Complete sequence of an isolate of snake melon asteroid mosaic virus confirms that it is a member of a distinct sobemovirus species.

A virus tentatively named "snake melon asteroid mosaic virus" (SMAMV) was found in Sudan in cucurbit crops (10% of 600 samples) between 1992 and 2003. Biological and cytological properties as well as sequence data on a 345-nt fragment suggested that SMAMV was a member of the genus Sobemovirus. However, no complete sequence had been obtained, and the relationship between SMAMV and the acknowledged sobemoviruses had not been ascertained. In this work, we obtained the full-length sequence of an SMAMV isolate. The sequence was 4225 nt long, with a typical sobemovirus genetic organization. Sequence identity to other sobemoviruses was below 50%, both for the full-length genome and for individual proteins. These data confirm that SMAMV belongs to a novel sobemovirus species.

Characterization of the first tenuivirus naturally infecting dicotyledonous plants.

A mechanically transmissible virus tentatively named "melon chlorotic spot virus" (MeCSV) was isolated in southeastern France from a melon plant showing chlorotic spots and yellowing of the older leaves. Its complete sequence was obtained by Illumina and Sanger sequencing. The genome comprises eight RNAs for a total size of 20,079 nt and is distantly related to Ramu stunt virus and maize yellow stunt virus, two tentative tenuiviruses. MeCSV differs from other tenuiviruses by its number of genomic fragments, by being readily mechanically transmissible, and by infecting only dicotyledonous hosts. MeCSV should thus be considered a member of a tentative new species related to tenuiviruses.

Biological and Genetic Characterization of New and Known Necroviruses Causing an Emerging Systemic Necrosis Disease of Corn Salad (Valerianella locusta) in France.

An emerging systemic necrosis disease of corn salad was first observed in the Nantes region of France in the late 2000s. Classical virology and high-throughput sequencing approaches demonstrated that the disease is associated with four different necroviruses: tobacco necrosis virus A (TNVA), tobacco necrosis virus D (TNVD), olive mild mosaic virus (OMMV), and a novel recombinant Alphanecrovirus for which the name corn salad necrosis virus (CSNV) is proposed. Satellite tobacco necrosis virus was also frequently observed. Koch's postulates were completed for all four agents, each one alone being able to cause systemic necrosis of varying severity in corn salad. OMMV was the most frequently observed virus and causes the most severe symptoms. TNVA was the second, both in terms of prevalence and symptom severity while TNVD and CSNV were only rarely observed and caused the less severe symptoms. The emergence of this systemic disease may have been favored by the short and repeated cropping cycles used for corn salad, possibly allowing the selection of necrovirus isolates with an improved ability to systemically invade this specialty crop.

Characterization and occurrence of squash chlorotic leaf spot virus, a tentative new torradovirus infecting cucurbits in Sudan.

During a survey conducted in Sudan in 2012, a virus with spherical particles was isolated from a squash plant showing chlorotic leaf spots. The virus was transmitted mechanically and by two whitefly species, but not by aphids. RT-PCR with generic torradovirus primers yielded a band of expected size from total RNA of a symptomatic plant. Next-generation sequencing confirmed that this is tentatively a new torradovirus, for which we propose the name 'squash chlorotic leaf spot virus'. Using specific RT-PCR primers, the virus was detected in cucurbit samples collected since 1992 at different locations in Sudan.

ß-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify ß-hydroxybutyrate (ßHB), a ketone body, as a regulator of protein solubility in the aging brain. ßHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions. We demonstrate ßHB-induced protein insolubility across in vitro, ex vivo, and in vivo mouse systems. This activity is shared by select structurally similar metabolites, is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-ß, and exogenous ßHB ameliorates pathology in nematode models of amyloid-ß aggregation toxicity. We have generated a comprehensive atlas of the ßHB-induced protein insolublome ex vivo and in vivo using mass spectrometry proteomics, and have identified common protein domains within ßHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among ßHB targets and the clearance of these targets from mouse brain, likely via ßHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.

Receptor-mediated vectorial transcytosis of epidermal growth factor by Madin-Darby canine kidney cells.

