AIDS/HIV
Abstract
Inhibiting the mammalian target of rapamycin (mTOR) during acute viral infection generates highly functional memory CD8 T cells. We investigated the effects of inhibiting mTOR by using rapamycin during the effector and contraction phases of the immune response to a DNA prime and Modified Vaccinia Ankara (MVA) boost SIV vaccination in rhesus macaques. Rapamycin administered either during MVA boosts alone (DMR) or during both primes and boosts (DRMR) reduced the contraction of effector CD8 T cells, resulting in higher frequencies of SIV-specific memory CD8 T cells with enhanced quality as indicated by expression of Bcl-2 and CD127. Additionally, rapamycin reduced the frequency of proliferating CCR5+ CD4 T cells in the blood following the MVA boost. Post SIV251 infection, rapamycin-treated macaques demonstrated marked expansion of SIV-specific CD8 T cells (reaching up to 50% in blood and 25% in gut). The heightened expansion of SIV-specific CD8 T cells in the DMR group was associated with markedly lower (2-logs compared to unvaccinated and 1-log compared to DM) peak viral load in the gut and set-point viremia, along with improved survival post infection. Thus, inhibiting the mTOR pathway during MVA boosts of a DNA/MVA vaccine enhances vaccine efficacy by improving memory CD4 and CD8 T cell function.
Authors
Shanmugalakshmi Sadagopal, Kasey Stokdyk, Suefen Kwa, Rahul Basu, Sailaja Gangadhara, Rafi Ahmed, Smita S. Iyer, Koichi Araki, Rama Rao Amara
Abstract
Antiretroviral therapy (ART) has prolonged the life expectancy of persons living with HIV, the majority of whom are now older than 50 years. Aging people with HIV are at increased risk for cardiovascular events driven by HIV-related inflammation and hypercoagulation. Apixaban is a factor Xa inhibitor that reduces cardiovascular risks and treats stroke, deep vein thrombosis, and pulmonary embolism. We assessed apixaban’s impact on key parameters of HIV/SIV pathogenesis in SIV-infected, aged rhesus macaques (RMs) receiving ART. Inflammation, coagulation, T cell subsets, B cells, and macrophages and their immune activation status were monitored throughout the study. We found no significant differences between the apixaban-treated and control groups for virus replication or CD4+ T cell recovery in blood and tissues after ART. Apixaban did not significantly affect D-dimer, immune activation, or inflammation of SIV-infected, ART-treated RMs. Apixaban-treated RMs experienced multiple bleeding episodes, tissue hemorrhages, and myocardial infarctions, as demonstrated by pathological examination of necropsy-collected tissues. Given apixaban’s lack of effect on immune activation, CD4+ T cell restoration, and inflammation, along with increased risk of hemorrhage, factor Xa inhibition may not be an efficient or safe option to target and prevent cardiovascular events in aging people with HIV.
Authors
Cuiling Xu, Haritha Annapureddy, Lilly Carson, Vansh Khurana, Ranjit Sivanandham, Sindhuja Sivanandham, Tianyu He, Kevin D. Raehtz, Janet Kim, Christie Biber, Norma Arbujas-Silva, Mohammed Daira, Sudhapriya Kandasamy, Matthew J. Feinstein, Irini Sereti, Cristian Apetrei, Ivona Pandrea
Abstract
HIV infection rapidly impairs the gastrointestinal (GI) barrier, contributing to persistent mucosal immune dysfunction, microbial translocation, and systemic inflammation despite antiretroviral therapy (ART). Using SIV-infected rhesus macaques on long-term ART, we investigated mechanisms underlying impairment in gut barrier-protective IL-17/IL-22 responses and the potential modulation of this pathway by dietary indoles. Longitudinal profiling of colonic epithelial and lamina propria cells revealed a selective loss of IL-17/IL-22–producing γδT cells and type 3 innate lymphoid cells (ILC3s). This loss correlated with reduced expression of the transcription factors AHR and RORγt and was associated with elevated plasma markers of intestinal epithelial barrier disruption (IEBD), including intestinal fatty acid–binding protein (iFABP), zonulin, and LPS-binding protein (LBP). Targeting this transcriptional deficiency, dietary indole supplementation for one month restored colonic AHR⁺IL-22-producing γδ T cells, RORγt⁺ ILC3s, and Vδ1 T cells, and was associated with reduced iFABP and zonulin levels. Immunohistochemical analyses further demonstrated enrichment of AHR/RORγt-co-expressing cells in the colon of indole-supplemented animals during chronic SIV infection on ART. Collectively, these findings indicate that disruption of the AHR-RORγt axis is a key pathogenic mechanism underlying persistent IEBD in chronic SIV/HIV infection. Modulation of AHR and RORγt signaling pathways in the gut may therefore represent a promising therapeutic strategy to reinforce mucosal barrier function and mitigate chronic inflammation in people living with HIV.
