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Henning Gruell, Florian Klein
Novel broadly neutralizing antibodies targeting HIV-1 hold promise for their use in the prevention and treatment of HIV-1 infection. Pre-clinical results have encouraged the evaluation of these antibodies in healthy and HIV-1-infected humans. In first clinical trials, highly potent broadly neutralizing antibodies have demonstrated their safety and significant antiviral activity by reducing viremia and delaying the time to viral rebound in individuals interrupting antiretroviral therapy. While emerging antibody-resistant viral variants have indicated limitations of antibody monotherapy, strategies to enhance the efficacy of broadly neutralizing antibodies in humans are under investigation...
November 16, 2018: Retrovirology
Tadasuke Naito, Jun-Ichirou Yasunaga, Yuichi Mitobe, Kazumasa Shirai, Hiroe Sejima, Hiroshi Ushirogawa, Yuetsu Tanaka, Tatsufumi Nakamura, Kousuke Hanada, Masahiro Fujii, Masao Matsuoka, Mineki Saito
BACKGROUND: Among human T cell leukemia virus type 1 (HTLV-1)-infected individuals, there is an association between HTLV-1 tax subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. To investigate the role of HTLV-1 subgroups in viral pathogenesis, we studied the functional difference in the subgroup-specific viral transcriptional regulators Tax and HBZ using microarray analysis, reporter gene assays, and evaluation of viral-host protein-protein interaction...
November 6, 2018: Retrovirology
Elizabeth M Anderson, Frank Maldarelli
Integration of viral DNA into the host genome is a central event in the replication cycle and the pathogenesis of retroviruses, including HIV. Although most cells infected with HIV are rapidly eliminated in vivo, HIV also infects long-lived cells that persist during combination antiretroviral therapy (cART). Cells with replication competent HIV proviruses form a reservoir that persists despite cART and such reservoirs are at the center of efforts to eradicate or control infection without cART. The mechanisms of persistence of these chronically infected long-lived cells is uncertain, but recent research has demonstrated that the presence of the HIV provirus has enduring effects on infected cells...
October 23, 2018: Retrovirology
Laura E McCoy
A large array of broadly neutralizing antibodies (bnAbs) against HIV have been isolated and described, particularly in the last decade. This continually expanding array of bnAbs has crucially led to the identification of novel epitopes on the HIV envelope protein via which antibodies can block a broad range of HIV strains. Moreover, these studies have produced high-resolution understanding of these sites of vulnerability on the envelope protein. They have also clarified the mechanisms of action of bnAbs and provided detailed descriptions of B cell ontogenies from which they arise...
October 16, 2018: Retrovirology
Bijan Mahboubi, Christina Gavegnano, Dong-Hyun Kim, Raymond F Schinazi, Baek Kim
BACKGROUND: SAM domain and HD domain containing protein 1 (SAMHD1) is a host anti-HIV-1 restriction factor known to suppress viral reverse transcription in nondividing myeloid cells by its dNTP triphosphorylase activity that depletes cellular dNTPs. However, HIV-2 and some SIV strains rapidly replicate in macrophages due to their accessory protein, viral protein X (Vpx), which proteosomally degrades SAMHD1 and elevates dNTP levels. Endogenous reverse transcription (ERT) of retroviruses is the extra-cellular reverse transcription step that partially synthesizes proviral DNAs within cell-free viral particles before the viruses infect new cells...
October 13, 2018: Retrovirology
Elisabeth Littwitz-Salomon, Thanh Nguyen, Simone Schimmer, Ulf Dittmer
Traditionally, NK cells belong to the innate immune system and eliminate virus-infected cells through their germline-encoded receptors. However, NK cells were recently reported to possess memory-like functions that were predominantly provided by hepatic NK cells. Memory properties were mainly documented in contact hypersensitivity models or during cytomegalovirus infections. However, the precise role and the physiologic importance of memory-like NK cells during retroviral infections are still under investigation...
October 6, 2018: Retrovirology
Catalina Méndez, Scott Ledger, Kathy Petoumenos, Chantelle Ahlenstiel, Anthony D Kelleher
BACKGROUND: Current antiretroviral therapy is effective in controlling HIV-1 infection. However, cessation of therapy is associated with rapid return of viremia from the viral reservoir. Eradicating the HIV-1 reservoir has proven difficult with the limited success of latency reactivation strategies and reflects the complexity of HIV-1 latency. Consequently, there is a growing need for alternate strategies. Here we explore a "block and lock" approach for enforcing latency to render the provirus unable to restart transcription despite exposure to reactivation stimuli...
October 4, 2018: Retrovirology
Allen Lin, Alejandro B Balazs
Vectored gene delivery of HIV-1 broadly neutralizing antibodies (bNAbs) using recombinant adeno-associated virus (rAAV) is a promising alternative to conventional vaccines for preventing new HIV-1 infections and for therapeutically suppressing established HIV-1 infections. Passive infusion of single bNAbs has already shown promise in initial clinical trials to temporarily decrease HIV-1 load in viremic patients, and to delay viral rebound from latent reservoirs in suppressed patients during analytical treatment interruptions of antiretroviral therapy...
October 1, 2018: Retrovirology
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
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