Transcellular transport of a variety of ligands may be an important mechanism by which regulatory substances reach their site of action. We have studied the transcellular transport of two 6,000-mol-wt proteins, epidermal growth factor (EGF) and insulin, across polarized Madin-Darby canine kidney (MDCK) cells grown on dual-sided chambers on a nitrocellulose filter substrate. When grown on these chambers, MDCK cells are polarized and express distinct basal and apical surfaces. MDCK cells are capable of unidirectional transport of EGF from the basal-to-apical direction, 50% of bound EGF transported in 2 h. Transport was inhibited by the addition of unlabeled EGF in a dose-dependent manner. Anti-EGF receptor Ab, which inhibited binding, also inhibited transport. No transport in the apical-to-basal direction is noted. Insulin transport is not observed in either direction. Transport correlates with the presence of ligand-specific receptors on the cell surface. Hence, EGF receptors (Ro = 48,000, Kd = 3.5 X 10(-10) M) are found only on the basal surface of the MDCK cells and neither surface expresses insulin receptors. Characterization of the EGF receptors on MDCK cells, as assessed by affinity, molecular mass, and anti-receptor antibody binding reveals that this receptor has similar characteristics to EGF receptors previously described on a variety of cells. Hence, the EGF receptor can function as a transporter of EGF across an epithelial cell barrier.

Reduced mobility of the alternate splicing factor (ASF) through the nucleoplasm and steady state speckle compartments.

Compartmentalization of the nucleus is now recognized as an important level of regulation influencing specific nuclear processes. The mechanism of factor organization and the movement of factors in nuclear space have not been fully determined. Splicing factors, for example, have been shown to move in a directed manner as large intact structures from sites of concentration to sites of active transcription, but splicing factors are also thought to exist in a freely diffusible state. In this study, we examined the movement of a splicing factor, ASF, green fluorescent fusion protein (ASF-GFP) using time-lapse microscopy and the technique fluorescence recovery after photobleaching (FRAP). We find that ASF-GFP moves at rates up to 100 times slower than free diffusion when it is associated with speckles and, surprisingly, also when it is dispersed in the nucleoplasm. The mobility of ASF is consistent with frequent but transient interactions with relatively immobile nuclear binding sites. This mobility is slightly increased in the presence of an RNA polymerase II transcription inhibitor and the ASF molecules further enrich in speckles. We propose that the nonrandom organization of splicing factors reflects spatial differences in the concentration of relatively immobile binding sites.

Duration of nuclear NF-kappaB action regulated by reversible acetylation.

The nuclear expression and action of the nuclear factor kappa B (NF-kappaB) transcription factor requires signal-coupled phosphorylation and degradation of the IkappaB inhibitors, which normally bind and sequester this pleiotropically active factor in the cytoplasm. The subsequent molecular events that regulate the termination of nuclear NF-kappaB action remain poorly defined, although the activation of de novo IkappaBalpha gene expression by NF-kappaB likely plays a key role. Our studies now demonstrate that the RelA subunit of NF-kappaB is subject to inducible acetylation and that acetylated forms of RelA interact weakly, if at all, with IkappaBalpha. Acetylated RelA is subsequently deacetylated through a specific interaction with histone deacetylase 3 (HDAC3). This deacetylation reaction promotes effective binding to IkappaBalpha and leads in turn to IkappaBalpha-dependent nuclear export of the complex through a chromosomal region maintenance-1 (CRM-1)-dependent pathway. Deacetylation of RelA by HDAC3 thus acts as an intranuclear molecular switch that both controls the duration of the NF-kappaB transcriptional response and contributes to the replenishment of the depleted cytoplasmic pool of latent NF-kappaB-IkappaBalpha complexes.

Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway.

Human immunodeficiency virus-type 1 (HIV-1) infection is characterized by a chronic state of immune hyperactivation in patients. Infection of human peripheral blood lymphocytes with HIV-1 in vitro resulted in increased interleukin-2 (IL-2) secretion in response to T cell activation via the CD3 and CD28 receptors. Expression of the HIV-1 transactivator Tat recapitulated this phenotype and was associated with increased IL-2 secretion in response to costimulation with CD3 plus CD28. IL-2 superinduction by Tat occurred at the transcriptional level, was mediated by the CD28-responsive element in the IL-2 promoter, and was exclusively dependent on the 29 amino acids encoded by the second exon of Tat.