Authors
Siva Thirugnanam, Alison R. Van Zandt, Alexandra B. McNally, Victoria A. Hart, Isabelle Berthelot, Cecily C. Midkiff, Lara A. Doyle-Meyers, David A. Welsh, Robert V. Blair, Andrew G. MacLean, Namita Rout
Abstract
BACKGROUND. Transplanting kidneys from donors with HIV to recipients with HIV has become standard clinical practice. However, donors with HIV may have higher prevalence of viral and bacterial infections and autoimmunity that could increase allograft rejection in recipients. METHODS. We included deceased kidney donors (60 with HIV and 41 without HIV) who participated in a multicenter prospective study of HIV kidney transplantation between April 2018-September 2021. Using Phage ImmunoPrecipitation Sequencing, we compared the human antibody repertoire (allergens, autoantibodies, viruses and bacterial toxins) between donors with and without HIV, and evaluated their association with recipient allograft rejection. Moderated t-tests were used to assess reactivity and a multivariate logistic regression model adjusted for donor sex and KDPI assessed the association between donor adenovirus reactivity and recipient allograft rejection. RESULTS. Compared to donors without HIV, donors with HIV had lower BMI and were more likely to be African American. The median number of positive autoantibodies was marginally higher among donors with HIV (499 [IQR = 357, 579]) compared to donors without HIV (395 [IQR = 256, 538] (P = 0.058). Donors with HIV additionally had significantly higher antibody reactivity to Epstein-Barr virus and cytomegalovirus (q < 0.05). Among all donors with and without HIV, antibodies to adenovirus were significantly associated with increased rejection among recipients, including after adjusting for false discovery (q < 0.05) and also adjusting for demographic factors using multivariable logistic regression (odds ratio = 4.97, 95% CI = 1.89–13.61). CONCLUSION. The presence of antibodies to adenovirus infection in kidney donors with HIV may be associated with allograft rejection. TRIAL REGISTRATION. ClinicalTrials.gov NCT03500315. FUNDING. US National Institute of Health
Authors
Xianming Zhu, William R. Morgenlander, Diane M. Brown, Yolanda Eby, Megan Morsheimer, Jonah Odim, Serena M. Bagnasco, Meenakshi M. Rana, Sander S. Florman, Rachel J. Friedman-Moraco, Peter G. Stock, Alexander J. Gilbert, Shikha Mehta, Valentina Stosor, Sapna A. Mehta, Marcus R. Pereira, Catherine B. Small, Michele I. Morris, Jonathan Hand, Saima Aslam, Ghady Haidar, Maricar Malinis, Carlos A.Q. Santos, Joanna Schaenman, David Wojciechowski, Karthik M. Ranganna, Emily Blumberg, Nahel Elias, Josa A. Castillo-Lugo, Emmanouil Giorgakis, Senu Apewokin, M. Kate Grabowski, Dorry L. Segev, Andrew D. Redd, Christine M. Durand, H. Benjamin Larman, Aaron A.R. Tobian
Abstract
