AIDS/HIV
Abstract
Background. HIV-infected patients with poor virologic control and multi-drug resistant virus have limited therapeutic options. The current study was undertaken to evaluate the safety, immunologic effects, and antiviral activity of peripheral lymphocytes transferred from an elite controller, whose immune system is able to control viral replication without antiretroviral medications, to an HLA-B*2705-matched progressor. Methods. Approximately 22 billion cells were collected from an elite controller by lymphaphersis and infused within 6 hours into a recipient with a pre-infusion CD4+ T cell count of 10 cells/μL (1%) and HIV plasma viral load of 114,993 copies/mL. Results. Donor cells were cleared from the recipient's peripheral blood by day 8. A transient decrease in viral load to 58,421 (day 3) was followed by a rebound to 702,972 (day 6) before returning to baseline values by day 8. The decreased viral load was temporally associated with peak levels of donor T cells, including CD8+ T cells that had high levels of expression of Ki67, perforin, and granzyme B. Notably, recipient CD8+ T cells also expressed increased expression of these markers, especially in HIV-specific tetramer positive cells. Conclusions. These results suggest that the adoptive transfer of lymphocytes from an HIV-infected elite controller to an HIV-infected patient with progressive disease may be able to perturb the immune system of the recipient in both positive and negative ways.
Authors
Stephen A. Migueles, Cheryl Chairez, Siying Lin, Noah V. Gavil, Danielle M. Rosenthal, Milad Pooran, Ven Natarajan, Adam Rupert, Robin Dewar, Tauseef Rehman, Brad T. Sherman, Joseph Adelsberger, Susan Leitman, David Stroncek, Caryn G. Morse, Mark Connors, H. Clifford Lane, Joseph A. Kovacs
Abstract
During chronic HIV infection, immune cells become increasingly dysfunctional and exhausted. Little is known about how immune functions are restored after initiation of antiretroviral therapy (ART). In this study, we assessed cellular and metabolic activity and evaluated the effect of individual antiretrovirals on cellular subsets ex vivo in ART-treated and treatment-naive chronically HIV-infected individuals. We observed that cellular respiration was significantly decreased in most immune cells in chronic HIV infection. The respiration was correlated to immune activation and the inhibitory receptor programmed cell death 1 on CD8+ T cells. ART restored the metabolic phenotype, but the respiratory impairment persisted in CD4+ T cells. This was particularly the case for individuals receiving integrase strand transfer inhibitors. CD4+ T cells from these individuals showed a significant reduction in ex vivo proliferative capacity compared with individuals treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors. We noticed a significant decrease in respiration of cells treated with dolutegravir (DLG) or elvitegravir (EVG) and a switch from polyfunctional to TNF-α–dominated “stress” immune response. There was no effect on glycolysis, consistent with impaired mitochondrial function. We detected increased levels of mitochondrial ROS and mitochondrial mass. These findings indicate that EVG and DLG use is associated with slow proliferation and impaired respiration with underlying mitochondrial dysfunction, resulting in overall decreased cellular function in CD4+ T cells.
Authors
Marek Korencak, Morgan Byrne, Enrico Richter, Bruce T. Schultz, Patrick Juszczak, Julie A. Ake, Anuradha Ganesan, Jason F. Okulicz, Merlin L. Robb, Buena de los Reyes, Sandra Winning, Joachim Fandrey, Timothy H. Burgess, Stefan Esser, Nelson L. Michael, Brian K. Agan, Hendrik Streeck
Abstract
In HIV-infected individuals on long-term antiretroviral therapy (ART), more than 40% of the infected cells are in clones. Although most HIV proviruses present in individuals on long-term ART are defective, including those in clonally expanded cells, there is increasing evidence that clones carrying replication-competent proviruses are common in patients on long-term ART and form part of the HIV reservoir that makes it impossible to cure HIV infection with current ART alone. Given the importance of clonal expansion in HIV persistence, we determined how soon after HIV acquisition infected clones can grow large enough to be detected (clones larger than ca. 1 × 105 cells). We studied 12 individuals sampled in early HIV infection (Fiebig stage III–V/VI) and 5 who were chronically infected. The recently infected individuals were started on ART at or near the time of diagnosis. We isolated more than 6,500 independent integration sites from peripheral blood mononuclear cells before ART was initiated and after 0.5–18 years of suppressive ART. Some infected clones could be detected approximately 4 weeks after HIV infection and some of these clones persisted for years. The results help to explain how the reservoir is established early and persists for years.
