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Meng Wang, Wei Yang, Yu Chen, Jian Wang, Juan Tan, Wentao Qiao
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) Tat protein plays an essential role in HIV-1 gene transcription. Tat transactivates HIV-1 long terminal repeat (LTR)-directed gene expression through direct interactions with the transactivation-responsive region (TAR) element and other cis elements in the LTR. The TAR-independent Tat-mediated LTR transactivation is modulated by several host factors, but the mechanism is not fully understood. RESULTS: Here, we report that Tat interacts with the Rel homology domain of RelB through its core region...
September 21, 2018: Retrovirology
S Mediouni, J A Jablonski, S Tsuda, A Richard, C Kessing, M V Andrade, A Biswas, Y Even, T Tellinghuisen, H Choe, M Cameron, M Stevenson, S T Valente
There is a constant need to improve antiretrovirals against HIV since therapy is limited by cost, side effects and the emergence of drug resistance. Kudzu is a climbing vine from which the root extract (Pueraria lobata), rich in isoflavones and saponins, has long been used in traditional Chinese medicine for a variety of purposes, from weight loss to alcoholism prevention. Here we show that Kudzu root extract significantly inhibits HIV-1 entry into cell lines, primary human CD4+ T lymphocytes and macrophages, without cell-associated toxicity...
September 20, 2018: Retrovirology
Alba Torrents de la Peña, Rogier W Sanders
An effective HIV-1 vaccine probably will need to be able to induce broadly neutralizing HIV-1 antibodies (bNAbs) in order to be efficacious. The many bNAbs that have been isolated from HIV-1 infected patients illustrate that the human immune system is able to elicit this type of antibodies. The elucidation of the structure of the HIV-1 envelope glycoprotein (Env) trimer has further fueled the search for Env immunogens that induce bNAbs, but while native Env trimer mimetics are often capable of inducing strain-specific neutralizing antibodies (NAbs) against the parental virus, they have not yet induced potent bNAb responses...
September 12, 2018: Retrovirology
Diogo Gama Caetano, Fernanda Heloise Côrtes, Gonzalo Bello, Sylvia Lopes Maia Teixeira, Brenda Hoagland, Beatriz Grinsztejn, Valdilea Gonçalves Veloso, Monick Lindenmeyer Guimarães, Mariza Gonçalves Morgado
BACKGROUND: Despite the low level of viral replication in HIV controllers (HICs), studies have reported viral mutations related to escape from cytotoxic T-lymphocyte (CTL) response in HIV-1 plasma sequences. Thus, evaluating the dynamics of the emergence of CTL-escape mutants in HICs reservoirs is important for understanding viremia control. To analyze the HIV-1 mutational profile and dynamics of CTL-escape mutants in HICs, we selected 11 long-term non-progressor individuals and divided them into the following groups: (1) viremic controllers (VCs; n = 5) and (2) elite controllers (ECs; n = 6)...
September 10, 2018: Retrovirology
Elise Landais, Penny L Moore
Broadly neutralizing antibodies (bNAbs), able to prevent viral entry by diverse global viruses, are a major focus of HIV vaccine design, with data from animal studies confirming their ability to prevent HIV infection. However, traditional vaccine approaches have failed to elicit these types of antibodies. During chronic HIV infection, a subset of individuals develops bNAbs, some of which are extremely broad and potent. This review describes the immunological and virological factors leading to the development of bNAbs in such "elite neutralizers"...
September 5, 2018: Retrovirology
Neal N Padte, Jian Yu, Yaoxing Huang, David D Ho
As increasing numbers of broadly neutralizing monoclonal antibodies (mAbs) against HIV-1 enter clinical trials, it is becoming evident that combinations of mAbs are necessary to block infection by the diverse array of globally circulating HIV-1 strains and to limit the emergence of resistant viruses. Multi-specific antibodies, in which two or more HIV-1 entry-targeting moieties are engineered into a single molecule, have expanded rapidly in recent years and offer an attractive solution that can improve neutralization breadth and erect a higher barrier against viral resistance...
August 29, 2018: Retrovirology
Robert J Gifford, Jonas Blomberg, John M Coffin, Hung Fan, Thierry Heidmann, Jens Mayer, Jonathan Stoye, Michael Tristem, Welkin E Johnson
Retroviral integration into germline DNA can result in the formation of a vertically inherited proviral sequence called an endogenous retrovirus (ERV). Over the course of their evolution, vertebrate genomes have accumulated many thousands of ERV loci. These sequences provide useful retrospective information about ancient retroviruses, and have also played an important role in shaping the evolution of vertebrate genomes. There is an immediate need for a unified system of nomenclature for ERV loci, not only to assist genome annotation, but also to facilitate research on ERVs and their impact on genome biology and evolution...