Visualization of viral clearance in the living animal.

The early events in viral dissemination via the bloodstream were identified by monitoring the fate of 123I-radiolabeled reovirus after it was injected intravenously in rats. Continuous scintillation camera imaging showed that reovirus serotypes 1 and 3 were cleared from the circulation in less than 10 minutes by specific and distinct target organs. Reovirus serotype 1 accumulated predominantly in the lungs and the liver, whereas serotype 3 accumulated in the liver and the spleen with very little virus uptake by the lungs. Incubation of reovirus serotype 1 with a monoclonal antibody directed against the viral hemagglutinin before injection totally inhibited the clearance of the virus by the lungs. Similar results were obtained when viruses biolabeled with 35S were used. These results demonstrate that viruses can be rapidly transported through the bloodstream to specific target organs and that the localization of the viruses depends on the interaction between specific viral surface components and the target organ.

First Report of Tomato torrado virus in Tomato Crops in France.

In June 2008, tomato (Solanum lycopersicum L.) plants cv. Fer De Lance (De Ruiter Seeds, Bergschenhoek, the Netherlands) grown in greenhouses near Perpignan (southern France) showed growth reduction and necrotic lesions on fruits, stems, and basal parts of the leaves. Tomato torrado virus (ToTV) was suspected on the basis of symptoms and its recent description in Spain (4). Primer set A (3), designed to ToTV RNA-2, was used for reverse transcription (RT)-PCR experiments on RNA extracted from four infected plants and allowed the amplification of a 493-bp fragment. No amplification was observed from healthy plant extracts. The RT-PCR product was directly sequenced (GQ303330) and a BLAST search in GenBank revealed 99.8- and 99.5%-nt identity with Polish (EU563947) and Spanish type strain (DQ388880) isolates of ToTV, respectively. Double-antibody sandwich-ELISA tests were conducted on these four samples to check for the presence of other viruses commonly found in tomato crops in France. Tomato spotted wilt virus, Parietaria mottle virus, Cucumber mosaic virus, Tomato mosaic virus, and Potato virus Y were not detected but Pepino mosaic virus (PepMV) was detected in all samples. ToTV was mechanically transmitted to Physalis floridana but PepMV was not. This plant was used to inoculate healthy tomatoes that served as a ToTV source for further experiments. Mechanical inoculation to test plants showed that Nicotiana benthamiana, N. clevelandii, N. debneyi, N. glutinosa, Capsicum annuum, Solanum melongena, and some tomato cultivars (including Fer De Lance), in which typical necrotic symptoms were observed, were systemically infected by the virus. Isometric particles ~28 nm in diameter were observed by electron microscopy in crude extracts of infected plants negatively stained with 1% ammonium molybdate, pH 7. To confirm ToTV identification, whitefly transmission experiments were performed with Trialeurodes vaporariorum and Bemisia tabaci. Adult whiteflies were placed in cages with infected tomato plants for 1-, 24-, or 48-h acquisition access periods (AAP) before transferring them by groups of ~50 on susceptible tomato plantlets placed under small containers (six plants per AAP). Forty-eight hours later, plants were treated with an insecticide and transferred to an insect-proof containment growth room. Ten days later, RNA preparation from all plants was tested by RT-PCR for the presence of ToTV. No transmission was observed with a 1-h AAP. With a 24-h AAP, transmission to four of six test plants was observed with both whitefly species, while at 48 h, AAP transmission to three and four plants of six was observed with T. vaporariorum and B. tabaci, respectively. Noninoculated control plants were all negative by RT-PCR. These experiments confirm T. vaporariorum and B. tabaci as natural vectors of ToTV as previously described (1,2). ToTV has been already reported in Spain, Poland, Hungary, and Australia, but to our knowledge, this is the first report of ToTV in France. Our detection of ToTV in April 2009 from the same area revealed 7 positive tomato plants of 17 tested. This observation suggests the persistence of the disease in the Perpignan Region. References: (1) K. Amari et al. Plant Dis. 92:1139, 2008. (2) H. Pospieszny et al. Plant Dis. 91:1364, 2007 (3) J. Van der Heuvel et al. Plant Virus Designated Tomato Torrado Virus. Online publication. World Intellectual Property Organization WO/2006/085749, 2006. (4) M. Verbeek et al. Arch. Virol. 152:881, 2007.

