AIDS/HIV
Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders
Abstract
Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that is critical for limiting oxidative stress, inflammation, and cellular injury within the CNS and other tissues. Here, we demonstrate a deficiency of HO-1 expression in the brains of HIV-infected individuals. This HO-1 deficiency correlated with cognitive dysfunction, HIV replication in the CNS, and neuroimmune activation. In vitro analysis of HO-1 expression in HIV-infected macrophages, a primary CNS HIV reservoir along with microglia, demonstrated a decrease in HO-1 as HIV replication increased. HO-1 deficiency correlated with increased culture supernatant glutamate and neurotoxicity, suggesting a link among HIV infection, macrophage HO-1 deficiency, and neurodegeneration. HO-1 siRNA knockdown and HO enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with nonselective pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. Furthermore, IFN-γ, which is increased in CNS HIV infection, reduced HO-1 expression in cultured human astrocytes and macrophages. These findings indicate that HO-1 is a protective host factor against HIV-mediated neurodegeneration and suggest that HO-1 deficiency contributes to this degeneration. Furthermore, these results suggest that HO-1 induction in the CNS of HIV-infected patients on antiretroviral therapy could potentially protect against neurodegeneration and associated cognitive dysfunction.
Authors
Alexander J. Gill, Colleen E. Kovacsics, Stephanie A. Cross, Patricia J. Vance, Lorraine L. Kolson, Kelly L. Jordan-Sciutto, Benjamin B. Gelman, Dennis L. Kolson
Abstract
The phase III RV144 HIV-1 vaccine trial estimated vaccine efficacy (VE) to be 31.2%. This trial demonstrated that the presence of HIV-1–specific IgG-binding Abs to envelope (Env) V1V2 inversely correlated with infection risk, while the presence of Env-specific plasma IgA Abs directly correlated with risk of HIV-1 infection. Moreover, Ab-dependent cellular cytotoxicity responses inversely correlated with risk of infection in vaccine recipients with low IgA; therefore, we hypothesized that vaccine-induced Fc receptor–mediated (FcR-mediated) Ab function is indicative of vaccine protection. We sequenced exons and surrounding areas of FcR-encoding genes and found one
Authors
Shuying S. Li, Peter B. Gilbert, Georgia D. Tomaras, Gustavo Kijak, Guido Ferrari, Rasmi Thomas, Chul-Woo Pyo, Susan Zolla-Pazner, David Montefiori, Hua-Xin Liao, Gary Nabel, Abraham Pinter, David T. Evans, Raphael Gottardo, James Y. Dai, Holly Janes, Daryl Morris, Youyi Fong, Paul T. Edlefsen, Fusheng Li, Nicole Frahm, Michael D. Alpert, Heather Prentice, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Jaranit Kaewkungwal, Sorachai Nitayaphan, Merlin L. Robb, Robert J. O’Connell, Barton F. Haynes, Nelson L. Michael, Jerome H. Kim, M. Juliana McElrath, Daniel E. Geraghty
Abstract
Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. Despite extensive evidence of B cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, we used HIV envelope gp140 and CD4 or coreceptor (CoR) binding site (bs) mutant probes to evaluate HIV-specific responses in peripheral blood B cells of HIV-infected individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs, which is a poorly neutralizing epitope, arose early, whereas those against the well-characterized neutralizing epitope CD4bs were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. The distribution of HIV-specific responses among memory B cell subsets was corroborated by transcriptional analyses. Taken together, our findings provide valuable insight into virus-specific B cell responses in HIV infection and demonstrate that memory B cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals.
Authors
Lela Kardava, Susan Moir, Naisha Shah, Wei Wang, Richard Wilson, Clarisa M. Buckner, Brian H. Santich, Leo J.Y. Kim, Emily E. Spurlin, Amy K. Nelson, Adam K. Wheatley, Christopher J. Harvey, Adrian B. McDermott, Kai W. Wucherpfennig, Tae-Wook Chun, John S. Tsang, Yuxing Li, Anthony S. Fauci
Abstract
Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS.
