AIDS/HIV
Abstract
Neurocognitive impairment is a prevalent co-morbidity in virologically suppressed people living with HIV (PLWH), yet the underlying mechanisms remain elusive and treatments lacking. We explored use of participant-derived directly induced neurons (iNs) to model neuronal biology and injury in PLWH. iNs retain age- and disease-related donor features, providing unique opportunities to reveal important aspects of neurological disorders. We obtained primary dermal fibroblasts from six virologically suppressed PLWH (range: 27-64 years, median: 53; 83% Male) and seven matched people without HIV (PWOH) (range: 27-66, median: 55; 71% Male). iNs were generated using transcription factors NGN2 and ASCL1, and validated by immunocytochemistry, single-cell-RNAseq, and electrophysiological recordings. Transcriptomic aging analyses confirmed retention of donor age-related signatures. Bulk-RNAseq identified 29 significantly differentially expressed genes between PLWH and PWOH iNs. Of these, 16 were downregulated and 13 upregulated in PLWH iNs. Protein-protein interaction network mapping indicates iNs from PLWH exhibit differences in extracellular matrix organization and synaptic transmission. IFI27 was upregulated in PLWH iNs, complementing independent post-mortem studies demonstrating elevated IFI27 expression in PLWH-derived brain tissue. FOXL2NB-FOXL2-LINC01391 expression was reduced in PLWH iNs and negatively correlated with neurocognitive impairment. Thus, we identified an iN gene signature of HIV revealing mechanisms of neurocognitive impairment in PLWH.
Authors
Philipp N. Ostermann, Youjun Wu, Scott Bowler, Samuel Martínez-Meza, Mohammad A. Siddiqui, David H. Meyer, Alberto Herrera, Brandon A. Sealy, Mega Sidharta, Kiran Ramnarine, Leslie Ann St. Bernard, Desiree Byrd, R. Jones, Masahiro Yamashita, Douglas F. Nixon, Lishomwa C. Ndhlovu, Ting Zhou, Teresa H. Evering
Abstract
Cytomegalovirus (CMV) is a prevalent β-herpesvirus that persists asymptomatically in immunocompetent hosts. In people with HIV-1 (PWH), CMV is associated with HIV-1 persistence and particular inflammatory-related co-morbidities. The true causative role of CMV in HIV-associated pathologies however remains unclear given that nearly all PWH are coinfected with CMV. In this study, we examined acute phase immune and virological dynamics in cohorts of SIV-infected rhesus macaques (RMs) that were naturally seropositive or -negative for rhesus CMV (RhCMV). We observed prior to SIV, RhCMV expanded a polyclonal population of target CCR5+CD4+ T cells in gut and lymph nodes (LN) that expressed the chemotactic receptor CXCR3 and were largely not specific for RhCMV. Upon SIV infection, RhCMV+ RMs exhibited higher peak viremia and elevated levels of SIV DNA in the upper and lower intestine. Greater seeding of SIV DNA was associated with a maintenance of CCR5-expressing CD4+ T cells that were enriched within the RhCMV+ gut along a CXCR3-CXCL9 chemotactic axis. Overall, the data suggest that RhCMV can promote SIV susceptibility within a diverse, polyclonal pool of CD4 T cells that are not entirely RhCMV-specific.
Authors
Chrysostomos Perdios, Naveen Suresh Babu, Celeste D. Coleman, Anna T. Brown, Shevon N. Alexander, Matilda J. Moström, Carolina Allers, Lara Doyle-Meyers, Christine M. Fennessey, Lori A. Rowe, Brandon F. Keele, Amitinder Kaur, Michael L. Freeman, Joseph C. Mudd
Abstract
BACKGROUND Among people living with HIV (PLWH), immunological nonresponders (INR) fail to adequately restore CD4+ T cell counts despite effective antiretroviral therapy (ART), placing them at greater risk for adverse outcomes and reduced vaccine efficacy. We aimed to study the robustness and longevity of vaccine-induced virus-specific cellular immune responses in INR.METHODS Virus-specific CD8+ T cell responses were analyzed in INR (CD4+ T cell count < 300 cells/μL) and immunological responders (IR) (CD4+ T cell count > 500 cells/μL), receiving ART, and HIV-uninfected controls following COVID-19 mRNA vaccination and infection. Virus-specific CD8+ T cells were characterized using peptide-loaded MHC I tetramer technology, after in vitro expansion and cytokine production assays. Virus-specific CD4+ T cells and IgG levels were determined by activation-induced marker (AIM) assay and ELISA, respectively.RESULTS We demonstrated that, while long-lasting virus-specific cellular immune responses were generated in INR, CD8+ T cell immunity remained limited compared with robust CD4+ T cell reactivity. CD8+ T cell responses in INR exhibited reduced breadth and frequency, accompanied by altered memory differentiation and suboptimal activation and effector response upon antigen exposure. This deficiency correlated with low CD4+ T cell counts, independent of other disease markers, highlighting the pivotal role of CD4+ T cells in orchestrating vaccine-induced immunity. Notably, repeated booster vaccinations enhanced virus-specific CD8+ T cell responses.CONCLUSION INR elicit limited vaccine-induced virus-specific CD8+ T cell immunity, but booster vaccinations can enhance these responses, suggesting better immune outcomes with tailored vaccination strategies.FUNDING Helmholtz Society, German Research Foundation, Federal Ministry of Education and Research.