Sirtuins: critical regulators at the crossroads between cancer and aging.

Sirtuins (SIRTs 1-7), or class III histone deacetylases (HDACs), are protein deacetylases/ADP ribosyltransferases that target a wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria for post-translational modification by acetylation (SIRT1, -2, -3 and -5) or ADP ribosylation (SIRT4 and -6). The orthologs of sirtuins in lower organisms play a critical role in regulating lifespan. As cancer is a disease of aging, we discuss the growing implications of the sirtuins in protecting against cancer development. Sirtuins regulate the cellular responses to stress and ensure that damaged DNA is not propagated and that mutations do not accumulate. SIRT1 also promotes replicative senescence under conditions of chronic stress. By participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers. Here, we review the growing implications of sirtuins both in cancer prevention and as specific and novel cancer therapeutic targets.

Regulation of human immunodeficiency virus-1 latency and its reactivation.

Treatment of human immunodeficiency virus (HIV) infection with highly active antiretroviral therapy (HAART) has become highly effective. However the persistence of a small population of infected cells containing transcriptionally silent but re-activatable HIV proviruses prevents complete elimination of the infection. Here, we review recent progress in our understanding of the molecular mechanisms underlying HIV proviral latency and highlight experimental therapies designed to eliminate the latent population.

Acetylation of the HIV-1 Tat protein by p300 is important for its transcriptional activity.

The human immunodeficiency virus 1 (HIV-1) Tat protein activates transcriptional elongation by recruiting the positive transcription elongation factor (pTEFb) complex to the TAR RNA element, which is located at the 5' extremity of all viral transcripts [1-3]. Tat also associates in vitro and in vivo with the transcriptional coactivator p300/CBP [4-6]. This association has been proposed to recruit the histone acetyltransferase (HAT) activity of p300 to the integrated HIV-1 promoter. We have observed that the purified p300 HAT domain acetylates recombinant Tat proteins in vitro and that Tat is acetylated in vivo. The major targets of acetylation by p300 are lysine residues (Lys50 and Lys51) in the arginine-rich motif (ARM) used by Tat to bind RNA and for nuclear import. Mutation of these residues in full-length recombinant Tat blocked its acetylation in vitro. Furthermore, mutation of these lysine residues to arginine markedly decreased the synergistic activation of he HIV promoter by Tat and p300 or by Tat and cyclin T1. These results demonstrate that acetylation of Tat by p300/CBP is important for its transcriptional activation of the HIV promoter.

First Report of the Presence of Tomato apical stunt viroid on Tomato in Sénégal.

Tomato apical stunt viroid (TASVd) was initially discovered in the Ivory Coast (2). It was later reported in Indonesia and more recently was found to be responsible for severe outbreaks in protected tomatoes in Israel (1) and Tunisia (3). Although not of quarantine status, TASVd is included in the EPPO alert list. In 2005, severe arrest of apical growth and leaf chlorosis were observed in tomato samples from northern Sénégal. Tomato yellow leaf curl virus was initially identified in some samples, but since the symptoms observed were reminiscent of those associated with viroid infection, samples were analyzed by return-polyacrylamide gel electrophoresis and molecular hybridization with a Potato spindle tuber viroid (PSTVd) probe. Positive results prompted a reanalysis by reverse transcription-PCR assays specific for PSTVd or TASVd. Positive amplification was only obtained with the TASVd-specific primers (Vir+ GGGGAAACCTGGAGGAA and Vir- GGGGATCCCTGAAGGAC), and the identity of the viroid confirmed by sequencing of the amplified fragment. The complete genome sequence obtained (GenBank Accession No. EF051631) shows 94 to 96% identity with other TASVd sequences in the databases, the highest homology being with the original Ivory Coast isolate (96%, 11 mutations, and 4 indels for the 362-nt genome). These results provide new information on the diversity of TASVd and of its detrimental potential for tomato crops and represent, to our knowledge, the first report of the presence of TASVd in Sénégal. References: (1) Y. Antignus et al. Phytoparasitica 30:502, 2002. (2) C. R. Walter. Acad. Sci. 292:537, 1981. (3) J. Th. J. Verhoeven et al. Plant Disease 90:528, 2006.

