follicular B cells, T follicular helper (Tfh) cells, and enhanced antigen presentation by viral trapping within follicular dendritic cell network. Gut transcriptomic analyses showed increased antiviral response mediated by unique pathways of type-I/II IFN signaling, viral restriction factors, innate immunity and B cell proliferation and provided the molecular signature underlying enhanced host immunity. Metabolic analysis revealed strong correlations between B and Tfh cell activation, anti-SIV antibodies, and IL-7 expression with enriched retinol metabolism, which facilitates gut homing of antigen-activated lymphocytes. Our findings discover new MSC functions in modulating anti-viral immunity for enhanced viral clearance predominantly through type-I/II IFN signaling and B cell signature and provide a roadmap for multi-pronged HIV eradication strategies.
Authors
Mariana G. Weber, Chara J. Walters-Laird, Amir Kol, Clarissa Santos Rocha, Lauren A. Hirao, Abigail Mende, Bipin Balan, Juan Arredondo, Sonny R. Elizaldi, Smita S. Iyer, Alice Tarantal, Satya Dandekar
Abstract
BACKGROUND. Identifying a quantitative biomarker of neuropsychiatric dysfunction in people with HIV (PWH) remains a significant challenge in the neuroHIV field. The strongest evidence to date implicates the role of monocytes in central nervous system (CNS) dysfunction in HIV, yet no study has examined monocyte subsets in blood as a correlate and/or predictor of neuropsychiatric function in virally suppressed PWH. METHODS. In two independent cohorts of virologically suppressed women with HIV (vsWWH; n=25 and n=18), whole blood samples were obtained either in conjunction with neuropsychiatric assessments (neuropsychological [NP] test battery, self-report depression and stress-related symptom questionnaires) or one year prior to assessments. Immune cell subsets were assessed by flow cytometry. RESULTS. A higher proportion of intermediate monocytes (CD14+CD16+) was associated with lower global NP function when assessing monocytes concurrently and approximately one year before (predictive) NP testing. The same pattern was seen for executive function (mental flexibility) and processing speed. Conversely, there were no associations with monocyte subsets and depression or stress-related symptoms. Additionally, we found that a higher proportion of classical monocytes was associated with better cognition. CONCLUSION. Although it is widely accepted that lentiviral infection of the CNS targets cells of monocyte-macrophage-microglial lineage, is associated with an increase in intermediate monocytes in the blood and monocyte migration into brain, the percentage of intermediate monocytes in blood of vsWWH has not been associated with neuropsychiatric outcomes. Our findings provide evidence for a new, easily measured blood-based cognitive biomarker in vsWWH. FUNDING. R01-MH113512, R01-MH113512-S, P30-AI094189, R01-MH112391, R01-AI127142, R00-DA044838, U01-AI35004, and P30-MH075673.
Authors
Rebecca T. Veenhuis, Dionna W. Williams, Erin N. Shirk, Celina Monteiro Abreu, Edna A. Ferreira, Jennifer M. Coughlin, Todd T. Brown, Pauline M. Maki, Kathryn Anastos, Joan W. Berman, Janice E. Clements, Leah H. Rubin
Abstract
The foreskin is a site of heterosexual acquisition of HIV-1 among uncircumcised men. However, some men remain HIV-negative despite repeated, unprotected vaginal intercourse with HIV-positive partners, while others become infected after few exposures. The foreskin microbiome includes a diverse group of anaerobic bacteria that have been linked to HIV acquisition. However, these anaerobes tend to coassociate, making it difficult to determine which species might increase HIV risk and which may be innocent bystanders. Here, we show that 6 specific anaerobic bacterial species, Peptostreptococcus anaerobius, Prevotella bivia, Prevotella disiens, Dialister propionicifaciens, Dialister micraerophilus, and a genetic near neighbor of Dialister succinatiphilus, significantly increased cytokine production, recruited HIV-susceptible CD4+ T cells to the inner foreskin, and were associated with HIV acquisition. This strongly suggests that the penile microbiome increases host susceptibility to HIV and that these species are potential targets for microbiome-based prevention strategies.
Authors
Jessica L. Prodger, Alison G. Abraham, Aaron A.R. Tobian, Daniel E. Park, Maliha Aziz, Kelsey Roach, Ronald H. Gray, Lane Buchanan, Godfrey Kigozi, Ronald M. Galiwango, Joseph Ssekasanvu, James Nnamutete, Joseph Kagaayi, Rupert Kaul, Cindy M. Liu
Abstract
HIV-1 is capable of integrating its genome into that of its host cell. We examined the influence of the activation state of CD4+ T-cells, the effect of antiretroviral therapy (ART), and the clinical stage of HIV-1 infection on HIV-1 integration site features and selection. HIV-1 integration sites were sequenced from longitudinally sampled resting and activated CD4+ T-cells from 12 HIV-1 infected individuals. In total, 589 unique HIV-1 integration sites were analyzed: 147, 391, and 51 during primary, chronic, and late presentation of HIV-1 infection, respectively. As early as during primary HIV-1 infection and independent of the activation state of CD4+ T-cells collected on and off ART, HIV-1 integration sites were preferentially detected in recurrent integration genes (RIGs), genes associated with clonal expansion of latently HIV-1 infected CD4+ T-cells, cancer related genes, and highly expressed genes. The preference for cancer related genes was more pronounced at late stages of HIV-1 infection. Host genomic features of HIV-1 integration site selection remained stable during the course of HIV-1 infection in both resting and activated CD4+ T-cells. In summary, characteristic HIV-1 integration site features are pre-established as early as during primary HIV-1 infection and are found in both resting and activated CD4+ T-cells.
