Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients

<p>Abstract</p> <p>Background</p> <p>The presence of HIV-1 preintegration reservoir was assessed in an <it>in vitro </it>experimental model of latent HIV-1 infection, and in patients treated or not with highly active antiretroviral therapy (HAART).</p> <p>Results</p> <p>In resting CD4⁺T lymphocytes latently infected <it>in vitro </it>with HIV-1, we demonstrated that the polyclonal activation induced a HIV-1 replication, which could be prevented by the use of an HIV-1 integrase inhibitor. We also showed that this reservoir was labile since the rescuable HIV-1-antigens production from unintegrated HIV-1 genomes declined over time. These data confirm that our experimental approach allows the characterization of a functional unintegrated HIV-1 reservoir. We then explored the preintegration reservoir in HIV-1-infected patients. This reservoir was detected in 11 of 12 untreated patients, in 4 of 10 sustained responders to HAART, and in one incomplete responder. This reservoir was also inducible, labile, and anti-HIV-1 integrase drug inhibited its induction. Finally, this reservoir was associated with the presence of spontaneous HIV-1 antigens producing CD4⁺T cells in blood from 3 of 3 untreated patients and 2 of 2 sustained responders to HAART harboring a preintegration reservoir.</p> <p>Conclusion</p> <p>This preintegration phase of HIV-1 latency could be a consequence of the ongoing viral replication in untreated patients and of a residual viral replication in treated patients.</p

Utilisation de la transformation pour l'etude des elements regulateurs des genes de la glu chez Drosophila melanogaster

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Evidence of genotypic adaptation to the exposure to volcanic risk at the dopamine receptor DRD4 locus

International audienceHumans have colonized and adapted to extremely diverse environments, and the genetic basis of some such adaptations, for example to high altitude, is understood. In some cases, local or regional variation in selection pressure could also cause behavioural adaptations. Numerous genes influence behaviour, such as alleles at the dopamine receptor locus D4 (DRD4), which are associated with attitude toward risk in experimental settings. We demonstrate genetic differentiation for this gene, but not for five unlinked microsatellite loci, between high- and low risk environments around Mount Merapi, an active volcano in Java, Indonesia. Using a behavioural experiment, we further show that people inhabiting the high risk environment are significantly more risk averse. We provide evidence of a genetic basis for this difference, showing that heterozygotes at the DRD4 locus are more risk averse than either homozygotes. In the high risk environment, allele frequencies are equilibrated, generating a high frequency of heterozygotes. Thus it appears that overdominance (i.e. selective advantage of heterozygotes) generates negative frequency dependent selection, favouring the rarer allele at this locus. Our results therefore provide evidence for adaptation to a marginal habitat through the selection of a neurocognitive trait with a genetic basis

Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients-0

<p><b>Copyright information:</b></p><p>Taken from "Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients"</p><p>http://www.retrovirology.com/content/4/1/60</p><p>Retrovirology 2007;4():60-60.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2048509.</p><p></p>HIV-1 integrase inhibitor L-731,988 at the final concentration of 40 μM. . To assess the correlation between the unintegrated HIV-1 DNA decay and the decline of rescuable viral production, infected resting CD4T cells were preincubated 1 or 2 days before polyclonal stimulation. In both cases, in order to prevent infection of others cells by -synthesized HIV-1, 1 μg/ml of the viral entry inhibitor T20 was also added in culture medium

Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients-7

<p><b>Copyright information:</b></p><p>Taken from "Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients"</p><p>http://www.retrovirology.com/content/4/1/60</p><p>Retrovirology 2007;4():60-60.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2048509.</p><p></p>vated in four experiments (nos. 1, 2, 3, and 4) or directly polyclonaly activated and cultured with L-731,988 in two other assays (nos. 3 and 4). . latently infected resting CD4T cells were directly polyclonaly activated or preincubated 2 days before polyclonal activation in two experiments (nos. 3 and 4)

Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients-1

<p><b>Copyright information:</b></p><p>Taken from "Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients"</p><p>http://www.retrovirology.com/content/4/1/60</p><p>Retrovirology 2007;4():60-60.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2048509.</p><p></p>vated in four experiments (nos. 1, 2, 3, and 4) or directly polyclonaly activated and cultured with L-731,988 in two other assays (nos. 3 and 4). . latently infected resting CD4T cells were directly polyclonaly activated or preincubated 2 days before polyclonal activation in two experiments (nos. 3 and 4)

Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients-6

<p><b>Copyright information:</b></p><p>Taken from "Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients"</p><p>http://www.retrovirology.com/content/4/1/60</p><p>Retrovirology 2007;4():60-60.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2048509.</p><p></p>HIV-1 integrase inhibitor L-731,988 at the final concentration of 40 μM. . To assess the correlation between the unintegrated HIV-1 DNA decay and the decline of rescuable viral production, infected resting CD4T cells were preincubated 1 or 2 days before polyclonal stimulation. In both cases, in order to prevent infection of others cells by -synthesized HIV-1, 1 μg/ml of the viral entry inhibitor T20 was also added in culture medium

Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients-3

<p><b>Copyright information:</b></p><p>Taken from "Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients"</p><p>http://www.retrovirology.com/content/4/1/60</p><p>Retrovirology 2007;4():60-60.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2048509.</p><p></p>umerated at the end of culture. The median values are shown as black bars

Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients-4

<p><b>Copyright information:</b></p><p>Taken from "Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients"</p><p>http://www.retrovirology.com/content/4/1/60</p><p>Retrovirology 2007;4():60-60.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2048509.</p><p></p>re preincubated one or two days before their polyclonal activation. A gate was set on the forward-scatter vs side-scatter histogram. As shown on different histograms, gate corresponded to CD69CD4T lymphocytes. The analysis of the 7AAD level expression demonstrated that activated CD4T lymphocytes were viable cells