Authors
Vivien Karl, Anne Graeser, Anastasia Kremser, Liane Bauersfeld, Florian Emmerich, Nadine Herkt, Siegbert Rieg, Susanne Usadel, Bertram Bengsch, Tobias Boettler, Hendrik Luxenburger, Christoph Neumann-Haefelin, Matthias C. Müller, Robert Thimme, Maike Hofmann
Abstract
Elite controllers (ECs) maintain undetectable levels of plasma viremia in the absence of treatment, but small reservoirs of replication-competent proviruses persist in the vast majority of these persons. We longitudinally studied paired blood and inguinal lymph node samples (LNMC) from two ECs to better characterize distinguishing features of viral reservoir cell dynamics in ECs. In both participants, we observed a 7- to 10-fold lower frequency of intact proviruses in LNMC samples relative to reservoir cells circulating in blood. The landscape of intact proviruses in both tissue compartments was dominated by shared large clones that were frequently integrated in non-coding DNA regions, but the frequency and diversity of intact proviruses was more limited in LNMCs. Of note, over 9-10 years of longitudinal follow-up, a 3- to 18-fold reduction of intact proviruses was observed. Together, these data support the hypothesis that viral reservoirs in ECs’ blood and lymphoid tissues are under strong, likely immune-mediated selection pressure.
Authors
Samantha K. Marzi, Chloé M. Naasz, Leah Carrere, Carmen Gasca-Capote, Isabelle C. Roseto, Ce Gao, Matthias Cavassini, Andrea Mastrangelo, Mathias Lichterfeld, Matthieu Perreau, Xu G. Yu
Abstract
Background. NK cell function is impaired in people with HIV (PWH), hindering their potential to reduce the lymphoid tissue (LT) reservoir. The IL-15 superagonist N-803 has been shown to enhance NK and T cell function, and thus may reduce viral reservoirs. Methods. To determine the impact of N-803 on LTs, we conducted a clinical trial where 10 PWH on effective antiretroviral therapy (ART) were given three 6 mcg/kg doses of N-803 subcutaneously. We obtained PBMCs and lymph node (LN) and gut biopsies at baseline and after the last N-803 dose. Results. We found a non-statistically significant ~0.50 median log reduction in the frequency of viral(v)RNA+ and vDNA+ cells/g in the 6 participants with baseline and post-treatment LNs. In the ileum, we observed reductions of vRNA+ cells in 8/10 participants and vDNA+ cells in all participants. We also found significant inverse correlations between NK cell proliferation and the frequency of vRNA+ cells, and between NKG2A expression on NK cells and the frequency of vRNA+ cells. Conclusions. Our findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function. Controlled studies assessing the impact of NK cell therapy on HIV LTs are needed.
Authors
Joshua Rhein, Jeffrey G. Chipman, Gregory J. Beilman, Ross Cromarty, Kevin Escandón, Jodi Anderson, Garritt Wieking, Jarrett Reichel, Rodolfo Batres, Alexander Khoruts, Christopher M. Basting, Peter Hinderlie, Zachary B. Davis, Anne Eaton, Byron P. Vaughn, Elnaz Eilkhani, Jeffrey T. Safrit, Patrick Soon-Shiong, Jason V. Baker, Nichole R. Klatt, Steven G. Deeks, Jeffrey S. Miller, Timothy W. Schacker
Abstract
Toll-like receptors (TLRs) are being explored to enhance immunity in HIV cure strategies. The TLR7 agonist GS-9620 promotes immune activation, reactivates latent HIV, and delays viral rebound in some people with HIV. Previous work has shown that biological sex influences TLR7 signaling. This study examined the interplay between biological sex, age, and the sex hormones 17β-estradiol, progesterone, and testosterone on GS-9620’s ability to promote cytokine secretion and activate CD4, CD8, and NK cells ex vivo. Interestingly, sex hormones had no effect on GS-9620-mediated immune activation or cytokine induction. However, we found that GS-9620 activity was influenced by age only in female donors. Further, we found that GS-9620-mediated CD4 T cell activation was positively correlated with the induction of IFN-γ and IL-12, while CD4 T cell activation and IL-12 production were negatively correlated with age. Additionally, CD8 T cell activation was positively correlated with IFN-γ production. Mechanistically, IFN-γ was sufficient to promote higher immune activation of both CD4 and CD8 T cells in female versus male donors. In conclusion, biological sex and age, but not sex hormones, influence GS-9620-mediated immune activation. Understanding these factors will help design and evaluate future clinical trials using GS-9620 for an HIV cure.