Authors
Jonathan Pitcher, Anna Abt, Jaclyn Myers, Rachel Han, Melissa Snyder, Alessandro Graziano, Lindsay Festa, Michele Kutzler, Fernando Garcia, Wen-Jun Gao, Tracy Fischer-Smith, Jay Rappaport, Olimpia Meucci
Abstract
While flow cytometry has been used to analyze the antigenic composition of individual cells, the antigenic makeup of viral particles is still characterized predominantly in bulk. Here, we describe a technology, “flow virometry,” that can be used for antigen detection on individual virions. The technology is based on binding magnetic nanoparticles to virions, staining the virions with monoclonal antibodies, separating the formed complexes with magnetic columns, and characterizing them with flow cytometers. We used this technology to study the distribution of two antigens (HLA-DR and LFA-1) that HIV-1 acquires from infected cells among individual HIV-1 virions. Flow virometry revealed that the antigenic makeup of virions from a single preparation is heterogeneous. This heterogeneity could not be detected with bulk analysis of viruses. Moreover, in two preparations of the same HIV-1 produced by different cells, the distribution of antigens among virions was different. In contrast, HIV-1 of two different HIV-1 genotypes replicating in the same cells became somewhat antigenically similar. This nanotechnology allows the study of virions in bodily fluids without virus propagation and in principle is not restricted to the analysis of HIV, but can be applied to the analysis of the individual surface antigenic makeup of any virus.
Authors
Anush Arakelyan, Wendy Fitzgerald, Leonid Margolis, Jean-Charles Grivel
Abstract
HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell–mediated in vivo control of HIV-1. Primary HIV-1–specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or “vertical” immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.
Authors
Michael K.P. Liu, Natalie Hawkins, Adam J. Ritchie, Vitaly V. Ganusov, Victoria Whale, Simon Brackenridge, Hui Li, Jeffrey W. Pavlicek, Fangping Cai, Melissa Rose-Abrahams, Florette Treurnicht, Peter Hraber, Catherine Riou, Clive Gray, Guido Ferrari, Rachel Tanner, Li-Hua Ping, Jeffrey A. Anderson, Ronald Swanstrom, CHAVI Core B, Myron Cohen, Salim S. Abdool Karim, Barton Haynes, Persephone Borrow, Alan S. Perelson, George M. Shaw, Beatrice H. Hahn, Carolyn Williamson, Bette T. Korber, Feng Gao, Steve Self, Andrew McMichael, Nilu Goonetilleke
Abstract
Acute HIV-1 infection results in dysregulated immunity, which contributes to poor control of viral infection. DCs are key regulators of both adaptive and innate immune responses needed for controlling HIV-1, and we surmised that factors elicited during acute HIV-1 infection might impede DC function. We derived immature DCs from healthy donor peripheral blood monocytes and treated them with plasma from uninfected control donors and donors with acute HIV-1 infections. We found that the plasma from patients with HIV specifically inhibited DC function. This suppression was mediated by elevated apoptotic microparticles derived from dying cells during acute HIV-1 infection. Apoptotic microparticles bound to and inhibited DCs through the hyaluronate receptor CD44. These data suggest that targeting this CD44-mediated inhibition by apoptotic microparticles could be a novel strategy to potentiate DC activation of HIV-specific immunity.
Authors
Davor Frleta, Carolyn E. Ochoa, Holger B. Kramer, Shaukat Ali Khan, Andrea R. Stacey, Persephone Borrow, Benedikt M. Kessler, Barton F. Haynes, Nina Bhardwaj
Abstract
The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we establish a rationale for eliminating HIV-1–infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of CD4+ T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)–specific CD8+ T cells obtained from HIV-1–infected human subjects responded to HIV-1–infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)–specific CD8+ T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)–specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)–targeted HIV-1 vaccines and immunotherapeutics.
