AIDS/HIV
Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death globally. Despite wide use of antiretroviral therapy (ART) by people living with HIV, the risk of TB remains increased. To understand immune interactions within lung granulomas, we compared spatial transcriptomics of Mtb and simian immunodeficiency virus (SIV) in co-infected macaques with or without ART as a model for HIV/Mtb co-infection. Spatially differentiated transcriptional profiles were observed in Mtb-only granulomas, with myeloid cells enriched in metabolic/antimicrobial pathways within the inner ring and T cell co-stimulatory/activation pathways enriched in the outer ring. These spatially distinct patterns were lost in SIV/Mtb granulomas with higher enrichment in type I IFN pathways compared to Mtb-only granulomas. SIV/ART/Mtb granulomas had an intermediate transcriptional pattern without restoration to Mtb-only granulomas, despite a lack of viral replication. Cell-cell communication was reduced among SIV/Mtb co-infected groups. These data suggest that HIV disrupts spatially organized immune functions of granulomas, which are not fully restored by ART.
Authors
Jessica M. Medrano, Persis Sunny, Collin R. Diedrich, Pauline Maiello, Christopher Kline, Tara Rutledge, Edwin Klein, Joshua T. Mattila, Jishnu Das, Zandrea Ambrose, Philana Ling Lin
Abstract
Early antiretroviral therapy (ART) limits viral reservoir establishment in infants but also constrains viral-specific immunity required to clear reactivated cells. In the early ART context, we evaluated whether combining adeno-associated virus serotype 9 (AAV9)–vectored eCD4-IgG1 with pharmacologic latency reversal using the second mitochondria-derived activator of caspases (SMAC) mimetic AZD5582 could promote reservoir reduction and control in simian immunodeficiency virus (SIV)–infected infant macaques. AAV9 delivery achieved sustained eCD4-IgG1 expression and AZD5582 induced on-ART viremia, but the combination did not reduce intact SIV proviral DNA relative to controls. Partial post-intervention control of viremia during Analytical Treatment Interruption (ATI) occurred in 2/6 infants receiving AAV9-eCD4-IgG1 + AZD5582 with restricted reservoir expansion during recrudescence at week 13. Intact reservoir size during ATI correlated inversely with on-ART viremia during AZD5582 treatment. Controllers did not show increased eCD4-IgG1 expression nor increased on-ART viremia during AZD5582 treatment, but harbored less pre-ART intact SIV DNA in PBMCs than non-controllers. Controllers also exhibited higher frequencies and greater polyfunctionality of virus-specific CD8+ T-cells prior to ATI. These findings implicate immune control of reservoir size and post-ART viral dynamics in early-treated infants and suggest that AAV9-eCD4-IgG1 + AZD5582 increases the likelihood of post-ART viral control.
Authors
Jairo A. Fonseca, Alexis C. King, Kaleaha S. Davis, Daniel O'Hagan, Adrian Khoei, Lucas Alves Britto Da Costa, Camryn Cockerham, Mackenzie Cottrell, Stephanie Ehnert, Jennifer S. Wood, Michael D. Alpert, Matthew R. Gardner, Jeffrey D. Lifson, Maud Mavigner, Mauricio A. Martins, Ann Chahroudi
Abstract
Rationale: Persistent monocyte activation contributes to HIV-associated neurocognitive disorders (HAND), yet biomarkers that predict neurocognitive impairment before and after antiretroviral therapy (ART) remain incompletely defined. Objectives: We evaluated monocyte subsets and activation markers in participants from the SEARCH007 cohort prior to ART initiation and at 6 and 12 months following treatment. Methods and Results: Increased frequencies of CD14+CD16+ monocytes and elevated CD163 expression were associated with worsening neurocognitive performance and HAND severity. Plasma soluble CD163 levels increased with neurocognitive impairment and correlated with plasma HIV RNA levels, while CCR2 expression was associated with NPZ Global scores. Notably, CD169 expression was elevated across all monocyte subsets and demonstrated a stepwise increase with worsening neurocognitive impairment. Although ART reduced overall monocyte activation, elevated CD169 expression persisted in some individuals despite virologic suppression. Bayesian kernel machine regression and random forest analyses identified CD169 expression as one of the strongest predictors of cognitive impairment, surpassing plasma viral load, CD4+ T-cell count, and several established monocyte activation markers. Conclusions: These findings identify monocyte CD169 expression as a biomarker of neurocognitive dysfunction before and during the first year of ART and support further investigation of its role in HAND pathogenesis.
