2012 IAS Towards an HIV Cure Symposium Day 2
The second day of the symposium was scientifically more interesting than the first one, although minimal time was devoted to discussions. The sessions were more clinically oriented, from the mechanisms controlling HIV persistence to new therapeutic approaches including immune-based therapies. As most of the abstracts presented after plenary overviews were under embargo until their final presentation at the World AIDS Conference, this summary is published later than initially planned.
The first overview lecture of this second day session 4 was given by Asier Saez Cirion from the Pasteur Institute in Paris. He focused on the "VISCONTI" cohort, a group of 14 HIV-infected patients who controlled viremia after stopping c-ART initiated very early at acute HIV infection.
The current follow up of this group is 79.5 months after a mean duration of c-ART of 36.5 months. Asier Saez Cirion found an increased frequency of the B35 allele in these patients.
He then cited the work in press from Cécile Goujard based on 164 patients from the French cohort of acutely infected patients and calculations done by Dominique Costagliola confirming the probability of being post treatment controllers for around 15% of cases.
Lisa Chakrabarti from Pasteur Institute in paris then compared 26 HIV Controllers to 16 patients on effective c-ART and showed that HIV Controllers maintain detectable Th17 cells and lack IL-10 production (although c-ART treated patients produce IL-10), which correspond to the maintenance of highly efficient Th1 effector cells in HIV Controllers.
Maria Pia De Pasquale from Vanderbilt University in Nashville, USA, then showed that Apobec 3G levels are inversely associated with resting CD4+ T memory cells integrated provirus in vivo, by comparing cells from LTNP and c-ART suppressed patients. In vitro, this inverse correlation was confirmed with infectivity of HIV produced from activated resting CD4 T cells.
Session 5 began by an overview from Sarah Palmer on biological assays to measure persistent infection. She first reminded that other cells than CD4+ T cells play a role in HIV persistence, and that there are different body compartments.
Investigating these tissue compartments is challenging. For example, the intestine corresponda to 300 m2 but when performing a pinch biopsy, we only obtain 0.000003 m2!
Palmer then detailed the special case of the Berlin patient with recent data showing the isolation in some laboratories, but not others, of persistent virus in this patient. Although most scientists currently interpret these data as lab contamination, Palmer concluded that currently available assays do not allow for sure to say that the Berlin patient is cured.
Charline Bacchus from Paris came back to the VISCONTI patients showing interesting data on the reservoir distribution in these patients.
These 11 VISCONTI patients were compared to elite controllers.
Bacchus showed that there is a skewed distribution of CD4 subsets containing the reservoir in VISCONTI patients, with TTM subset containing more than half of the reservoir.
On the contrary, naive and central memory subsets were minor contributors of the HIV reservoir in the VISCONTI patients.
Joe Wong, on behalf of S. Yukl, presented the distribution of HIV DNA in the GALT of patients under suppressive c-ART. Eight patients were analyzed and underwent 15 biopsies in the ileum and same number in rectum.
Data showed that ileal R7+ cells had significantly more HIV DNA than blood R7+ cells (p= 0.016).
In the ileum, the vast majority of the HIV reservoir was in EM CD4+ T cells.
Remi Fromentin then described a new assay called "HPDA" (for HIV Persistence Detection Assay) using CD4+ T cells from patients.
This assay ias a measure of viral release after stimulation and is positive in 85% of patients on long term c-ART.
When comparing the HPDA with integrated proviral DNA levels, no correlation was found (p=0.05), although a significant correlation was found with the infectivity assay (p<0.01).
This assay also shows that prostratin is more potent than bryostatin as anti-latency agent.
Session 6 began with a lecture from David Margolis on anti-latency agents. Margolis first underlined the challenge of the clearance of cells once latent HIV has been reactivated.
Margolis results with vorinostat have just been published in the 25 July issue of Nature (http://www.ncbi.nlm.nih.gov/pubmed/22837004).
In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4+ cells (mean increase, 4.8-fold).
