Abstract:
:Drug resistance remains a major concern for human immunodeficiency virus (HIV) treatment. To date, very few resistance mutations have emerged in first-line combination therapy that includes the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). In vitro, DTG selects for several primary mutations that induce low-level DTG resistance; secondary mutations, while increasing the level of resistance, however, further impair replication fitness, which raised the idea that DTG monotherapy may be feasible. The simian immunodeficiency virus (SIV) rhesus macaque model of HIV infection can be useful to explore this concept. Nine macaques were infected with virulent SIVmac251 and started on DTG monotherapy during either acute (n = 2) or chronic infection (n = 7). Within 4 weeks of treatment, all animals demonstrated a reduction in viremia of 0.8 to 3.5 log RNA copies/ml plasma. Continued treatment led to overall sustained benefits, but the outcome after 10 to 50 weeks of treatment was highly variable and ranged from viral rebound to near pretreatment levels to sustained suppression, with viremia being 0.5 to 5 logs lower than expected based on pretreatment viremia. A variety of mutations previously described to confer low-level resistance of HIV-1 to DTG or other INSTI were detected, and these were sometimes followed by mutations believed to be compensatory. Some mutations, such as G118R, previously shown to severely impair the replication capacity in vitro, were associated with more sustained virological and immunological benefits of continued DTG therapy, while other mutations, such as E92Q and G140A/Q148K, were associated with more variable outcomes. The observed variability of the outcomes in macaques warrants avoidance of DTG monotherapy in HIV-infected people.IMPORTANCE A growing number of anti-HIV drug combinations are effective in suppressing virus replication in HIV-infected persons. However, to reduce their cost and risk for toxicity, there is considerable interest in simplifying drug regimens. A major concern with single-drug regimens is the emergence of drug-resistant viral mutants. It has been speculated that DTG monotherapy may be a feasible option, because DTG may have a higher genetic barrier for the development of drug resistance than other commonly used antiretrovirals. To explore treatment initiation with DTG monotherapy, we started SIV-infected macaques on DTG during either acute or chronic infection. Although DTG initially reduced virus replication, continued treatment led to the emergence of a variety of viral mutations previously described to confer low-level resistance of HIV-1 to DTG, and this was associated with variable clinical outcomes. This unpredictability of mutational pathways and outcomes warns against using DTG monotherapy as initial treatment for HIV-infected people.
journal_name
J Viroljournal_title
Journal of virologyauthors
Van Rompay KKA,Hassounah S,Keele BF,Lifson JD,Ardeshir A,Watanabe J,Pham HT,Chertova E,Sowder R,Balzarini J,Mesplède T,Wainberg MAdoi
10.1128/JVI.01189-18subject
Has Abstractpub_date
2019-01-04 00:00:00issue
2eissn
0022-538Xissn
1098-5514pii
JVI.01189-18journal_volume
93pub_type
杂志文章abstract::Poliovirus (PV) is easily transferred to humans orally; however, no rodent model for oral infections has been developed because of the alimentary tract's low sensitivity to the virus. Here we showed that PV is inactivated by the low pH of the gastric contents in mice. The addition of 3% NaHCO3 to the viral inoculum in...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02675-06
更新日期:2007-08-01 00:00:00
abstract::The major immediate-early (MIE) gene of human cytomegalovirus (HCMV) produces multiple mRNAs through differential splicing and polyadenylation. Reverse transcriptase PCR was used to characterize transcripts from exons 1, 2, 3, and 4 (immediate-early 1 [IE1]). The expected IE72 and IE19 mRNAs were detected, as well as ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.15.8191-8200.2004
更新日期:2004-08-01 00:00:00
abstract::Forty isolates of herpes simplex virus were compared by means of cross-neutralization curves. The 11 oral isolates were serotype 1, and all 29 genital/anal isolates were serotype 2. The cytopathic effects of the two serotypes were consistently different. Passage of strains of type 1 and type 2 in mice and in rabbits y...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.5.1.51-59.1970
更新日期:1970-01-01 00:00:00
abstract::The vif gene of human immunodeficiency virus type 1 is absolutely required for productive infection of primary cells derived from human blood and certain immortalized T lymphoid cells, for example, H9. Cells with this restrictive phenotype are termed nonpermissive, whereas cell lines in which vif-deficient virus can r...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.8.5297-5305.1996
更新日期:1996-08-01 00:00:00
abstract:UNLABELLED:Inhibitor-of-apoptosis (IAP) proteins are key regulators of the innate antiviral response by virtue of their capacity to respond to signals affecting cell survival. In insects, wherein the host IAP provides a primary restriction to apoptosis, diverse viruses trigger rapid IAP depletion that initiates caspase...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.03659-14
