The central nervous system HIV reservoir is incompletely understood and is a major barrier to HIV cure. We profiled people with HIV (PWH) and uninfected controls through single-cell transcriptomic and T cell receptor (TCR) sequencing to understand the dynamics of HIV persistence in the CNS. In PWH on ART, we found that most participants had single cells containing HIV-1 RNA, which was found predominantly in CD4 central memory T cells, in both cerebrospinal fluid (CSF) and blood. HIV-1 RNA–containing cells were found more frequently in CSF than blood, indicating a higher burden of reservoir cells in the CNS than blood for some PWH. Most CD4 T cell clones containing infected cells were compartment specific, while some (22%) — including rare clones with members of the clone containing detectable HIV RNA in both blood and CSF — were found in both CSF and blood. These results suggest that infected T cells trafficked between tissue compartments and that maintenance and expansion of infected T cell clones contributed to the CNS reservoir in PWH on ART.
Meng Wang, Jennifer Yoon, Hailey Reisert, Bibhuprasad Das, Benjamin Orlinick, Jennifer Chiarella, Elias K. Halvas, John Mellors, Alina P.S. Pang, Lydia Aoun Barakat, Margaret Fikrig, Joshua Cyktor, Yuval Kluger, Serena Spudich, Michael J. Corley, Shelli F. Farhadian
BACKGROUND Broadly neutralizing monoclonal antibodies (bNAbs) represent a promising strategy for HIV-1 immunoprophylaxis and treatment. 10E8VLS and VRC07-523LS are bNAbs that target the highly conserved membrane-proximal external region (MPER) and the CD4-binding site of the HIV-1 viral envelope glycoprotein, respectively.METHODS In this phase 1, open-label trial, we evaluated the safety and pharmacokinetics of 5 mg/kg 10E8VLS administered alone, or concurrently with 5 mg/kg VRC07-523LS, via s.c. injection to healthy non–HIV-infected individuals.RESULTS Eight participants received either 10E8VLS alone (n = 6) or 10E8VLS and VRC07-523LS in combination (n = 2). Five (n = 5 of 8, 62.5%) participants who received 10E8VLS experienced moderate local reactogenicity, and 1 participant (n = 1/8, 12.5%) experienced severe local reactogenicity. Further trial enrollment was stopped, and no participant received repeat dosing. All local reactogenicity resolved without sequelae. 10E8VLS retained its neutralizing capacity, and no functional anti-drug antibodies were detected; however, a serum t1/2 of 8.1 days was shorter than expected. Therefore, the trial was voluntarily stopped per sponsor decision (Vaccine Research Center, National Institute of Allergy and Infectious Diseases [NIAID], NIH). Mechanistic studies performed to investigate the underlying reason for the reactogenicity suggest that multiple mechanisms may have contributed, including antibody aggregation and upregulation of local inflammatory markers.CONCLUSION 10E8VLS resulted in unexpected reactogenicity and a shorter t1/2 in comparison with previously tested bNAbs. These studies may facilitate identification of nonreactogenic second-generation MPER-targeting bNAbs, which could be an effective strategy for HIV-1 immunoprophylaxis and treatment.TRIAL REGISTRATION Clinicaltrials.gov, accession no. NCT03565315.FUNDING Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.
Seemal F. Awan, Amarendra Pegu, Larisa Strom, Cristina A. Carter, Cynthia S. Hendel, LaSonji A. Holman, Pamela J. Costner, Olga Trofymenko, Renunda Dyer, Ingelise J. Gordon, Ro Shauna S. Rothwell, Somia P. Hickman, Michelle Conan-Cibotti, Nicole A. Doria-Rose, Bob C. Lin, Sarah O’Connell, Sandeep R. Narpala, Cassandra G. Almasri, Cuiping Liu, Sungyoul Ko, Young D. Kwon, Aryan M. Namboodiri, Janardan P. Pandey, Frank J. Arnold, Kevin Carlton, Jason G. Gall, Peter D. Kwong, Edmund V. Capparelli, Robert T. Bailer, Adrian B. McDermott, Grace L. Chen, Richard A. Koup, John R. Mascola, Emily E. Coates, Julie E. Ledgerwood, Martin R. Gaudinski, the VRC 610 study team
People with HIV (PWH) have a higher age-adjusted mortality due to chronic immune activation and age-related comorbidities. PWH also have higher rates of clonal hematopoiesis (CH) than age-matched non-HIV cohorts, however, risk factors influencing the development and expansion of CH in PWH remain incompletely explored. We investigated the relationship between CH, immune biomarkers, and HIV-associated risk factors (CD4, CD8 T-cells, nadir CD4 count, opportunistic infections [OIs], and immune reconstitution inflammatory syndrome [IRIS]) in a diverse cohort of 197-PWH with median age of 42-years, using a 56-gene panel. Seventy-nine percent had a CD4 nadir < 200, 58.9% had prior OIs, and 34.5% had a history of IRIS. The prevalence of CH was high (27.4%), even in younger individuals, and CD8 T-cells and nadir CD4 counts strongly associated with CH after controlling for age. A history of IRIS was associated with CH in a subgroup analysis of ≥ 35-years-old patients. Inflammatory biomarkers were higher in CH carriers compared to non-carriers supporting a dysregulated immune state. These findings suggest PWH with low nadir CD4 and/or inflammatory complications may be at high risk of CH regardless of age and represent a high-risk group that could benefit from risk reduction and potentially targeted immunomodulation.