Authors
Hai Duc Nguyen, Andrew K. Ding-Su, Caroline Soulas, Tricia H. Burdo, Patrick Autissier, Pasiri Sithinamsuwan, Nitiya Chomchey, Jintanat Ananworanich, Victor Valcour, Silvia Ratto-Kim, Woong-Ki Kim, Kenneth C. Williams
Abstract
Mycobacteriumtuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection in people living with HIV-1 (PLWH). This coinfection is associated with accelerated HIV-1 disease progression and reduced survival. However, the immunological and virological mechanisms driving this progression are not completely understood. To address this knowledge gap, using pleural effusion samples from PLWH and TB, we investigated how the HIV-1 genetic landscape and the anti-HIV-1 immune response are impacted by a TB-associated microenvironment. Our results revealed an enrichment of genetically intact HIV-1 and impaired CD8+ T cell-mediated antiviral response at this site of HIV-1/Mtb coinfection. Moreover, efficient CD8+ T cell activation was inhibited by lipids present in the TB-associated pleural effusion. These findings indicate that this immune microenvironment induced by TB promotes the persistence of cells infected with replication-competent HIV-1 by creating a niche of reduced antiviral immune pressure, potentially contributing to the worsened clinical outcomes observed in PLWH and TB.
Authors
Samantha Cronin, Jennifer Simpson, Andrea Pereyra-Casanova, Yuchen Li, Josefina Marín-Rojas, Freja A. Warner van Dijk, Katie Fisher, Daniel J. Buffa, Hafsa Rana, Zoï Vahlas, Joaquina Barros, Mariano Maio, Thomas R. O'Neil, Kirstie M. Bertram, Eunok Lee, Najla Nasr, Andrew N. Harman, Gabriela Turk, Maria Florencia Quiroga, Anthony D. Kelleher, Christel Vérollet, Luciana Balboa, Sarah Palmer, Gabriel Duette
Abstract
Serious non-AIDS events (SNAEs), including non-AIDS malignancies, cardiovascular disease, and hepatic complications, remain major causes of mortality in treated HIV infection. These outcomes are driven by persistent immune activation, systemic inflammation, and metabolic dysfunction despite effective viral suppression with antiretroviral therapy (ART). To investigate mechanisms underlying SNAE pathogenesis, we performed a cross-site multi-omic analysis integrating plasma proteins, plasma metabolites, and mucosal microbiomes in 82 ART-treated people with HIV (PWH) and 10 people without HIV from the United States and Mexico. Geography was the dominant source of variation, particularly across lipid classes. However, individuals at high risk for SNAEs, defined by low CD4+ T cell counts and low CD4/CD8 ratios, shared a consistent signature of systemic inflammation, mitochondrial dysfunction, and microbial dysbiosis, including elevated plasma IL-6 and ω-oxidation products (adipic and suberic acids) and depletion of short-chain fatty acid–producing commensals in the gut mucosa, including Akkermansia muciniphila, Bacteroides uniformis, and Ruminococcus. A. muciniphila abundance correlated with lower IL-6 levels, fewer HIV RNA-producing cells in lymph nodes, and higher CD4/CD8 ratios. These findings identify a shared inflammatory and metabolic phenotype in PWH and implicate A. muciniphila as a potential microbiome-based target to mitigate immune activation and SNAE risk in treated HIV.
