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Nuria González, Krisha McKee, Rebecca M Lynch, Ivelin S Georgiev, Laura Jimenez, Eulalia Grau, Eloísa Yuste, Peter D Kwong, John R Mascola, José Alcamí
BACKGROUND: Only a small fraction of HIV-1-infected patients develop broadly neutralizing antibodies (bNAbs), a process generally associated to chronic antigen stimulation. It has been described that rare aviremic HIV-1-infected patients can generate bNAbs but this issue remains controversial. To address this matter we have assessed bNAb responses in a large cohort of long-term non-progressors (LTNPs) with low or undetectable viremia. METHODS: Samples from the LTNP cohort of the Spanish AIDS Research Network (87 elite and 42 viremic controllers) and a control population of 176 viremic typical-progressors (TPs) were screened for bNAbs using Env-recombinant viruses...
2018: PloS One
Jiehua Zhou, Daniel Lazar, Haitang Li, Xin Xia, Sangeetha Satheesan, Paige Charlins, Denis O'Mealy, Ramesh Akkina, Sheena Saayman, Marc S Weinberg, John J Rossi, Kevin V Morris
Gene-based therapies represent a promising therapeutic paradigm for the treatment of HIV-1, as they have the potential to maintain sustained viral inhibition with reduced treatment interventions. Such an option may represent a long-term treatment alternative to highly active antiretroviral therapy. Methods: We previously described a therapeutic approach, referred to as transcriptional gene silencing (TGS), whereby small noncoding RNAs directly inhibit the transcriptional activity of HIV-1 by targeting sites within the viral promoter, specifically the 5' long terminal repeat (LTR)...
2018: Theranostics
Hannah F Löchel, Mona Riemenschneider, Dmitrij Frishman, Dominik Heider
Motivation: The V3 loop of the gp120 glycoprotein of the Human Immunodeficiency Virus 1 (HIV-1) is considered to be responsible for viral coreceptor tropism. gp120 interacts with the CD4 receptor of the host cell and subsequently V3 binds either CCR5 or CXCR4. Due to the fact that the CCR5 coreceptor is targeted by entry inhibitors, a reliable prediction of the coreceptor usage of HIV-1 is of great interest for antiretroviral therapy. Although several methods for the prediction of coreceptor tropism are available, almost all of them have been developed based on only subtype B sequences, and it has been shown in several studies that the prediction of non-B sequences, in particular subtype A sequences, are less reliable...
March 15, 2018: Bioinformatics
Aisha Nazli, Sara Dizzell, Muhammad Atif Zahoor, Victor H Ferreira, Jessica Kafka, Matthew William Woods, Michel Ouellet, Ali A Ashkar, Michel J Tremblay, Dawn Me Bowdish, Charu Kaushic
More than 40% of HIV infections occur via female reproductive tract (FRT) through heterosexual transmission. Epithelial cells that line the female genital mucosa are the first line of defense against HIV-1 and other sexually transmitted pathogens. These sentient cells recognize and respond to external stimuli by induction of a range of carefully balanced innate immune responses. Previously, we have shown that in response to HIV-1 gp120, the genital epithelial cells (GECs) from upper reproductive tract induce an inflammatory response that may facilitate HIV-1 translocation and infection...
March 19, 2018: Cellular & Molecular Immunology
Kelei Li, Zhe Cong, Zhuoying Peng, Ting Chen, Jing Xue, Qiang Wei
CD45 has been reported to regulate the HIV-1 gp120-induced apoptosis of Jurkat cells. Here, we demonstrate that the extracellular domain of CD45 plays an important role in this function. We observed that CD45RO-transfected cells, but not cells transfected with other CD45 isoforms, underwent significant apoptosis induced by gp120. However, a CD45RA-transfected cell line treated with an O-glycan inhibitor was able to undergo apoptosis. The role of the extracellular domain of CD45 was further confirmed using CD45 isoformtransfected cell lines by analyzing the phosphorylation of Lck, which is a direct substrate of CD45 tyrosine phosphatase, and by using an Lck inhibitor...