Authors
John M. Coffin, David W. Wells, Jennifer M. Zerbato, Joann D. Kuruc, Shuang Guo, Brian T. Luke, Joseph J. Eron, Michael Bale, Jonathan Spindler, Francesco R. Simonetti, Shawn Hill, Mary F. Kearney, Frank Maldarelli, Xiaolin Wu, John W. Mellors, Stephen H. Hughes
Abstract
Reduction/elimination of HIV-1 reservoirs that persist despite combination antiretroviral therapy (cART) will likely require induction of viral expression by residual infected cells and enhanced clearance of these cells. TLR7 agonists have potential to mediate these activities. We evaluated immunologic and virologic effects of repeated doses of the TLR7 agonist GS-9620 in SIV-infected rhesus macaques receiving cART, which was initiated at 13 days after infection and was continued for 75 weeks prior to GS-9620 administration. During cART, GS-9620 induced transient upregulation of IFN-stimulated genes in blood and tissues, increases in plasma cytokines, and changes in immune cell population activation and phenotypes but did not result in measurable increases in plasma viremia or viral RNA–to–viral DNA ratio in PBMCs or tissues nor decreases in viral DNA in PBMC or tissues. SIV-specific CD8+ T cell responses, negligible prior to GS-9620 treatment, were not measurably boosted by treatment; a second course of GS-9620 administration overlapping with later cART discontinuation was associated with increased CD8+ T cell responses during viral recrudescence. These results confirm and extend evidence for GS-9620–mediated enhancement of antiviral immune responses in SIV-infected macaques but suggest that GS-9620–mediated viral induction may depend critically on the timing of initiation and duration of cART and resulting characteristics of viral reservoirs.
Authors
Gregory Q. Del Prete, W. Gregory Alvord, Yuan Li, Claire Deleage, Mukta Nag, Kelli Oswald, James A. Thomas, Cathi Pyle, William J. Bosche, Vicky Coalter, Adam Wiles, Rodney Wiles, Brian Berkemeier, Michael Hull, Elizabeth Chipriano, Lorna Silipino, Randy Fast, Jacob Kiser, Rebecca Kiser, Tyler Malys, Joshua Kramer, Matthew W. Breed, Charles M. Trubey, Jacob D. Estes, Tiffany L. Barnes, Joseph Hesselgesser, Romas Geleziunas, Jeffrey D. Lifson
Abstract
BACKGROUND. The goal of antiretroviral therapy (ART) is to suppress HIV-1 replication and reconstitute CD4+ T cells. Here, we report on HIV-infected individuals who had a paradoxical decline in CD4+ T cells despite ART-mediated suppression of plasma HIV-1 load (pVL). We defined such an immunological outcome as extreme immune decline (EXID). METHODS. EXID’s clinical and immunological characteristics were compared to immunological responders (IRs), immunological nonresponders (INRs), healthy controls (HCs), and idiopathic CD4+ lymphopenia (ICL) patients. T cell immunophenotyping and assembly/activation of inflammasomes were evaluated by flow cytometry. PBMC transcriptome analysis and genetic screening for pathogenic variants were performed. Levels of cytokines/chemokines were measured by electrochemiluminescence. Luciferase immunoprecipitation system and NK-mediated antibody-dependent cellular cytotoxicity (ADCC) assays were used to identify anti-lymphocyte autoantibodies. RESULTS. EXIDs were infected with non-B HIV-1 subtypes and after 192 weeks of consistent ART-mediated pVL suppression had a median CD4+ decrease of 157 cells/μl, compared with CD4+ increases of 193 cells/μl and 427 cells/μl in INR and IR, respectively. EXID had reduced naive CD4+ T cells, but similar proportions of cycling CD4+ T cells and HLA-DR+CD38+CD8+ T cells compared with IR and INR. Levels of inflammatory cytokines were also similar in EXID and INR, but the IL-7 axis was profoundly perturbed compared with HC, IR, INR, and ICL. Genes involved in T cell and monocyte/macrophage function, autophagy, and cell migration were differentially expressed in EXID. Two of the 5 EXIDs had autoantibodies causing ADCC, while 2 different EXIDs had an increased inflammasome/caspase-1 activation despite consistently ART-suppressed pVL. CONCLUSIONS. EXID is a distinct immunological outcome compared with previously described INR. Anti–CD4+ T cell autoantibodies and aberrant inflammasome/caspase-1 activation despite suppressed HIV-1 viremia are among the mechanisms responsible for EXID.