Authors
Christopher M. Basting, Jodi Anderson, Kevin Escandón, Garritt Wieking, Candace Guerrero, Jarrett Reichel, Ross T. Cromarty, Erik Swanson, Ty Schroeder, Elaina Creagan, Maura Barrett, Fernanda Torres-Ruiz, Maribel Soto-Nava, Lady Carvajal-Ruiz, Karla Krystel Ordaz-Candelario, Olivia Briceño, Nicholas Funderburg, Melanie Graham, Peter Hunt, Santiago Avila-Rios, Gonzalo Salgado Montes de Oca, Timothy W. Schacker, Nichole R. Klatt
Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in HIV-1 Infection
Abstract
The role of aromatic gut-derived bacterial metabolites (GDBMs) in shaping immune cell metabolism and function remains poorly explored. Using ex vivo metabolomic profiling of paired plasma and CD4⁺ T-cells from people living with HIV-1 (PLWH), we identified a network of aromatic GDBMs whose cell-associated abundance, rather than systemic levels, was linked to broad alterations in CD4⁺ T-cell metabolic and functional states. Among these, p-cresol sulfate (PCS) emerged as a mechanistic prototype. Ex vivo flow cytometry and single-cell RNA sequencing of CD4⁺ T-cells stratified by cell-associated PCS levels revealed dose-dependent enrichment of transcriptional programs associated with impaired differentiation, regulatory-like identity, and cellular senescence. In vitro transcriptomic and proteomic analyses of PCS-exposed CD4⁺ T cells demonstrated induction of cell-cycle arrest, mitochondrial dysfunction, and senescence-associated programs, including upregulation of p16 and p21. Integration of these immunometabolic findings with HIV-1 reservoir measurements revealed that CD4⁺ T-cell states defined by cell-associated GDBMs track with intact proviral DNA levels in vivo. These findings define a microbiome-derived axis that reshapes CD4⁺ T-cell metabolism and fate, promotes immune aging in PLWH, and may foster immunometabolic states linked to long-term HIV-1 reservoir persistence.
Authors
Amanda Cabral da Silva, Luke Flantzer, Jaclyn Weinberg, Shuya Kyu, Lisa P. Daley-Bauer, Anyce Godoy, Ana Carolina Santana, Aarthi Talla, Amber Rittgers, Sarah Welbourn, David E. Gordon, Jeffrey A. Tomalka, Vincent C. Marconi, Dean P. Jones, Souheil-Antoine Younes
Abstract
Myeloid-Derived Suppressor Cells (MDSCs) represent a heterogeneous population of immature myeloid cells with potent immunosuppressive capabilities that contribute to viral persistence in chronic infections. However, their direct impact on the latent HIV reservoir remains poorly understood. Here, we report that people with HIV (PWH) exhibit elevated levels of MDSCs with notable immunosuppressive activity. Both granulocytic (G-MDSCs) and monocytic (M-MDSCs) subsets expressing arginase 1 (ARG1) or indoleamine 2,3-dioxygenase (IDO) are increased during treated infection, with low-level viral transcription preferentially associated with the expansion of highly suppressive G-MDSCs. Functional assays revealed that G-MDSCs robustly inhibit HIV reactivation from latent reservoirs. Mechanistically, G-MDSCs mediate this inhibition through a contact-independent mechanism, primarily involving ARG1 activity. Our findings demonstrate the capacity of G-MDSCs to sustain HIV reservoirs, suggesting that targeting these cells could potentiate therapeutic strategies aimed at eliminating HIV reservoirs through viral reactivation.
Authors
Ana Gallego-Cortés, Judith Grau-Expósito, Irene Mota-Gómez, Aleix Benitez-Martinez, Josep Castellvi, Jordi Navarro, Adrian Curran, Joaquin Burgos, Paula Suanzes, Vicenç Falcó, Meritxell Genescà, Maria J. Buzon
Abstract
The estrogen receptor is hypothesized to directly influence HIV-transcription and latency but is also critical for immune signaling. However, the mechanisms of action of the estrogen receptor (ER) in immune cells in the context of HIV are limited, and relevant to HIV cure strategies, the influence of latency reversal agents (LRAs) on the ER pathway are unknown. We evaluated a) the impact of estrogen (E2) on the nuclear translocation of estrogen receptor α (ERα) in CD4+ T cells, b) the ability of Fulvestrant, a selective estrogen receptor degrader (SERD), and ARV-471, a novel, potent, PROteolysis TArgeting Chimera (PROTAC) selective ERα degrader to modulate ER and c) the impact of different classes of LRAs on ER signaling. In contrast to what has been demonstrated in oncology, E2 does not induce ERα nuclear translocation in CD4+ T cells. Similarly, neither Fulvestrant nor ARV-471 induced degradation of ERα in CD4+ T cells. LRAs significantly downregulated ERα gene and protein expression in both PBMCs and CD4+ T cells. Collectively, our results suggest that estrogen influences on HIV transcription are not likely a consequence of canonical nuclear ERα mechanisms. The consequences of LRA downregulation of ER, a protein important for immune signaling, warrants further investigation.