New species in the papaya ringspot virus cluster: Insights into the evolution of the PRSV lineage.

The "Papaya ringspot virus (PRSV) cluster" of cucurbit-infecting potyviruses contains five acknowledged species that have similar biological, serological and molecular properties. Additional data suggest there are other uncharacterized species from various locations in the world that likely belong to the PRSV cluster including a new PRSV-like virus reported from Sudan in 2003. Molecular and biological data indicated that the virus from Sudan belongs to a new species, tentatively named wild melon vein banding virus (WMVBV). The complete nucleotide sequence of a second virus from Sudan revealed it was a divergent relative of Moroccan watermelon mosaic virus (MWMV). Based on sequence similarity this virus was determined to be a distinct species and tentatively named Sudan watermelon mosaic virus (SuWMV). Molecular analyses indicate that SuWMV is a recombinant between WMVBV- and MWMV-related viruses. Based on surveys performed in Sudan between 1992 and 2012, SuWMV appeared 10 times more frequent than WMVBV in that country (14.6% vs. 1.5% of the samples tested). The geographic structure and molecular diversity patterns of the putative and acknowledged species suggest that the PRSV-like cluster originated in the Old World about 3600 years ago, with an important diversification in Africa.

Detection and characterization of tobacco mild green mosaic virus (TMGMV) large type isolate from trailing petunia in France.

During 2003 and 2004, unusual viral symptoms were observed on Surfinia trailing petunias in protected cultivations of Southern France. Symptoms consisted in yellow mosaic and distortion of the leaves accompanied by vein necrosis in some samples. The flowers were deformed and showed light colour break of the petals. Electron microscope observation of negatively stained leaf-dip from symptomatic leaves showed straight rod-shaped virus particles of about 300 nm in length. Sap extracts reacted in double-immunodiffusion tests by forming weak precipitin bands with antisera against Tomato mosaic virus (ToMV) and Tobacco mild green mosaic virus (TMGMV). However, symptoms developed on host range after mechanical inoculation suggested that ToMV was not involved in the disease. By using specific primer pairs designed to amplify the coat protein (CP) genes of ToMV and TMGMV in reverse transcriptase-polymerase chain reaction (RT-PCR), expected amplicon was obtained only with TMGMV primer pair. The identity of the virus was also confirmed by using a specific TMGMV riboprobe in dot-blot hybridization assays of symptomatic leaf extracts. The nucleotide sequence of TMGMV CP of the isolate from trailing petunia, named TMGMV-Pt, was determined and compared with those available from EMBL. The percentage of nucleotide identity was 97-98% compared with those of other isolates. Further molecular and biological characterization revealed that TMGMV-Pt belonging to the large type group of TMGMV isolates. In fact, the 3' UTR region of TMGMV-Pt consisted of 360 nucleotides, comprising of a 147 base repeat, as reported only for TMGMV large type isolates. Moreover, symptoms development observed on a differentially host range, used to distinguish between large type and small type isolates, confirmed that TMGMV-Pt belonging to the large type group of isolates. Only one commercial variety of trailing petunia out of 12 tested remained symptomless after mechanical inoculation with TMGMV-Pt. This highlights the potential risk that TMGMV could represent to petunia cultivations. To our knowledge this is the first report of a natural infection by TMGMV in trailing petunia.

Similar metabolic effects of pulsatile versus continuous human insulin delivery during euglycemic, hyperinsulinemic glucose clamp in normal man.