Authors
Andrea Lisco, Chun-Shu Wong, Silvia Lucena Lage, Itzchak Levy, Jason Brophy, Jeffrey Lennox, Maura Manion, Megan V. Anderson, Yolanda Mejia, Christopher Grivas, Harry Mystakelis, Peter D. Burbelo, Ainhoa Perez-Diez, Adam Rupert, Craig A. Martens, Sarah L. Anzick, Caryn Morse, Shanna Chan, Claire Deleage, Irini Sereti
Abstract
Actinic keratosis (AK) is a precancerous skin lesion that is common in HIV-positive patients. Without effective treatment, AKs can progress to squamous cell carcinoma. Ingenol mebutate, a PKC agonist, is a US Food and Drug Administration–approved (FDA-approved) topical treatment for AKs. It can induce reactivation of latent HIV transcription in CD4+ T cells both in vitro and ex vivo. Although PKC agonists are known to be potent inducers of HIV expression from latency, their effects in vivo are not known because of the concerns of toxicity. Therefore, we sought to determine the effects of topical ingenol mebutate gel on the HIV transcription profile in HIV-infected individuals with AKs, specifically in the setting of suppressive antiretroviral therapy (ART). We found that AKs cleared following topical application of ingenol mebutate and detected marginal changes in immune activation in the peripheral blood and in skin biopsies. An overall increase in the level of HIV transcription initiation, elongation, and complete transcription was detected only in skin biopsies after the treatment. Our data demonstrate that application of ingenol mebutate to AKs in ART-suppressed HIV-positive patients can effectively cure AKs as well as disrupt HIV latency in the skin tissue microenvironment in vivo without causing massive immune activation.
Authors
Guochun Jiang, Emanual Maverakis, Michelle Y. Cheng, Maher M. Elsheikh, Claire Deleage, Gema Méndez-Lagares, Michiko Shimoda, Steven A. Yukl, Dennis J. Hartigan-O’Connor, George R. Thompson III, Jacob D. Estes, Joseph K. Wong, Satya Dandekar
Abstract
Antibodies and cytotoxic T cells represent 2 arms of host defense against pathogens. We hypothesized that vaccines that induce both high-magnitude CD8+ T cell responses and antibody responses might confer enhanced protection against HIV. To test this hypothesis, we immunized 3 groups of nonhuman primates: (a) Group 1, which includes sequential immunization regimen involving heterologous viral vectors (HVVs) comprising vesicular stomatitis virus, vaccinia virus, and adenovirus serotype 5–expressing SIVmac239 Gag; (b) Group 2, which includes immunization with a clade C HIV-1 envelope (Env) gp140 protein adjuvanted with nanoparticles containing a TLR7/8 agonist (3M-052); and (c) Group 3, which includes a combination of both regimens. Immunization with HVVs induced very high–magnitude Gag-specific CD8+ T cell responses in blood and tissue-resident CD8+ memory T cells in vaginal mucosa. Immunization with 3M-052 adjuvanted Env protein induced robust and persistent antibody responses and long-lasting innate responses. Despite similar antibody titers in Groups 2 and 3, there was enhanced protection in the younger animals in Group 3, against intravaginal infection with a heterologous SHIV strain. This protection correlated with the magnitude of the serum and vaginal Env-specific antibody titers on the day of challenge. Thus, vaccination strategies that induce both CD8+ T cell and antibody responses can confer enhanced protection against infection.