December 20, 2017: Biological Chemistry
Tongqing Zhou, Anqi Zheng, Ulrich Baxa, Gwo-Yu Chuang, Ivelin S Georgiev, Rui Kong, Sijy O'Dell, Syed Shahzad-Ul-Hussan, Chen-Hsiang Shen, Yaroslav Tsybovsky, Robert T Bailer, Syna K Gift, Mark K Louder, Krisha McKee, Reda Rawi, Catherine H Stevenson, Guillaume B E Stewart-Jones, Justin D Taft, Eric Waltari, Yongping Yang, Baoshan Zhang, Sachin S Shivatare, Vidya S Shivatare, Chang-Chun D Lee, Chung-Yi Wu, James C Mullikin, Carole A Bewley, Dennis R Burton, Victoria R Polonis, Lawrence Shapiro, Chi-Huey Wong, John R Mascola, Peter D Kwong, Xueling Wu
Virtually the entire surface of the HIV-1-envelope trimer is recognized by neutralizing antibodies, except for a highly glycosylated region at the center of the "silent face" on the gp120 subunit. From an HIV-1-infected donor, #74, we identified antibody VRC-PG05, which neutralized 27% of HIV-1 strains. The crystal structure of the antigen-binding fragment of VRC-PG05 in complex with gp120 revealed an epitope comprised primarily of N-linked glycans from N262, N295, and N448 at the silent face center...
March 7, 2018: Immunity
F Nici, G Oliviero, A P Falanga, S D'Errico, M Marzano, D Musumeci, D Montesarchio, S Noppen, C Pannecouque, G Piccialli, N Borbone
By combining the ability of short G-rich oligodeoxyribonucleotides (ODNs) containing the sequence 5'CGGA3' to form higher order G-quadruplex (G4) complexes with the tetra-end-linked (TEL) concept to produce aptamers targeting the HIV envelope glycoprotein 120 (gp120), three new TEL-ODNs (1-3) having the sequence 5'CGGAGG3' were synthesized with the aim of studying the effect of G4 dimerization on their anti-HIV activity. Furthermore, in order to investigate the effect of the groups at the 5' position, the 5' ends of 1-3 were left uncapped (1) or capped with either the lipophilic dimethoxytrityl (DMT) (2) or the hydrophilic glucosyl-4-phosphate (3) moieties...
March 15, 2018: Organic & Biomolecular Chemistry
Matthew V Green, Jonathan D Raybuck, Xinwen Zhang, Mariah M Wu, Stanley A Thayer
A defining feature of HIV-associated neurocognitive disorder (HAND) is the loss of excitatory synaptic connections. Synaptic changes that occur during exposure to HIV appear to result, in part, from a homeostatic scaling response. Here we discuss the mechanisms of these changes from the perspective that they might be part of a coping mechanism that reduces synapses to prevent excitotoxicity. In transgenic animals expressing the HIV proteins Tat or gp120, the loss of synaptic markers precedes changes in neuronal number...
March 14, 2018: Neurochemical Research
Quang N Nguyen, David R Martinez, Jonathon E Himes, R Whitney Edwards, Qifeng Han, Amit Kumar, Riley Mangan, Nathan I Nicely, Guanhua Xie, Nathan Vandergrift, Xiaoying Shen, Justin Pollara, Sallie R Permar
BACKGROUND: The initial envelope (Env)-specific antibody response in acutely HIV-1-infected individuals and simian immunodeficiency virus (SIV)-infected rhesus monkeys (RMs) is dominated by non-neutralizing antibodies targeting Env gp41. In contrast, natural primate SIV hosts, such as African green monkeys (AGMs), develop a predominant Env gp120-specific antibody response to SIV infection. However, the fine-epitope specificity and function of SIV Env-specific plasma IgG, and their potential role on autologous virus co-evolution in SIV-infected AGMs and RMs remain unclear...
March 9, 2018: Retrovirology
Vani G S Narasimhulu, Anna K Bellamy-McIntyre, Annamarie E Laumaea, Chan-Sien Lay, David N Harrison, Hannah A D King, Heidi E Drummer, Pantelis Poumbourios
HIV-1 is spread by cell-free virions and by cell-cell viral transfer. We asked whether the structure and function of a broad neutralizing antibody (bNAb) epitope, the membrane-proximal ectodomain region (MPER) of the viral gp41 transmembrane glycoprotein, differ in cell-free and cell-cell transmitted viruses and whether this difference could be related to Ab neutralization sensitivity. Whereas cell-free viruses bearing W666A and I675A substitutions in the MPER lacked infectivity, cell-associated mutant viruses were able to initiate robust spreading infection...