Authors
Carissa S. Holmberg, Callie Levinger, Adam R. Ward, Alberto Bosque
Abstract
People living with HIV treated during acute infection are the group for whom achieving functional cure appears most viable. Follicular CD8+ T cells could contribute to HIV reservoir clearance by accessing B cell follicles through CXCR5 expression. This study examines peripheral follicular CD8+ T cells using flow cytometry, transcriptome analyses, and functional assays in people treated during acute (n = 37) and chronic (n = 18) infection, as well as in individuals naturally controlling HIV (n = 20) and living without HIV (n = 10). Our results reveal that early, as opposed to late, treatment initiation preserves antiviral effector functions of follicular CD8+ T cells, which are further enhanced by PD1 inhibition. We also identify a correlation between follicular CD8+ T cells and intact proviral HIV DNA levels in acute, but not chronic, infection. Longitudinal transcriptomic analysis of peripheral effector cells after 48 weeks of suppressive therapy indicated traits of recent antigen exposure, suggesting potential recirculation into lymphoid tissue. These findings underscore the pivotal role of follicular CD8+ T cells in anti-HIV responses and support investigating targeted cure strategies, such as anti-PD1 therapy, especially in individuals initiating treatment during acute infection.
Authors
Susanne Rueger, Eva Gruener, Danni Wang, Faiaz Shaik Abdool, Veronica Ober, Theresa Vallée, Renate Stirner, Raffaele Conca, Immanuel Andrä, Lisa Rogers, Robert Zahn, Elke Gersbacher, Joanna Eger, Ramona Pauli, Nils Postel, Christoph D. Spinner, Jörg J. Vehreschild, Melanie Stecher, Hans Nitschko, Josef Eberle, Johannes R. Bogner, Ulrich Seybold, Rika Draenert, Al Leslie, Henrik N. Kløverpris, Christof Geldmacher, Maximilian Muenchhoff, Kathrin Held, Julia Roider
Abstract
BACKGROUND HIV-1–specific broadly neutralizing monoclonal antibodies (bNAbs) have emerged as promising interventions with the potential to effectively treat and prevent HIV-1 infections. We conducted a phase I clinical trial evaluating the potent CD4-binding site–specific (CD4bs-specific) bNAbs VRC01LS and VRC07-523LS in people with HIV-1 (PWH) not receiving antiretroviral therapy (ART).METHODS Participants received a single intravenous 40 mg/kg dose of either VRC01LS (n = 7) or VRC07-523LS (n = 9) and did not initiate ART for a minimum of 14 days. The primary study objective was to evaluate safety and tolerability; the secondary study objectives were to evaluate pharmacokinetics (PK) and the impact of administered bNAbs on viral loads (VL) and CD4+ T cell counts in the absence of ART.RESULTS This trial enrolled 16 PWH aged 20 to 57 years. Both bNAbs were safe and well tolerated. Mild local reactogenicity was only reported in participants who received VRC07-523LS, while both bNAbs were associated with mild systemic symptoms. Maximum serum concentrations (Cmax) following VRC01LS or VRC07-523LS were 1,566 ± 316 and 1,295 ± 376 μg/mL, respectively. VRC07-523LS administration significantly decreased VL in 8 out of 9 participants, with an average decline of 1.7 ± 0.8 log10 copies/mL within 14 days after administration. In contrast, VRC01LS administration resulted in a smaller average decline (0.8 ± 0.8 log10 copies/mL), and 3 out of 7 participants showedno change in VL. Postinfusion maximum decline in VL correlated with post hoc baseline in vitro viral susceptibility results for both bNAbs.CONCLUSION The results of this trial support inclusion of potent CD4bs-specific bNAbs, such as VRC07-523LS, into next-generation treatment regimens for HIV-1.TRIAL REGISTRATION ClinicalTrials.gov NCT02840474.FUNDING National Institute of Allergy and Infectious Diseases (NIAID)/NIH (grants UM1 AI068634, UM1 AI068636, UM1 AI106701, UM1AI069424, UM1AI069501, UM1AI69415, UM1AI069534, UM1AI69494); the Intramural Research Program of the NIAID/NIH; National Center for Advancing Translational Sciences/NIH (grants UM1TR004548, UL1TR001881, and UL1TR001878); and the National Cancer Institute/NIH (contract 75N91019D00024).