Authors
Yik Lim Kok, Valentina Vongrad, Sandra E. Chaudron, Mohaned Shilaih, Christine Leemann, Kathrin Neumann, Katharina Kusejko, Francesca Di Giallonardo, Herbert Kuster, Dominique L. Braun, Roger D. Kouyos, Huldrych F. Günthard, Karin J. Metzner
Abstract
Chronic inflammation and immune dysfunction play a key role in the development of non-AIDS related comorbidities. The aim of our study was to characterize the functional phenotype of immune cells in people living with HIV (PLHIV). We enrolled a cross-sectional cohort study of PLHIV on stable antiretroviral therapy and healthy controls. We assessed ex vivo cytokine production capacity and transcriptomics of monocytes and T-cells upon bacterial, fungal and viral stimulation. PLHIV exhibited an exacerbated pro-inflammatory profile in monocyte-derived cytokines, but not in lymphocyte-derived cytokines. Particularly, the production of the IL-1β to imiquimod, E. coli LPS and Mycobacterium tuberculosis was increased, and this production correlated with plasma concentrations of hsCRP and sCD14. This increase in monocyte responsiveness remained stable over time in subsequent blood sampling after >1year. Transcriptome analyses confirmed priming of the monocyte IL-1β pathway, consistent with a monocyte trained immunity phenotype. Increased plasma concentrations of β-glucan, a well-known inducer of trained immunity, were associated with increased innate cytokine responses. Monocytes of PLHIV exhibit a sustained pro-inflammatory immune phenotype with priming of the IL-1β pathway. Training of the innate immune system in PLHIV likely plays a role in long-term HIV complications and provides a promising therapeutic target for inflammation-related comorbidities.
Authors
Wouter A. van der Heijden, Lisa van de Wijer, Farid Keramati, Wim Trypsteen, Sofie Rutsaert, Rob ter Horst, Martin Jaeger, Hans J.P.M. Koenen, Hendrik G. Stunnenberg, Irma Joosten, Paul E. Verweij, Jan van Lunzen, Charles A. Dinarello, Leo A.B. Joosten, Linos Vandekerckhove, Mihai G. Netea, André J. van der Ven, Quirijn de Mast
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with CCR5– donor cells is the only treatment known to cure HIV-1 in patients with underlying malignancy. This is likely due to a donor cell–mediated graft-versus-host effect targeting HIV reservoirs. Allo-HSCT would not be an acceptable therapy for most people living with HIV due to the transplant-related side effects. Chimeric antigen receptor (CAR) immunotherapies specifically traffic to malignant lymphoid tissues (lymphomas) and, in some settings, are able to replace allo-HSCT. Here, we quantified the engraftment of HSC-derived, virus-directed CAR T cells within HIV reservoirs in a macaque model of HIV infection, using potentially novel IHC assays. HSC-derived CAR cells trafficked to and displayed multilineage engraftment within tissue-associated viral reservoirs, persisting for nearly 2 years in lymphoid germinal centers, the brain, and the gastrointestinal tract. Our findings demonstrate that HSC-derived CAR+ cells reside long-term and proliferate in numerous tissues relevant for HIV infection and cancer.
Authors
Isaac M. Barber-Axthelm, Valerie Barber-Axthelm, Kai Yin Sze, Anjie Zhen, Gajendra W. Suryawanshi, Irvin S.Y. Chen, Jerome A. Zack, Scott G. Kitchen, Hans-Peter Kiem, Christopher W. Peterson
Abstract
Antiretroviral therapies (ART) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which re-seed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T-cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time, and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T-cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.
Authors
Eva M. Stevenson, Adam R. Ward, Ronald Truong, Allison S. Thomas, Szu-Han Huang, Thomas R. Dilling, Sandra Terry, John K. Bui, Talia M. Mota, Ali Danesh, Guinevere Q. Lee, Andrea Gramatica, Pragya Khadka, Winiffer D. Conce Alberto, Rajesh T. Gandhi, Deborah K. McMahon, Christina M. Lalama, Ronald J. Bosch, Bernard J. Macatangay, Joshua C. Cyktor, Joseph J. Eron, John W. Mellors, R. Brad Jones
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