August 28, 2018: Retrovirology
Matthew S Parsons, Amy W Chung, Stephen J Kent
Anti-HIV-1 broadly neutralizing antibodies (BnAbs) exhibit an impressive capacity to protect against chimeric SIV-HIV (SHIV) challenges in macaques and potently reduce viremia in both SHIV-infected macaques and HIV-1-infected humans. There is a body of evidence suggesting Fc-mediated functions of anti-HIV-1 binding antibodies are important in protecting from infection and controlling viremia. The degree to which the efficacy of BnAbs is assisted by Fc-mediated functions is of great interest. Challenge experiments with the older generation BnAb b12 showed that mutating the Fc region to abrogate Fcγ receptor binding reduced protective efficacy in macaques...
August 22, 2018: Retrovirology
Meagan Montesion, Zachary H Williams, Ravi P Subramanian, Charlotte Kuperwasser, John M Coffin
BACKGROUND: Increased transcription of the human endogenous retrovirus group HERV-K (HML-2) is often seen during disease. Although the mechanism of its tissue-specific activation is unclear, research shows that LTR CpG hypomethylation alone is not sufficient to induce its promoter activity and that the transcriptional milieu of a malignant cell contributes, at least partly, to differential HML-2 expression. RESULTS: We analyzed the relationship between LTR sequence variation and promoter expression patterns in human breast cancer cell lines, finding them to be positively correlated...
August 20, 2018: Retrovirology
Maureen Oliveira, Ruxandra-Ilinca Ibanescu, Kaitlin Anstett, Thibault Mésplède, Jean-Pierre Routy, Marjorie A Robbins, Bluma G Brenner
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are recommended for first-line HIV therapy based on their relatively high genetic barrier to resistance. Although raltegravir (RAL) and elvitegravir (EVG) resistance profiles are well-characterized, resistance patterns for dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) remain largely unknown. Here, in vitro drug selections compared the development of resistance to DTG, BIC, CAB, EVG and RAL using clinical isolates from treatment-naïve primary HIV infection (PHI) cohort participants (n = 12), and pNL4...
August 17, 2018: Retrovirology
Eirini Moysi, Constantinos Petrovas, Richard A Koup
The induction of HIV-1-specific antibodies that can neutralize a broad number of isolates is a major goal of HIV-1 vaccination strategies. However, to date no candidate HIV-1 vaccine has successfully elicited broadly neutralizing antibodies of sufficient quality and breadth for protection. In this review, we focus on the role of follicular helper CD4 T-cells (Tfh) in the development of such cross-reactive protective antibodies. We discuss germinal center (GC) formation and the dynamics of Tfh and GC B cells during HIV-1/SIV infection and vaccination...
August 6, 2018: Retrovirology
Joel Finney, Garnett Kelsoe
A central puzzle in HIV-1 research is the inability of vaccination or even infection to reliably elicit humoral responses against broadly neutralizing epitopes in the HIV-1 envelope protein. In infected individuals, broadly neutralizing antibodies (bNAbs) do arise in a substantial minority, but only after 2 or more years of chronic infection. All known bNAbs possess at least one of three traits: a high frequency of somatic hypermutation, a long third complementarity determining region in the antibody heavy chain (HCDR3), or significant poly- or autoreactivity...
July 28, 2018: Retrovirology
Jérémy Dufloo, Timothée Bruel, Olivier Schwartz
HIV-1 spreads through contacts between infected and target cells. Polarized viral budding at the contact site forms the virological synapse. Additional cellular processes, such as nanotubes, filopodia, virus accumulation in endocytic or phagocytic compartments promote efficient viral propagation. Cell-to-cell transmission allows immune evasion and likely contributes to HIV-1 spread in vivo. Anti-HIV-1 broadly neutralizing antibodies (bNAbs) defeat the majority of circulating viral strains by binding to the viral envelope glycoprotein (Env)...
July 28, 2018: Retrovirology
Harini Subbaraman, Merle Schanz, Alexandra Trkola
The elicitation of broadly neutralizing antibodies (bnAbs) is considered crucial for an effective, preventive HIV-1 vaccine. Led by the discovery of a new generation of potent bnAbs, the field has significantly advanced over the past decade. There is a wealth of knowledge about the development of bnAbs in natural infection, their specificity, potency, breadth and function. Yet, devising immunogens and vaccination regimens that evoke bnAb responses has not been successful. Where are the roadblocks in their development? What can we learn from natural infection, where bnAb induction is possible but rare? Herein, we will reflect on key discoveries and discuss open questions that may bear crucial insights needed to move towards creating effective bnAb vaccines...