BACKGROUND. High-dose influenza vaccine, containing four times more antigen than standard-dose, is recommended for people aged ≥ 65 years, but there is a knowledge gap surrounding its effect in people with HIV (PWH), who remain more vulnerable to serious influenza infections than people without HIV (PWoH) despite virological suppression. The primary goal of this study was to assess whether high-dose improves antibody responses in PWH, with a particular focus on older PWH. METHODS. We conducted a study to assess antibody responses to sequential high- versus standard-dose influenza vaccination in PWH. Young (18-40 years) PWoH (n=55) and PWH (n=37); and older (≥ 60 years) PWoH (n=72) and PWH (n=67) received standard-dose during the 2020-2024 seasons and 123 participants, including 41 older PWH, received high-dose the consecutive season. All PWH were virologically suppressed on ART. Hemagglutination inhibition (HAI) titer and HA-specific IgG were analyzed at 0- to 180-days post-vaccination (dpv); T cell activation-induced responses were assessed by flow cytometry. RESULTS. All groups mounted significant HAI and IgG responses to all vaccine antigens at 28 dpv, after standard- and high-dose vaccination. Responses to A/H1N1 were lower in magnitude and durability in older PWH compared to young PWoH following standard-dose and were not boosted with high-dose, whereas high-dose enhanced A/H3N2 and B/Victoria IgG, and CD4+ T cell responses to all antigens, in older PWH. CONCLUSION. Our data demonstrate partial efficacy of high-dose in augmenting antibody responses of older PWH while highlighting limitations in boosting A/H1N1-specific responses. TRIAL REGISTRATION. ClinicalTrials.gov NCT04487041. FUNDING. NIH grant (5R01AG068110).
Authors
Jonah Kupritz, Sheldon Davis, TianHao Liu, Prabhsimran Singh, Daniel Andrés Díaz–Pachón, Allan Rodriguez, Scott D. Boyd, Rajendra Pahwa, Suresh Pallikkuth, Savita G. Pahwa
Abstract
Coinfection with both HIV and M. tuberculosis (Mtb) results in disseminated tuberculosis (TB) and accelerated HIV progression. Despite greater access to antiretroviral treatment (ART), it remains unclear whether suppression of HIV replication protects against severe Mtb infection. Here, using a macaque model of SIV/Mtb coinfection, we investigated whether treatment of SIV infection with ART influenced control of a subsequent Mtb challenge compared with SIV-infected macaques that were not treated with ART. Macaques were first infected with SIVB670, SIVB670 with ART, or saline followed by a low-dose Mtb inoculation with serial clinical and PET-CT imaging assessments. At necropsy, gross pathology, viremia, bacterial burden, and immunologic parameters were compared. SIV-TB animals had greater gross pathology and total bacterial burden than TB-only and SIV/ART/TB groups. However, despite normal blood CD4 counts and undetectable SIV RNA, SIV/ART/TB macaques showed similar clinical parameters and extrapulmonary involvement as SIV/TB animals. Analysis of barcoded-Mtb suggests that ART control of SIV replication did not prevent Mtb extrapulmonary dissemination. These data indicate that people living with HIV on ART remain at high risk of bacterial dissemination and extrapulmonary TB disease. Understanding the mechanisms of extrapulmonary spread and disease severity during HIV/TB coinfection remains an important issue.