Joseph M. Rocco, Yifan Zhou, Nicholas S. Liu, Elizabeth Laidlaw, Frances Galindo, Megan V. Anderson, Adam Rupert, Silvia Lucena Lage, Ana M. Ortega-Villa, Shiqin Yu, Andrea Lisco, Maura Manion, George S. Vassiliou, Cynthia E. Dunbar, Irini Sereti
Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly influence immune cell function and differentiation, including NK cell responses. Persistent HIV-1 infection leads to a state of chronic immune activation, NK cell subset redistribution, and progressive NK cell dysregulation. In this study, we examined the metabolic processes that characterize NK cell subsets in HIV-1 infection, including adaptive NK cell subpopulations expressing the activating receptor NKG2C, which expand during chronic infection. These adaptive NK cells exhibit an enhanced metabolic profile in HIV-1– individuals infected with human cytomegalovirus (HCMV). However, the bioenergetic advantage of adaptive CD57+NKG2C+ NK cells is diminished during chronic HIV-1 infection, where NK cells uniformly display reduced oxidative phosphorylation (OXPHOS). Defective OXPHOS was accompanied by increased mitochondrial depolarization, structural alterations, and increased DRP-1 levels promoting fission, suggesting that mitochondrial defects are restricting the metabolic plasticity of NK cell subsets in HIV-1 infection. The metabolic requirement for the NK cell response to receptor stimulation was alleviated upon IL-15 pretreatment, which enhanced mammalian target of rapamycin complex 1 (mTORC1) activity. IL-15 priming enhanced NK cell functionality to anti-CD16 stimulation in HIV-1 infection, representing an effective strategy for pharmacologically boosting NK cell responses.
Elia Moreno-Cubero, Aljawharah Alrubayyi, Stefan Balint, Ane Ogbe, Upkar S. Gill, Rebecca Matthews, Sabine Kinloch, Fiona Burns, Sarah L. Rowland-Jones, Persephone Borrow, Anna Schurich, Michael Dustin, Dimitra Peppa
BACKGROUND Identifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODS We performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTS Compared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre–treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSION The results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATION ClinicalTrials.gov NCT03001128FUNDING NIH National Institute of Allergy and Infectious Diseases, Merck
Jonathan Z. Li, Meghan Melberg, Autumn Kittilson, Mohamed Abdel-Mohsen, Yijia Li, Evgenia Aga, Ronald J. Bosch, Elizabeth R. Wonderlich, Jennifer Kinslow, Leila B. Giron, Clara Di Germanio, Mark Pilkinton, Lynsay MacLaren, Michael Keefer, Lawrence Fox, Liz Barr, Edward Acosta, Jintanat Ananworanich, Robert Coombs, John Mellors, Steven Deeks, Rajesh T. Gandhi, Michael Busch, Alan Landay, Bernard Macatangay, Davey M. Smith, for the AIDS Clinical Trials Group A5345 Study Team
BACKGROUND Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.METHODS This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible.RESULTS Seventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication.CONCLUSION The unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options.FUNDING US National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.
Carolina Caro-Vegas, Alice Peng, Angelica Juarez, Allison Silverstein, William Kamiyango, Jimmy Villiera, Casey L. McAtee, Rizine Mzikamanda, Tamiwe Tomoka, Erin C. Peckham-Gregory, Razia Moorad, Carrie L. Kovarik, Liane R. Campbell, Parth S. Mehta, Peter N. Kazembe, Carl E. Allen, Michael E. Scheurer, Nmazuo W. Ozuah, Dirk P. Dittmer, Nader Kim El-Mallawany
IL-15 is under clinical investigation towards the goal of curing HIV infection, due to its abilities to reverse HIV latency and enhance immune effector function. However, increased potency through combination with other agents may be needed. 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhances IL-15-mediated latency reversal and NK function, by increasing STAT5 activation. We hypothesized that HODHBt would also synergize with IL-15, via STAT5, to directly enhance HIV-specific cytotoxic T-cell responses. We show that ex vivo IL-15+HODHBt treatment markedly enhances HIV-specific granzyme B-releasing T-cell responses in PBMCs from ARV-suppressed donors. We also observed upregulation of antigen processing and presentation in CD4+ T-cells, and increased surface MHC-I. In ex vivo PBMCs, IL-15+HODHBt was sufficient to reduce intact proviruses in 1 of 3 ARV-suppressed donors. Our findings reveal the potential for 2nd-generation IL-15 studies incorporating HODHBt-like therapeutics. Iterative studies layering on additional latency reversal or other agents are needed to achieve consistent ex vivo reservoir reductions.