July 28, 2018: Retrovirology
Sweety Samal, Supratik Das, Saikat Boliar, Huma Qureshi, Tripti Shrivastava, Naresh Kumar, Sandeep Goswami, Manish Bansal, Bimal K Chakrabarti
BACKGROUND: HIV-1 Env gp160 is cleaved to form gp120 and gp41 and the functional HIV-1 Env is a trimer of non-covalently associated heterodimeric subunits, gp120 and gp41. The cleaved, native, trimeric form of Envs expose only broadly neutralizing antibody (bNAb) epitopes while occluding epitopes targeted by non-neutralizing antibodies (non-NAbs). We and others have previously observed that efficient cleavage of Envs into their constituent subunits co-relates with specific binding to bNAbs and poor binding to non-neutralizing antibodies (non-NAbs)...
July 20, 2018: Retrovirology
Ruxia Ren, Shuwen Yin, Baolong Lai, Lingzhen Ma, Jiayong Wen, Xuanxuan Zhang, Fangyuan Lai, Shuwen Liu, Lin Li
BACKGROUND: Semen is a critical vector for human immunodeficiency virus (HIV) sexual transmission and harbors seminal amyloid fibrils that can markedly enhance HIV infection. Semen-derived enhancer of viral infection (SEVI) is one of the best-characterized seminal amyloid fibrils. Due to their highly cationic properties, SEVI fibrils can capture HIV virions, increase viral attachment to target cells, and augment viral fusion. Some studies have reported that myricetin antagonizes amyloid β-protein (Aβ) formation; myricetin also displays strong anti-HIV activity in vitro...
July 16, 2018: Retrovirology
Joris Paris, Joëlle Tobaly-Tapiero, Marie-Lou Giron, Julien Burlaud-Gaillard, Florence Buseyne, Philippe Roingeard, Pascale Lesage, Alessia Zamborlini, Ali Saïb
BACKGROUND: Nuclear localization of Gag is a property shared by many retroviruses and retrotransposons. The importance of this stage for retroviral replication is still unknown, but studies on the Rous Sarcoma virus indicate that Gag might select the viral RNA genome for packaging in the nucleus. In the case of Foamy viruses, genome encapsidation is mediated by Gag C-terminal domain (CTD), which harbors three clusters of glycine and arginine residues named GR boxes (GRI-III). In this study we investigated how PFV Gag subnuclear distribution might be regulated...
July 11, 2018: Retrovirology
Art F Y Poon, Jessica L Prodger, Briana A Lynch, Jun Lai, Steven J Reynolds, Jingo Kasule, Adam A Capoferri, Susanna L Lamers, Christopher W Rodriguez, Daniel Bruno, Stephen F Porcella, Craig Martens, Thomas C Quinn, Andrew D Redd
BACKGROUND: The ability of HIV-1 to integrate into the genomes of quiescent host immune cells, establishing a long-lived latent viral reservoir (LVR), is the primary obstacle to curing these infections. Quantitative viral outgrowth assays (QVOAs) are the gold standard for estimating the size of the replication-competent HIV-1 LVR, measured by the number of infectious units per million (IUPM) cells. QVOAs are time-consuming because they rely on culturing replicate wells to amplify the production of virus antigen or nucleic acid to reproducibly detectable levels...
July 5, 2018: Retrovirology
Danica D Wiredja, Caroline O Tabler, Daniela M Schlatzer, Ming Li, Mark R Chance, John C Tilton
BACKGROUND: Viral reprogramming of host cells enhances replication and is initiated by viral interaction with the cell surface. Upon human immunodeficiency virus (HIV) binding to CD4+ T cells, a signal transduction cascade is initiated that reorganizes the actin cytoskeleton, activates transcription factors, and alters mRNA splicing pathways. METHODS: We used a quantitative mass spectrometry-based phosphoproteomic approach to investigate signal transduction cascades initiated by CCR5-tropic HIV, which accounts for virtually all transmitted viruses and the vast majority of viruses worldwide...
July 3, 2018: Retrovirology
Hayato Murakoshi, Chengcheng Zou, Nozomi Kuse, Tomohiro Akahoshi, Takayuki Chikata, Hiroyuki Gatanaga, Shinichi Oka, Tomáš Hanke, Masafumi Takiguchi
BACKGROUND: Development of AIDS vaccines for effective prevention of circulating HIV-1 is required, but no trial has demonstrated definitive effects on the prevention. Several recent T-cell vaccine trials showed no protection against HIV-1 acquisition although the vaccines induced HIV-1-specific T-cell responses, suggesting that the vaccine-induced T cells have insufficient capacities to suppress HIV-1 replication and/or cross-recognize circulating HIV-1. Therefore, it is necessary to develop T-cell vaccines that elicit T cells recognizing shared protective epitopes with strong ability to suppress HIV-1...
July 3, 2018: Retrovirology
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