Authors
Collin R. Diedrich, Tara Rutledge, Janelle L. Gleim, Christopher Kline, Pauline Maiello, Jessica M. Medrano, H. Jacob Borish, Harris B. Chishti, Justin L. Gaines, Edwin Klein, Forrest Hopkins, Jacob E. Klein, Daniel Fillmore, Kara Kracinovsky, Jaime Tomko, Jennifer Schober, Sarah M. Fortune, Michael C. Chao, JoAnne L. Flynn, Zandrea Ambrose, Philana Ling Lin
Abstract
We previously demonstrated that blocking TGF-β with galunisertib, a safe, orally available small drug, reactivated latent SIV in vivo by shifting T cells toward a transitional effector phenotype. Here, we investigated the mechanisms underlying this effect using single-cell RNA sequencing, metabolic profiling, and high-dimensional spectral flow cytometry of samples from SIV-infected, antiretroviral therapy–treated (ART-treated) macaques before and after galunisertib. To characterize virus-transcribing, infected cells during ART, we developed a novel, sensitive SIV Transcripts Capture Assay (SCAP) that detected 127 SIV-expressing cells within lymph node single-cell transcriptome libraries. Galunisertib drove broad metabolic reprogramming in CD4+ T cells, with transcriptional upregulation of inflammatory and mitochondrial biosynthesis pathways, confirmed by Seahorse profiling. Metabolomics revealed increased energy metabolites and amino acids and enhanced metabolic flux without proliferation. SIV transcript–positive cells before galunisertib were metabolically quiescent compared with cells without detectable viral transcripts. After galunisertib, virus-expressing cells showed a dramatic metabolic activation, with upregulation of glycolysis, fatty acid metabolism, and TNF-α signaling. High-dimensional flow cytometry demonstrated effects beyond CD4+ T cells, including fewer tissue-resident memory T cells, but more inflammatory macrophages. In conclusion, SCAP represents a specific tool for characterizing rare SIV-infected cells transcribing virus during ART, and it reveals TGF-β as a key mediator of viral latency in vivo through metabolic suppression.
Authors
Romaila Abd-El-Raouf, Jakob Harrison-Gleason, Jinhee Kim, Ching Man Wai, Kayla L. Yerlioglu, Catarina Ananias-Saez, Alec Ksiazek, Jeffrey T. Poomkudy, Mariluz Araínga, Deepanwita Bose, Claudia Cicala, James Arthos, Francois J. Villinger, Ramon Lorenzo-Redondo, Elena Martinelli
Abstract
Latently infected cells persist in people living with HIV (PWH) despite suppressive antiretroviral therapy (ART) and evade immune clearance. Shock and Kill cure strategies are hampered by insufficient enhancement of targeted immune responses following latency reversal. We previously demonstrated autologous Vδ2 T cells from PWH retain anti-HIV activity and can reduce CD4+ T cell reservoirs, although their use in cure approaches is limited due to their dual role as a viral reservoir. However, promising clinical data in oncology shows their unique MHC- unrestricted antigen recognition affords potent on-target cytotoxicity in the absence of graft-versus-host disease when used as an allogeneic adoptive cell therapy modality. Here, we found expanded allogeneic Vδ2 T cells specifically eliminated HIV-infected CD4+ T cells and monocyte-derived macrophages (MDM), overcoming inherent resistance to killing by other cell types such as NK and CD8+ T cells. Notably, we demonstrated allogeneic Vδ2 T cells recognized and eliminated the HIV-latent CD4+ T cell reservoir following latency reversal. Our study provides evidence for developing an allogeneic γδ T cell therapy for HIV cure and warrants pre-clinical investigation in combination approaches.