更新日期:2015-04-01 00:00:00
abstract::The influenza virus NS1 protein inhibits the nuclear export of a spliced viral mRNA, NS2 mRNA (F. V. Alonso-Caplen, M. E. Nemeroff, Y. Qiu, and R. M. Krug, Genes Dev. 6:255-267, 1992). To identify the sequence in NS2 mRNA that is recognized by the NS1 protein, we developed a gel shift assay for the formation of specif...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.4.2425-2432.1994
更新日期:1994-04-01 00:00:00
abstract::To identify the domains of Vpr that are involved nuclear localization, we transfected HeLa cells with a panel of expression vectors that encode mutant Vpr protein with deletions or substitutions within putative domains. Immunofluorescence staining of transfected cells revealed that wild-type Vpr was localized predomin...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.15.7179-7186.2000
更新日期:2000-08-01 00:00:00
abstract::In gene therapy, the innate immune system is a significant barrier to the effective application of adenovirus (Ad) vectors. In kidney epithelium-derived (REC) cells, serotype 5 Ad vectors induce the expression of the chemokine CXCL10 (IP-10), a response that is dependent on NFkappaB. Compared to the parental vector Ad...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.23.14507-14515.2005
更新日期:2005-12-01 00:00:00
abstract::The role of cellular genes in West Nile virus (WNV) replication is not well understood. Examination of cellular transcripts upregulated during WNV infection revealed an increase in the expression of the src family kinase (SFK) c-Yes. WNV-infected cell lines treated with the SFK inhibitor PP2 demonstrated a 2- to 4-log...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.18.11943-11951.2005
更新日期:2005-09-01 00:00:00
abstract::The relationship between virus-specific CD8(+)-T-cell responses and viral persistence was studied in mice by using Hantaan virus (HTNV). We first established a simple method for measuring levels of virus-specific CD8(+) T cells by flow cytometry. Next, to produce a mouse model of persistent HTNV infection, newborn mic...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.15.8408-8417.2003
更新日期:2003-08-01 00:00:00
abstract::Human cytomegalovirus (HCMV) productive replication in vitro is most often studied in fibroblasts. In vivo, fibroblasts amplify viral titers, but transmission and pathogenesis require the infection of other cell types, most notably epithelial cells. In vitro, the study of HCMV infection of epithelial cells has been al...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00903-18
更新日期:2018-07-31 00:00:00
abstract::Interleukin-10 (IL-10) suppresses the maturation and cytokine production of dendritic cells (DCs), key regulators of adaptive immunity, and prevents the activation and polarization of naïve T cells towards protective gamma interferon-producing effectors. We hypothesized that human cytomegalovirus (HCMV) utilizes its v...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.16.8720-8731.2004
更新日期:2004-08-01 00:00:00
abstract::Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses. There are two ZAP isoforms arising from alternative splicing, which differ only at the C termini. It was recently reported that the long isoform (ZAPL) promotes proteasomal degradation of influenza A vir...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01909-16
更新日期:2017-01-03 00:00:00
abstract::Parvoviruses infect humans and a broad range of animals, from mammals to crustaceans, and generally are associated with a variety of acute and chronic diseases. However, many others cause persistent infections and are not known to be associated with any disease. Viral persistence is likely related to the ability to in...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00828-11
更新日期:2011-10-01 00:00:00
abstract::Viruses actively interact with host metabolism because viral replication relies on host cells to provide nutrients and energy. Vaccinia virus (VACV; the prototype poxvirus) prefers glutamine to glucose for efficient replication to the extent that VACV replication is hindered in glutamine-free medium. Remarkably, our d...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01834-18
更新日期:2019-06-14 00:00:00
abstract::Recombinant DNA clones of a viral clone of spleen necrosis virus, an avian retrovirus, were found to have long terminal repeats of different sizes. The variation was in the U3 region of the long terminal repeats, and any one clone had U3 of the same size in both long terminal repeats. The U3 regions in the 5' and 3' l...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.41.1.163-171.1982
更新日期:1982-01-01 00:00:00
abstract::The polypeptides of three paramyxoviruses (simian virus 5, Newcastle disease virus, and Sendai virus) were separated by polyacrylamide gel electrophoresis. Glycoproteins were identified by the use of radioactive glucosamine as a carbohydrate precursor. The protein patterns reveal similarities among the three viruses. ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.7.1.47-52.1971
更新日期:1971-01-01 00:00:00
abstract::The vesicular stomatitis virus (VSV) RNA-dependent RNA polymerase consists of two viral proteins; the large (L) protein is the main catalytic subunit, and the phosphoprotein (P) is an essential cofactor for polymerase function. The P protein interacts with the L protein and the N-RNA template, thus connecting the poly...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02384-13