March 1, 2018: Journal of Biological Chemistry
Manickam Ashokkumar, Shambhu G Aralaguppe, Srikanth P Tripathy, Luke Elizabeth Hanna, Ujjwal Neogi
Adequate information on the precise molecular and biological composition of the viral strains that establish HIV-infection in the human host will provide effective means of immunization against HIV-infection. In an attempt to identify and differentiate the biological properties and infectious potential of the transmitted founder (TF) virus from the population of the early transmitted virus, patient-derived 250 envelope glycoprotein, gp120 were cloned in pMN-K7-Luc-IRESs-NefΔgp120 to obtain chimeric viruses...
February 28, 2018: Journal of Virology
P J Klasse, Thomas J Ketas, Christopher A Cottrell, Gabriel Ozorowski, Gargi Debnath, Diawoye Camara, Erik Francomano, Pavel Pugach, Rajesh P Ringe, Celia C LaBranche, Marit J van Gils, Christine A Bricault, Dan H Barouch, Shane Crotty, Guido Silvestri, Sudhir Kasturi, Bali Pulendran, Ian A Wilson, David C Montefiori, Rogier W Sanders, Andrew B Ward, John P Moore
The native-like, soluble SOSIP.664 trimer based on the BG505 clade A env gene of HIV-1 is immunogenic in various animal species, of which the most studied are rabbits and rhesus macaques. The trimer induces autologous neutralizing antibodies (NAbs) consistently but at a wide range of titers and with incompletely determined specificities. A precise delineation of immunogenic neutralization epitopes on native-like trimers could help strategies to extend the NAb response to heterologous HIV-1 strains. One autologous NAb epitope on the BG505 Env trimer is known to involve residues lining a hole in the glycan shield that is blocked by adding a glycan at either residue 241 or 289...
February 23, 2018: PLoS Pathogens
Gavin R Owen, Doris Le, Stoyan Stoychev, Nichole M Cerutti, Maria Papathanasopoulos
CD4, a membrane glycoprotein expressed by specific leukocytes, plays a vital role in the human immune response and acts as a primary receptor for HIV entry. Of its four ecto-domains (D1-D4), D1, D2, and D4 each contain a distinctive disulfide bond. Whereas the disulfides of D1 and D4 are more traditional in nature, providing structural functions, that of D2 is referred to as an "allosteric" disulfide due to its high dihedral strain energy and relative ease of reduction that is thought to regulate CD4 structure and function by shuffling its redox state...
February 19, 2018: Biochemical and Biophysical Research Communications
Keiya Takahashi, Hyun Yi, Ching-Hang Liu, Shue Liu, Yuta Kashiwagi, Dennis J Patin, Shuanglin Hao
The symptoms of HIV-sensory neuropathy are dominated by neuropathic pain. Recent data show that repeated use of opiates enhances the chronic pain states in HIV patients. Limited attention has so far been devoted to exploring the exact pathogenesis of HIV painful disorder and opiate abuse in vivo, for which there is no effective treatment. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal domain protein (BET) family and functions as a chromatin 'reader' that binds acetylated lysines in histones in brain neurons to mediate the transcriptional regulation underlying learning and memory...
February 20, 2018: Neuroreport
Jason Yolitz, Catherine Schwing, Julia Chang, Donald Van Ryk, Fatima Nawaz, Danlan Wei, Claudia Cicala, James Arthos, Anthony S Fauci
The HIV-1 envelope protein (Env) of early-replicating viruses encodes several distinct transmission signatures. One such signature involves a reduced number of potential N-linked glycosylation sites (PNGs). This transmission signature underscores the importance of posttranslational modifications in the fitness of early-replicating isolates. An additional signature in Env involves the overrepresentation of basic amino acid residues at a specific position in the Env signal peptide (SP). In this report, we investigated the potential impact of this SP signature on gp120 glycosylation and antigenicity...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Myungguen Chung, Soo Young Cho, Young Seek Lee
We aimed to understand the molecular changes in host cells that accompany infection by the seasonal influenza A H1N1 virus because the initial response rapidly changes owing to the fact that the virus has a robust initial propagation phase. Human epithelial alveolar A549 cells were infected and total RNA was extracted at 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, and 48 h post infection (h.p.i.). The differentially expressed host genes were clustered into two distinct sets of genes as the infection progressed over time...