Authors
Caroline Petitdemange, Sudhir Pai Kasturi, Pamela A. Kozlowski, Rafiq Nabi, Clare F. Quarnstrom, Pradeep Babu Jagadeesh Reddy, Cynthia A. Derdeyn, Lori M. Spicer, Parin Patel, Traci Legere, Yevgeniy O. Kovalenkov, Celia C. Labranche, François Villinger, Mark Tomai, John Vasilakos, Barton Haynes, C. Yong Kang, James S. Gibbs, Jonathan W. Yewdell, Dan Barouch, Jens Wrammert, David Montefiori, Eric Hunter, Rama R. Amara, David Masopust, Bali Pulendran
Abstract
Recent guidelines recommend antiretroviral therapy (ART) to be administered as early as possible during HIV-1 infection. Few studies addressed the immunological benefit of commencing ART during the acute phase of infection. We used mass cytometry to characterize blood CD4+ T cells from HIV-1–infected patients who initiated ART during acute or chronic phase of infection. Using this method, we analyzed a large number of markers on millions of individual immune cells. The results revealed that CD4+ T cell clusters with high expression of CD27, CD28, CD127, and CD44, whose function involves T cell migration to inflamed tissues and survival, are more abundant in healthy controls and patients initiating ART during the acute phase; on the contrary, CD4+ T cell clusters in patients initiating ART during the chronic phase had reduced expression of these markers. The results are suggestive of a better preserved immune function in HIV-1–infected patients initiating ART during acute infection.
Authors
Yonas Bekele, Tadepally Lakshmikanth, Yang Chen, Jaromir Mikes, Aikaterini Nasi, Stefan Petkov, Bo Hejdeman, Petter Brodin, Francesca Chiodi
HIV-associated sensory polyneuropathy and neuronal injury are associated with miRNA–455-3p induction
Abstract
Symptomatic distal sensory polyneuropathy (sDSP) is common and debilitating in people with HIV/AIDS, leading to neuropathic pain, although the condition’s cause is unknown. To investigate biomarkers and associated pathogenic mechanisms for sDSP, we examined plasma miRNA profiles in HIV/AIDS patients with sDSP or without sDSP in 2 independent cohorts together with assessing related pathogenic effects. Several miRNAs were found to be increased in the Discovery Cohort (sDSP, n = 29; non-DSP, n = 40) by array analyses and were increased in patients with sDSP compared with patients without sDSP. miR–455-3p displayed a 12-fold median increase in the sDSP group, which was confirmed by machine learning analyses and verified by reverse transcription PCR. In the Validation Cohort (sDSP n = 16, non-DSP n = 20, healthy controls n = 15), significant upregulation of miR–455-3p was also observed in the sDSP group. Bioinformatics revealed that miR–455-3p targeted multiple host genes implicated in peripheral nerve maintenance, including nerve growth factor (NGF) and related genes. Transfection of cultured human dorsal root ganglia with miR–455-3p showed a concentration-dependent reduction in neuronal β-III tubulin expression. Human neurons transfected with miR–455-3p demonstrated reduced neurite outgrowth and NGF expression that was reversed by anti–miR–455-3p antagomir cotreatment. miR–455-3p represents a potential biomarker for HIV-associated sDSP and might also exert pathogenic effects leading to sDSP.
Authors
Eugene L. Asahchop, William G. Branton, Anand Krishnan, Patricia A. Chen, Dong Yang, Linglong Kong, Douglas W. Zochodne, Bruce J. Brew, M. John Gill, Christopher Power
Abstract
HIV eradication studies have focused on developing latency-reversing agents (LRAs). However, it is not understood how the rate of latent reservoir reduction is affected by different steps in the process of latency reversal. Furthermore, as current LRAs are host-directed, LRA treatment is likely to be intermittent to avoid host toxicities. Few careful studies of the serial effects of pulsatile LRA treatment have yet been done. This lack of clarity makes it difficult to evaluate the efficacy of candidate LRAs or predict long-term treatment outcomes. We constructed a mathematical model that describes the dynamics of latently infected cells under LRA treatment. Model analysis showed that, in addition to increasing the immune recognition and clearance of infected cells, the duration of HIV antigen expression (i.e., the period of vulnerability) plays an important role in determining the efficacy of LRAs, especially if effective clearance is achieved. Patients may benefit from pulsatile LRA exposures compared with continuous LRA exposures if the period of vulnerability is long and the clearance rate is high, both in the presence and absence of an LRA. Overall, the model framework serves as a useful tool to evaluate the efficacy and the rational design of LRAs and combination strategies.
Authors
Ruian Ke, Jessica M. Conway, David M. Margolis, Alan S. Perelson
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