Dennis C. Copertino, Jr, Carissa S. Holmberg, Jared Weiler, Adam R. Ward, J. Natalie Howard, Callie Levinger, Alina P.S. Pang, Michael J. Corley, Friederike Dündar, Paul Zumbo, Doron Betel, Rajesh T. Gandhi, Deborah K. McMahon, Ronald J. Bosch, Noemi Linden, Bernard J. Macatangay, Joshua C. Cyktor, Joseph J. Eron, John W. Mellors, Colin Kovacs, Erica Benko, Alberto Bosque, R. Brad Jones
Resolution of T cell activation and inflammation is a key determinant of the lack of SIV disease progression in African green monkeys (AGMs). Although frequently considered together, T cell activation occurs in response to viral stimulation of acquired immunity, while inflammation reflects innate immune responses to mucosal injury. We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs. This intervention abolished control of T cell immune activation beyond the transition from acute to chronic infection. Ontak had no effect on gut barrier integrity, microbial translocation, inflammation, and hypercoagulation, despite increasing T cell activation. Ontak administration increased macrophage counts yet decreased their activation. Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4+ T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs.
Cristian Apetrei, Thaidra Gaufin, Egidio Brocca-Cofano, Ranjit Sivanandham, Paola Sette, Tianyu He, Sindhuja Sivanandham, Natalie Martinez Sosa, Kathryn J. Martin, Kevin D. Raehtz, Adam J. Kleinman, Audrey Valentine, Noah Krampe, Rajeev Gautam, Andrew A. Lackner, Alan L. Landay, Ruy M. Ribeiro, Ivona Pandrea
Identifying immune cells and anatomical tissues that contribute to the establishment of viral reservoirs is of central importance in HIV-1 cure research. Herein, we used rhesus macaques (RMs) infected with SIVmac251 to analyze viral seeding in the liver and lungs of either untreated or early antiretroviral therapy–treated (ART-treated) RMs. Consistent with viral replication and sensing, transcriptomic analyses showed higher levels of inflammation, pyroptosis, and chemokine genes as well as of interferon-stimulating gene (ISG) transcripts, in the absence of ART. Our results highlighted the infiltration of monocyte-derived macrophages (HLA-DR+CD11b+CD14+CD16+) in inflamed liver and lung tissues associated with the expression of CD183 and CX3CR1 but also with markers of tissue-resident macrophages (CD206+ and LYVE+). Sorting of myeloid cell subsets demonstrated that CD14+CD206–, CD14+CD206+, and CD14–CD206+ cell populations were infected, in the liver and lungs, in SIVmac251-infected RMs. Of importance, early ART drastically reduced viral seeding consistent with the absence of ISG detection but also of genes related to inflammation and tissue damage. Viral DNA was only detected in CD206+HLA-DR+CD11b+ cells in ART-treated RMs. The observation of pulmonary and hepatic viral rebound after ART interruption reinforces the importance of early ART implementation to limit viral seeding and inflammatory reactions.
Julien A. Clain, Henintsoa Rabezanahary, Gina Racine, Steven Boutrais, Calaiselvy Soundaramourty, Charles Joly Beauparlant, Mohammad-Ali Jenabian, Arnaud Droit, Petronela Ancuta, Ouafa Zghidi-Abouzid, Jérôme Estaquier
Transgender women (TGW) are disproportionally affected by HIV infection, with a global estimated prevalence of 19.9%, often attributed to behavioral risk factors, with less known about biological factors. We evaluated potential biological risk factors for HIV acquisition in TGW at the sites of viral entry by assessing immune parameters of neovaginal surface and gut mucosa. The neovagina in TGW, compared to the vagina in CW, shows distinct cell composition and may pose a more inflammatory environment, evidenced by increased CD4+ T cell activation and higher levels of soluble markers of inflammation (CRP, sCD30). Increased inflammation may be driven by microbiome composition, showing a greater abundance of Prevotella and a higher Shannon diversity. In addition, we have observed higher frequency of CD4+CCR5+ target cells and decreased DNA methylation of the CCR5 gene in the gut mucosa of TGW compared to CW and MSM which was inversely correlated with testosterone levels. The rectal microbiome composition in TGW appears to favor a proinflammatory milieu as well as mucosal barrier disruption. Thus, it is possible that increased inflammation and higher frequencies of CCR5-expressing target cells at sites of mucosal viral entry may contribute to increased risk of HIV acquisition in TGW, with further validation in larger studies warranted.
Alexandra Schuetz, Michael Corley, Carlo Sacdalan, Yuwadee Phuang-Ngern, Thitiyanun Nakpor, Tanyaporn Wansom, Philip K. Ehrenberg, Somchai Sriplienchan, Rasmi Thomas, Nisakorn Ratnaratorn, Suchada Sukhumvittaya, Nipattra Tragonlugsana, Bonnie M. Slike, Siriwat Akapirat, Suteeraporn Pinyakorn, Rungsun Rerknimitr, Alina P.S. Pang, Eugène Kroon, Nipat Teeratakulpisan, Shelly J. Krebs, Nittaya Phanuphak, Lishomwa C. Ndhlovu, Sandhya Vasan
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