更新日期:2014-02-01 00:00:00
abstract::Glycoprotein H (gH) is conserved among all herpesviruses and is essential for virus entry and cell fusion along with gL, gB, and, in most alphaherpesviruses, gD. Within the gH/gL heterodimer, it is thought that gH accounts for the fusion function and gL acts as a chaperone for the folding and transport of gH. Here, we...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00097-07
更新日期:2007-05-01 00:00:00
abstract::The Tax transactivator protein of human T-cell leukemia virus type 1 (HTLV-1) plays a central role in the activation of viral gene expression. In addition, Tax is capable of activating the expression of specific cellular genes and is involved in the transformation of T-lymphocytes resulting in the development of adult...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.1.738-745.1999
更新日期:1999-01-01 00:00:00
abstract::The Roseobacter clade has been recognized as one of the abundant bacterial lineages in marine environments, which makes the characterization of bacteriophages infecting members of the clade important. Here we report the complete genome sequence of bacteriophage P12053L, which infects Celeribacter sp. strain IMCC12053,...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01153-12
更新日期:2012-08-01 00:00:00
abstract::Innate immunity provides an immediate defense against infection after host cells sense danger signals from microbes. Endoplasmic reticulum (ER) stress arises from accumulation of misfolded/unfolded proteins when protein load overwhelms the ER folding capacity, which activates the unfolded protein response (UPR) to res...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01690-17
更新日期:2017-12-14 00:00:00
abstract::We investigated the cis-acting sequences involved in termination of vesicular stomatis virus mRNA synthesis by using bicistronic genomic analogs. All of the cis-acting signals necessary for termination reside within the first 13 nucleotides of the 23-nucleotide conserved gene junction. This 13-nucleotide termination s...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.11.8718-8725.1997
更新日期:1997-11-01 00:00:00
abstract::Herpes simplex virus (HSV) glycoprotein B (gB) is an integral part of the multicomponent fusion system required for virus entry and cell-cell fusion. Here we investigated the mechanism of viral neutralization by the monoclonal antibody (MAb) 2c, which specifically recognizes the gB of HSV type 1 (HSV-1) and HSV-2. Bin...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01924-10
更新日期:2011-02-01 00:00:00
abstract::Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL) cells are predominantly infected with latent Kaposi's sarcoma-associated herpesvirus (KSHV), presenting a barrier to the destruction of tumor cells. Latent KSHV can be reactivated to undergo lytic replication. Here we report that in PEL cells, oxidative stress ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01742-10
更新日期:2011-01-01 00:00:00
abstract::Sulfation is a posttranslational modification of proteins which occurs on either the tyrosine residues or the carbohydrate moieties of some glycoproteins. In the case of secretory proteins, sulfation has been hypothesized to act as a signal for export from the cell. We have shown that the human immunodeficiency virus ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.12.6953-6959.1992
更新日期:1992-12-01 00:00:00
abstract::A series of recombinant molecules were constructed which direct the expression of the easily assayed gene chloramphenicol acetyltransferase. We have used these recombinants to show that the 73/72-base-pair tandem repeat unit from the Moloney murine sarcoma virus long terminal repeat shares a number of properties with ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.49.1.183-189.1984
更新日期:1984-01-01 00:00:00
abstract::The in vitro transcription of the genome segments of insect cytoplasmic polyhedrosis virus was examined for a possible mechanism of coordinate control. Initiation of the first transcription cycle, primed by preincubation in the absence of CTP, was synchronous for all 10 viral genome segments. The time required for the...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.41.1.326-329.1982
更新日期:1982-01-01 00:00:00
abstract::Human papillomavirus type 16 (HPV16) is the primary etiologic agent for cervical cancer. The infectious entry of HPV16 into cells occurs via a so-far poorly characterized clathrin- and caveolin-independent endocytic pathway, which involves tetraspanin proteins and actin. In this study, we investigated the specific rol...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02906-12
更新日期:2013-03-01 00:00:00
abstract:UNLABELLED:CBFβ was recently found to be a key regulator of the ability of human immunodeficiency virus type 1 (HIV-1) Vif to overcome host antiviral APOBEC3 proteins. However, the detailed molecular requirements for the Vif-CBFβ interaction are still not clear. Here, we mapped the minimum Vif domain required for CBFβ ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.03604-13
更新日期:2014-03-01 00:00:00