Authors
Brendan T. Mann, Marta Sanz, Alisha Chitrakar, Kayley Langlands, Marc Siegel, Natalia Soriano-Sarabia
Abstract
Cardiovascular disease (CVD), both atherosclerosis-related and heart failure with preserved ejection fraction (HFpEF) linked to cardiac fibrosis, contributes to morbidity and mortality in people with HIV (PWH) receiving antiretroviral therapy (ART). In the REPRIEVE trial, pitavastatin reduces atherosclerotic CVD risk to a magnitude inconsistent with pitavastatin’s impact solely on LDL-cholesterol and inflammation. We hypothesized that HFpEF in PWH is related to HIV-induced fibrosis mediated by platelet TGFβ1, is accelerated by certain contemporary ART, and may also be inhibited by statins. ART drugs used in REPRIEVE, including a nucleoside/nucleotide, integrase inhibitor-based regimen (tenofovir (TDF), emtricitabine (FTC), and dolutegravir (DTG)), and the protease inhibitors ritonavir (RTV) and darunavir (DRV), and the impact of atorvastatin, were examined in two HIV mouse models: transgenic HIV-Tg26 mice and HIV-PDX mice engrafted with T cells isolated from PWH. HIV-Tg26 and HIV-PDX mice had higher cardiac fibrosis than littermate controls without HIV (p<0.05). Administration of TDF-FTC-DTG or RTV, but not DRV, resulted in a further ~2-fold increase in fibrosis (p<0.01). Cardiac fibrosis and intracardiac fat accumulation correlated with reduced diastolic function. Mice depleted of platelet TGFβ1 (TGFβ1Platelet-ΔTg26), or treated with atorvastatin, were partially protected from HIV- and ART-induced cardiac fibrosis, steatosis, and diastolic dysfunction. Atorvastatin effects were independent of changes in inflammatory cytokines. These effects correlated with reduced platelet activation and TGFβ signaling in cardiac endothelial cells, fibroblasts, and macrophages undergoing mesenchymal transition. Our results indicate that certain ART regimens accelerate HIV-associated CVD characterized by HFpEF via platelet TGFβ1-dependent processes, which were mitigated by atorvastatin. We postulate that our findings provide a potential mechanism for the pleiotropic effects of statins in HIV/ART-linked CVD which could be targeted by antiplatelet agents or inhibition of TGFβ signaling.
Authors
Kumar Subramani, Denys Babii, Brienne Cole, Tayyab A. Afzal, Thamizhiniyan Venkatesan, Trevor Word, Sandra Gostynska, Sixia Chen, Kar-Ming Fung, Ali Danesh, Itzayana G. Miller, Paul Klotman, Brad R. Jones, Jeffrey Laurence, Jasimuddin Ahamed
Abstract
Few HIV-specific epitopes restricted by non-classical HLA-E have been described, and even less is known about the functional profile of responding CD8 T cells (CD8s). This study evaluates the functional characteristics of CD8s targeting the Gag epitope KF11 (KAFSPEVIPMF) restricted by either HLA-E (E-CD8s) or HLA-B57 (B57-CD8s). CD8s from eight people with HIV (PWH) were cocultured with KF11 peptide presented by cell lines expressing HLA-B*57:01, HLA-E*01:01 or E*01:03. CD8 responses were analyzed using scRNA-seq and scTCR-seq. Supernatants were also assessed for soluble protein profiling. HLA-I multimers were developed to identify CD8s restricted by HLA-B57 and/or HLA-E ex vivo. B57-CD8s secreted higher levels of cytotoxic cytokines such as IFNγ, whereas E-CD8s produced more chemotactic cytokines, including RANTES, CXCL10 (IP-10), and IL27, findings which were corroborated through scRNA sequencing. TCR clonotypes stimulated by KF11 were cross-restricted by HLA-B*57 and HLA-E*01/03 as demonstrated by in vitro T cell reporter assays and ex vivo multimer screening. Ex vivo CD8s were singly restricted by HLA-B57 and HLA-E, with dual restriction only observed in PWH with lower viral load. These findings demonstrate that certain HIV-specific CD8s in PWH exhibit dual restriction by HLA-B*57 and HLA-E*01/03, leading to functionally distinct immune responses depending upon the restricting allele(s).
Authors
Kevin J. Maroney, Michael A. Rose, Allisa K. Oman, Abha Chopra, Hua-Shiuan Hsieh, Zerufael Derza, Rachel Waterworth, Mark A. Brockman, Spyros A. Kalams, Anju Bansal, Paul A. Goepfert
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