Authors
Cristina Ceriani, Priya Khetan, Anthony Abeyta-Lopez, Kena J. Lemu, Prachi Meher, Brigitte Allard, Katherine S. James, Anne-Marie W. Turner, David M. Margolis, Nancie M. Archin
Abstract
BACKGROUND. Despite antiretroviral therapy (ART), people with HIV (PWH) are at heightened risk for insulin resistance (IR) and type 2 diabetes (T2D). Subcutaneous adipose tissue (SAT) fibrosis contributes to metabolic disease, but its role in IR among PWH is unknown. We investigated the relationship between SAT fibrosis and IR in PWH, along with transcriptional signatures to distinguish it from SAT fibrosis due to obesity. METHODS. We analyzed body composition and SAT fibrosis (hydroxyproline) in 46 PWH and 74 people without HIV (PWoH), excluding individuals with T2D. We examined fibrosis-related gene transcription in the SAT using a targeted panel and measured plasma endotrophin, a marker of extracellular matrix (ECM) remodeling. RESULTS. PWH had substantially more SAT fibrosis than PWoH, notably in non-obese individuals. Moreover, SAT fibrosis in these PWH was strongly associated with IR, independently of prior legacy ART or ongoing integrase strand inhibitor treatment. This SAT fibrosis was highlighted by a distinct transcriptional pattern marked by upregulation of COL14A1, key immune-related genes (e.g., CCL4, NLRP3), and pathways governing ECM remodeling and immune activation, as well as downregulation of thermogenic, lipid metabolic, and insulin signaling pathways. Plasma endotrophin levels were also elevated in PWH and correlated independently with SAT fibrosis. CONCLUSION. SAT fibrosis was associated with IR independent of obesity in PWH and was mirrored by circulating endotrophin levels, offering a plausible noninvasive biomarker for early intervention. The distinct transcriptional signature of HIV-associated SAT fibrosis highlights candidate mechanisms that may underlie metabolic risk and offer therapeutic avenues in this population.
Authors
Diana L. Alba, Alaa Abdellatif, Moon K. Choi, Stephen M. Brown Mayfield, Thuy An T. Pham, David I. Berrios, Antonio E. Rodriguez, Marin Ewing, Tony R. Figueroa, Judy Gonzalez-Vargas, Ningyan Zhang, Zhiqiang An, Dawei Bu, Steven G. Deeks, Philipp E. Scherer, Peter W. Hunt, Suneil K. Koliwad
Abstract
Virally suppressed people with HIV (PWH) remain at risk for developing comorbidities due to chronic inflammation with one potential contributor being the HIV reservoir. Associations between the CD4-reservoir and inflammation have been extensively characterized, while the role the monocyte-reservoir is poorly understood despite evidence that inflammatory monocytes play a role in HIV-associated comorbidities. Additionally, most studies focus on a single cellular reservoir, while it is highly likely that these reservoirs are interdependent. In a cohort of 164 PWH, we used the intact proviral DNA assay to quantify cell-specific reservoirs, applied unsupervised clustering to identify reservoir phenotypes, and then determined if reservoir phenotypes were associated with distinct immune signatures compared to people without HIV. Five unique reservoir clusters emerged driven primarily by variability in the monocyte reservoir, and each associated with a distinct immune landscape. These included profiles characterized by systemic inflammation, leukocyte–vascular activation, T cell activation with vascular and neuronal injury, enhanced CD8 activation and NK cell recovery, and altered monocyte survival, activation, and migration. This multidimensional approach provides a framework to identify reservoir-immune profiles that may explain heterogeneity in inflammation despite viral suppression and may inform strategies to mitigate HIV-associated comorbidities.
Authors
Ruoyu Wang, Aparna B. Bhattacharyya, Lily Pohlenz, Erin N. Shirk, Hayley S. Romero, Katherine Haas, Jennifer M. Coughlin, Raha M. Dastgheyb, Leah H. Rubin, Rebecca T. Veenhuis
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