February 5, 2018: Biomolecules & Therapeutics
Nicole L Yates, Allan C deCamp, Bette T Korber, Hua-Xin Liao, Carmela Irene, Abraham Pinter, James Peacock, Linda J Harris, Sheetal Sawant, Peter Hraber, Xiaoying Shen, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Phillip W Berman, Merlin L Robb, Giuseppe Pantaleo, Susan Zolla-Pazner, Barton F Haynes, S Munir Alam, David C Montefiori, Georgia D Tomaras
Induction of broadly cross-reactive anti-viral humoral responses with the capacity to target globally diverse circulating strains is a key goal for HIV-1 immunogen design. A major gap in the field is the identification of diverse HIV-1 envelope antigens to evaluate vaccine regimens for binding antibody breadth. In this study, we define unique antigen panels to map HIV-1 vaccine-elicited antibody breadth and durability. Diverse HIV-1 envelope glycoproteins were selected based on genetic and geographic diversity to cover the global epidemic, with a focus on sexually acquired transmitted/founder viruses with a tier-2 neutralization phenotype...
January 31, 2018: Journal of Virology
Coral M Capó-Vélez, Bryan Morales-Vargas, Aurian García-González, José G Grajales-Reyes, Manuel Delgado-Vélez, Bismark Madera, Carlos A Báez-Pagán, Orestes Quesada, José A Lasalde-Dominicci
Currently, there are no specific therapies to treat HIV-1 associated neurocognitive disorders (HAND). The HIV-1 envelope, gp120, induces neuropathological changes similar to those in HAND patients; furthermore, it triggers an upregulation of the α7-nicotinic acetylcholine receptor (α7-nAChR), facilitating intracellular calcium overload and neuronal cell death. Using a gp120IIIB-transgenic mouse (gp120-tgm) model, we demonstrate that α7-nAChRs are upregulated on striatal neurons. Activation of α7-nAChRs leads to an increase in both intracellular calcium and percentage of apoptotic cells, which can be abrogated by antagonizing the receptor, suggesting a role for α7-nAChRs in gp120-induced neurotoxicity...
January 29, 2018: Scientific Reports
Masato Ogishi, Hiroshi Yotsuyanagi
BACKGROUND: HIV-associated neurocognitive disorder (HAND) remains an important and yet potentially underdiagnosed manifestation despite the fact that the modern combination antiretroviral therapy (cART) has achieved effective viral suppression and greatly reduced the incidence of life-threatening events. Although HIV neurotoxicity is thought to play a central role, the potential of viral genetic signature as diagnostic and/or prognostic biomarker has yet to be fully explored. RESULTS: Using a manually curated sequence metadataset (80 specimens, 2349 sequences), we demonstrated that only three genetic features are sufficient to predict HAND status regardless of sampling tissues; the accuracy reached 100 and 94% in the hold-out testing subdataset and the entire dataset, respectively...
January 27, 2018: Retrovirology
Blake F Frey, Jiansheng Jiang, Yongjun Sui, Lisa F Boyd, Bin Yu, Gwen Tatsuno, Rolf Billeskov, Shahram Solaymani-Mohammadi, Phillip W Berman, David H Margulies, Jay A Berzofsky
Unlike cytosolic processing and presentation of viral Ags by virus-infected cells, Ags first expressed in infected nonprofessional APCs, such as CD4+ T cells in the case of HIV, are taken up by dendritic cells and cross-presented. This generally requires entry through the endocytic pathway, where endosomal proteases have first access for processing. Thus, understanding virus escape during cross-presentation requires an understanding of resistance to endosomal proteases, such as cathepsin S (CatS). We have modified HIV-1MN gp120 by mutating a key CatS cleavage site (Thr322Thr323) in the V3 loop of the immunodominant epitope IGPGRAFYTT to IGPGRAFYVV to prevent digestion...
January 26, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
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