Authors
R. Brad Jones, Keith E. Garrison, Shariq Mujib, Vesna Mihajlovic, Nasra Aidarus, Diana V. Hunter, Eric Martin, Vivek M. John, Wei Zhan, Nabil F. Faruk, Gabor Gyenes, Neil C. Sheppard, Ingrid M. Priumboom-Brees, David A. Goodwin, Lianchun Chen, Melanie Rieger, Sophie Muscat-King, Peter T. Loudon, Cole Stanley, Sara J. Holditch, Jessica C. Wong, Kiera Clayton, Erick Duan, Haihan Song, Yang Xu, Devi SenGupta, Ravi Tandon, Jonah B. Sacha, Mark A. Brockman, Erika Benko, Colin Kovacs, Douglas F. Nixon, Mario A. Ostrowski
Abstract
Depletion of CD4+ T cells from the gut occurs rapidly during acute HIV-1 infection. This has been linked to systemic inflammation and disease progression as a result of translocation of microbial products from the gut lumen into the bloodstream. Combined antiretroviral therapy (cART) substantially restores CD4+ T cell numbers in peripheral blood, but the gut compartment remains largely depleted of such cells for poorly understood reasons. Here, we show that a lack of recruitment of CD4+ T cells to the gut could be involved in the incomplete mucosal immune reconstitution of cART-treated HIV-infected individuals. We investigated the trafficking of CD4+ T cells expressing the gut-homing receptors CCR9 and integrin α4β7 and found that many of these T cells remained in the circulation rather than repopulating the mucosa of the small intestine. This is likely because expression of the CCR9 ligand CCL25 was lower in the small intestine of HIV-infected individuals. The defective gut homing of CCR9+β7+ CD4+ T cells — a population that we found included most gut-homing Th17 cells, which have a critical role in mucosal immune defense — correlated with high plasma concentrations of markers of mucosal damage, microbial translocation, and systemic T cell activation. Our results thus describe alterations in CD4+ T cell homing to the gut that could prevent efficient mucosal immune reconstitution in HIV-infected individuals despite effective cART.
Authors
Maud Mavigner, Michelle Cazabat, Martine Dubois, Fatima-Ezzahra L’Faqihi, Mary Requena, Christophe Pasquier, Pascale Klopp, Jacques Amar, Laurent Alric, Karl Barange, Jean-Pierre Vinel, Bruno Marchou, Patrice Massip, Jacques Izopet, Pierre Delobel
Abstract
CD4+ T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of CD4+ T cells as mediators of antiviral immune responses and targets for virus replication is still unclear. Here, we have generated data in SIV-infected rhesus macaques (RMs) that suggest that CD4+ T cells are essential in establishing control of virus replication during acute infection. To directly assess the role of CD4+ T cells during primary SIV infection, we in vivo depleted these cells from RMs prior to infecting the primates with a pathogenic strain of SIV. Compared with undepleted animals, CD4+ lymphocyte–depleted RMs showed a similar peak of viremia, but did not manifest any post-peak decline of virus replication despite CD8+ T cell– and B cell–mediated SIV-specific immune responses comparable to those observed in control animals. Interestingly, depleted animals displayed rapid disease progression, which was associated with increased virus replication in non-T cells as well as the emergence of CD4-independent SIV-envelopes. Our results suggest that the antiviral CD4+ T cell response may play an important role in limiting SIV replication, which has implications for the design of HIV vaccines.
Authors
Alexandra M. Ortiz, Nichole R. Klatt, Bing Li, Yanjie Yi, Brian Tabb, Xing Pei Hao, Lawrence Sternberg, Benton Lawson, Paul M. Carnathan, Elizabeth M. Cramer, Jessica C. Engram, Dawn M. Little, Elena Ryzhova, Francisco Gonzalez-Scarano, Mirko Paiardini, Aftab A. Ansari, Sarah Ratcliffe, James G. Else, Jason M. Brenchley, Ronald G. Collman, Jacob D. Estes, Cynthia A. Derdeyn, Guido Silvestri
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)