Seven normal volunteers were studied on two different occasions during which 4-h pulsatile (PULS: 0.8 mU X kg-1 X min-1, 7.5 min of 15) and continuous (CONT: 0.4 mU X kg-1 X min-1) intravenous (i.v.) infusions of human insulin (Actrapid HM, Novo) were randomly compared. A euglycemic glucose clamp was performed and a 3-3H-glucose infusion was used for determination of endogenous glucose production (EGP) and metabolic clearance rate (MCR) of glucose. Plasma glucose was similar in both conditions; plasma insulin was stable at about 29 mU/L (CONT) and fluctuated between 10 and 45 mU/L (mean: 28, PULS). Exogenous glucose infused was 1.137 +/- 0.058 and 1.088 +/- 0.099 g X kg-1 X 4 h-1 in CONT and PULS, respectively (NS). EGP was totally suppressed in both conditions. Glucose MCR increased similarly to a maximum of 6.71 +/- 0.19 (CONT) and 6.79 +/- 0.59 (PULS) ml X kg-1 X min-1 during the fourth hour. C-peptide plasma levels remained stable, whereas plasma glucagon, free fatty acids, and 3-hydroxybutyrate were similarly suppressed in both tests. Thus, under these conditions, pulsatile and continuous insulin infusions have similar metabolic effects. These data contrast with those of Matthews et al. (1983) who reported that, at lower plasma concentrations (5-19 mU/L), pulsatile insulin had greater hypoglycemic effect than did continuous delivery. It is concluded that pulsatile insulin shows no greater activity under normoglycemic, moderately hyperinsulinemic conditions in man.

Insulin oscillations per se do not affect glucose turnover parameters in normal man.

To compare the metabolic effects of pulsatile vs. continuous iv insulin infusion, normal men had two glucose-controlled iv glucose infusions using the Biostator for 260 min, during which endogenous pancreatic hormone secretion was inhibited by a somatostatin infusion and glucagon was replaced by continuous glucagon infusion. The two tests were performed at 1-week intervals, during which human insulin was infused either continuously at a constant rate of 0.2 mU kg-1 min-1 or in a pulsatile manner at a rate of 1.3 mU kg-1 min-1 with a switching on/off length of 2/11 min. Blood glucose levels and glucose infusion rates (GIR) were continuously monitored, and glucose turnover was estimated using a [3H]glucose infusion. In both tests, plasma C-peptide dropped markedly, whereas plasma glucagon levels were about twice basal values. Plasma insulin averaged 7 mU liter-1 during continuous infusion and oscillated between 1.5 and 35 mU liter-1 during pulsatile delivery. During the first 30-60 min of both tests, the glucose appearance rate and endogenous glucose production (EGP) increased, resulting in moderate hyperglycemia, which completely suppressed GIR. During the last 65 min, EGP declined, while the glucose disappearance rate and the glucose MCR increased, so that GIR increased progressively to maintain the blood glucose clamped at about 5 mmol liter-1. During this period, no significant differences were found between the two modes of insulin administration for any of the parameters studied. Thus, continuous and pulsatile insulin iv infusion, resulting in physiological peripheral plasma insulin levels, altered the glucose turnover parameters equally, in particular inhibiting EGP, which was stimulated by glucagon during the first part of the study, and stimulating peripheral glucose uptake at the end of the study period.

Isoquinolinesulphonamide derivatives inhibit transcriptional elongation of human immunodeficiency virus type 1 RNA in a promyelocytic model of latency.

Using the OM-10.1 promyelocytic model of inducible human immunodeficiency virus type 1 (HIV-1) infection, we tested a panel of known protein kinase inhibitors for an ability to block tumour necrosis factor-alpha-induced HIV-1 expression. Among the compounds tested, the broad-spectrum protein kinase inhibitor H-7 uniquely blocked HIV-1 expression at the level of viral transcription, but did not inhibit nuclear factor kappaB activation or function. In structure-activity analysis this inhibitory activity of H-7 on HIV-1 expression corresponded with the known structural requirements for the interaction of H-7 with the ATP-binding region of protein kinase C, suggesting that it was indeed related to the kinase inhibitory properties of H-7. The mechanism of H-7 transcriptional inhibition did not involve chromatin remodelling at the HIV-1 long terminal repeat promoter, as shown by nuc-1 disruption, and appeared to involve HIV-1 RNA elongation but not initiation. Therefore, H-7 and related isoquinolinesulphonamide analogues are most likely inhibiting a kinase target essential for HIV-1 transcriptional elongation whose identity may provide new therapeutic targets for intervention.