Authors
Myra Happe, Rebecca M. Lynch, Carl J. Fichtenbaum, Sonya L. Heath, Susan L. Koletar, Raphael J. Landovitz, Rachel M. Presti, Jorge L. Santana-Bagur, Randall L. Tressler, LaSonji A. Holman, Laura Novik, Jhoanna C. Roa, Ro Shauna Rothwell, Larisa Strom, Jing Wang, Zonghui Hu, Michelle Conan-Cibotti, Anjali M. Bhatnagar, Bridget Dwyer, Sung Hee Ko, Frida Belinky, Aryan M. Namboodiri, Janardan P. Pandey, Robin Carroll, Manjula Basappa, Leonid Serebryannyy, Sandeep R. Narpala, Bob C. Lin, Adrian B. McDermott, Eli A. Boritz, Edmund V. Capparelli, Emily E. Coates, Richard A. Koup, Julie E. Ledgerwood, John R. Mascola, Grace L. Chen, Pablo Tebas, the VRC 607/A5378 Study Team
Abstract
Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. Further, ART interruption results in reservoir reactivation and rebound viremia. Both IL-21 and anti-α4β7 improve gut barrier functions, and we hypothesized combining them would synergize as a dual therapy to improve immunological outcomes in SIV-infected rhesus macaques (RMs). We found no significant differences in CD4+ T-cell reservoir size by intact proviral DNA assay. SIV rebounded in both dual-treated and control RMs following analytical therapy interruption (ATI), with time to rebound and initial rebound viremia comparable between groups; however, dual-treated RMs showed slightly better control of viral replication at the latest time points post-ATI. Additionally, following post-ATI, dual-treated RMs showed immunological benefits, including T-cell preservation and lower PD-1+ central memory T-cell (TCM) frequency. Notably, PD-1+ TCMs were associated with reservoir size, which predicted viral loads (VLs) post-ATI. Finally, 16S rRNA sequencing revealed better recovery from dysbiosis in treated animals, and the butyrate-producing Firmicute Roseburia predicted PD-1-expressing TCMs and VLs after ATI. PD-1+ TCMs and gut dysbiosis represent mechanisms of HIV persistence and pathogenesis, respectively. Therefore, combining IL-21 and anti-α4β7 may be an effective therapeutic strategy to improve immunological outcomes for people with HIV.
Authors
Samuel D. Johnson, Maria Pino, Arpan Acharya, Julien A. Clain, Deepanwita Bose, Kevin Nguyen, Justin Harper, Francois Villinger, Mirko Paiardini, Siddappa N. Byrareddy
Abstract
African green monkeys (AGMs) are natural hosts of SIV whose infection does not progress to AIDS. Since early events of infection may be critical to pathogenesis in nonnatural hosts, we investigated early SIV infection in 29 adult male AGMs intrarectally inoculated with SIVsab92018 (SIVsab) and serially sacrificed throughout acute into early chronic infection to understand patterns of viral establishment, dissemination, and their effect on disease progression. Using this model, we showed that foci of virus replication could be detected at the site of inoculation and in the draining lymphatics as early as 1–3 days postinfection (dpi). Furthermore, testing with ultrasensitive assays showed rapid onset of viremia (2–4 dpi). After systemic spread, virus was detected in all tissues surveyed. Multiple transmitted/founder viruses were identified, confirming an optimal challenge dose, while demonstrating a moderate mucosal genetic bottleneck. Resident CD4+ T cells were the initial target cells; other immune cell populations were not significantly altered at the site of entry. Thus, intrarectal SIVsab infection is characterized by swift dissemination of the virus, a lack of major target cell recruitment, and no window of opportunity for interventions to prevent virus dissemination during the earliest stages of infection, similar to intrarectal transmission but different from vaginal transmission in macaques.
Authors
Kevin D. Raehtz, Cuiling Xu, Claire Deleage, Dongzhu Ma, Benjamin B. Policicchio, Egidio Brocca-Cofano, Daniele Piccolo, Kathryn Weaver, Brandon F. Keele, Jacob D. Estes, Cristian Apetrei, Ivona Pandrea
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