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Vaccine and HIV science moving forward CROI 2007 in LA continued ......



I read over 1000 papers at the   CROI 2007 in LA  these look the most interesting to me...

this looks good... it says they are working on new powerful meds to wipe out the latent hiv cd4 try to get rid of hiv completely... it is a few steps ...  look for more on.....Inhibitors of Histone Deacetylases
HDAC) inhibitors

Small Molecule Inhibitors of Histone Deacetylases as a Means to Induce HIV Expression from Latently Infected CD4 T Cells
Shannon Weiman*1, V Terry2, A Espeseth3, D Hazuda3, D Richman1,2, D Richman1,2, and C Spina2
1Univ of California, San Diego, US; 2VA San Diego Hlthcare System, La Jolla, CA, US; and 3Merck Res Labs, West Point, PA, US

Background:  Latently infected, resting memory CD4 T cells represent a major obstacle to eradication of HIV from infected individuals. Histone deacetylase (HDAC) inhibitors  have been shown to induce viral expression from latently infected cells by changing chromatin structure at the integrated HIV promoter. We have tested 7 small-molecule HDAC inhibitors for their ability to block deacetylation of histones (H) 3 and 4 in primary CD4 T cells in vitro.

Methods:  Uninfected primary CD4 cells were isolated from peripheral blood of healthy HIV-seronegative donors by negative selection. CD4 cells were treated with individual HDAC inhibitor at their highest tolerated dose (85% cell viability), and histone acetylation was assayed 4, 24, and 48 hours following treatment. Western blots of whole cell lysates were performed with acetylation-specific antibodies for H3 and H4, followed by stripping and re-probing with antibodies reactive to total histone. The ratio of acetylated to total H relative to the time 0 was used to compare the activity of the various compounds. Dose-response curves for each HDAC inhibitor were generated by treating primary CD4 cells with 10-fold dilutions over a 4-log range after 24 hours.

Results:  All but 1 compound increased both H3 and, more dramatically, H4 acetylation.  H3 and H4 acetylation increased 3- to 9- and 5- to 50-fold, respectively, until 24 hours after treatment, after which the response plateaued. Test compounds were more than twice as effective as valproic acid, a well-established HDAC inhibitor. At the highest tolerated dose, all 6 effective compounds were on the ascending slope of the dose-response curve.

Conclusions:  The ability of several of the test compounds to increase H3 and, more dramatically, H4 acetylation is very encouraging in light of the fact that H4 acetylation is more directly associated with transcriptional control. The failure of 1 of the compounds, the only preferred class II HDAC inhibitor tested, to induce substantial acetylation, in contrast to the success of the other 4 class I specific and 2 nonselective HDAC inhibitors, suggests that class I HDAC may provide the best targets for viral induction from latency.   Future studies will assess these compounds up to the maximum tolerated dose for the induction of HIV from our in vitro model of primary CD4 T-cell latency.


this one says... good news we found that if you are on HAART   identifies" HIV+ DN T cells as the major  producing infection....  ...HIV+ DN T cells     is DN =   CD4–CD8– (double negative, DN)
so that may help with things...

 HIV Production in vivo Predominantly Takes Place after CD4-Down-modulation
Philipp Kaiser*, B Joos, B Niederöst, H Günthard, and M Fischer
Univ Hosp, Zurich, Switzerland

Background:  Peripheral blood mononuclear cell (PBMC)-associated viral RNA can be detected during all stages of HIV disease, including prolonged periods of successful ART. To assess its potential significance for HIV persistence, we dissected HIV-infected cells in PBMC according to their degree of viral transcriptional activity and their cellular phenotype.

Methods:  PBMC from 6 treated and 6 viremic HIV+ individuals were fractionated into total, resting (CD25–CD69–HLA–DR–) and activated CD4+T cells, CD4–CD8– (double negative, DN) T cells and monocytes using paramagnetic beads and FACS. HIV DNA, unspliced, multiply spliced and, to mark virus production, virion-enclosed genomic HIV RNA associated with cells was quantified using patient-matched real-time polymerase chain reaction (PCR). Cells were classified for HIV transcriptional activity and frequencies determined by terminal dilution. Phylogenetic analyses were performed on clones of HIV-env of 2 viremic patients.

Results:  Only low levels of HIV-1 nucleic acids were detected in monocytes, while the majority of infected cells were CD4+ and transcribed HIV provirus at low levels presumably insufficient for virion production. In untreated patients, an elevated proportion of both infected resting, as well as activated, CD4 cells (4.9%, range 3.4 to 10.0%) expressed significant levels of multiply spliced HIV RNA. However, T cells carrying virion-enclosed RNA were rare among CD4 cells but enriched in DN T cells (65%, range 16 to 100%). HIV+ DN T cells were virtually absent under ART. CD4+ and DN T cell-derived viral quasispecies were closely related.

Conclusions:  Regardless of ART, the majority of HIV-infected cells harbor latent provirus engaged in basal viral transcription. Enhanced HIV transcription is associated with a DN phenotype rather than activation marker expression on CD4+ T cells. In conjunction with the phylogenetic proximity of CD4+ and DN T cell-derived quasispecies these findings provide strong in vivo evidence for CD4 down-modulation on HIV+ T cells during transition to productive infection. The abundance of viral RNA in PBMC-derived DN T cells from viremic patients and the almost complete absence of viral DNA and RNA in this cell type during ART identifies HIV+ DN T cells as the major phenotype for productive infection.


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