Roger Sutmuller from Janssen presented the screening method used by his firm to find anti-latency agents. They were able to test acting on PKC inhibition or Histone acetylation and used micro array as mode of action tool.
35,000 compounds were screened from which 23 acted on PKC activation, 14 on histone acetylation and 3 remained with unknown mechanism of action.
Timothy Henrick presented data on 2 patients who received without pre ablative chemotherapy or radiation stem cell transplants for lymphomas. The patients were on c-ART during the transplant, which could have protected the cells. They first received autologous stem cell, then allogenic stem cell transplants.
The first patient presented Hodgkin lymphoma and the second one a large B cell lymphoma followed by a Hodgkin lymphoma 3 years later. One hundred percent chimerism was obtained and no HIV RNA, DNA, LTR could be found in these patients who also had negative cocultures for HIV. They also exhibited a decrease in HIV antibodies after the transplantation. Both patients were heterozygous for the CCR5 delta 32 mutation before the transplants. Both patients remained virologically suppressed on ART, but were either started on prednisone or continued on tacrolimus/sirolimus immunosuppressive therapy for chronic graft-versus-host disease near the time of loss of HIV-1 reservoir detection. As c-ART was not discontinued in these patients, it is unclear weather HIV was eradicated or not. Confirmation of these results by sampling large-volume blood collections and other tissue compartments is warranted.
Jeffrey Lifson presented the results of vorinostat treatment in 6 SIVmac-infected Rhesus macaques. Variable modifications of histone acetylation and cell-associated RNA were found from one animal to another and no effect on plasma viremia was observed.
Fabio Romerio from the Institute of Human Virology in Baltimore presented micro array analysis of latently infected CD4 T cells. He found profound differences between latently infected and uninfected cells derived from the same culture.
First, a number of genes involved in all major cellular metabolic pathways were down-modulated in latently infected cells.
Second, several messengers involved in gene expression (including chromatin organization, transcription, translation, post-translational modification, transport and assembly) were also down-regulated in latently infected cells.
Third, genes involved in signal transduction, cell activation, cell proliferation and cell cycle progression were down-modulated in latently infected cells.
Finally, several genes encoding cell surface molecules were differently expressed in latently infected vs. uninfected cells. During a collaborative research with VGTI Florida, they found in 6 patients an enrichment (3 to 8 fold) in HIV DNA in CD4+ CD2high T cells.
Finally, session 7 was devoted to the strategies to enhance the capacity of the host response to control active virus replication. Giuseppe Pantaleo from Lausanne reviewed the (mainly negative) results of different trials performed over the years using either a vaccine approach, a cytokine approach or a blockade of regulatory receptors. He pointed out that one of the reasons why these approaches failed could be their testing as monotherapies.
Yves Levy from Paris confirmed this thinking by calling for a Collaboration for HIV/AIDS Immunological Therapy (CHAIT). He detailed the results of the DALIA 1 trial published earlier this year at CROI (http://www.retroconference.org/2012b/Abstracts/43713.htm) using, in 19 patients, using a vaccination with Dendritic Cells Loaded with HIV-1 Lipopeptides. DC vaccination elicited polyfunctional HIV-specific responses associated with a reduced peak of viral load following treatment interruption.
Christian Apetrei from Pittsburgh presented his model of functional cure of SIVagm infected Rhesus macaques published last year (http://www.ncbi.nlm.nih.gov/pubmed/21829366). He showed that rebounding virus after CD8+ T cell depletion is replication competent and clonal. To prove that, the researchers used pooled plasma rebounding virus that they inoculated to new macaques.
Patrice Debré from Paris showed that a remarkably conserved motif of the gp41, called 3S, is linked to CD4 depletion, T cell-activation, inflammation and apoptosis. The 3S motif induces NKp44L, an activating ligand of NK cells, on uninfected CD4 T cells, and thus makes these cells sensitive to NK lysis. A 3S vaccine induces antibodies which in vivo macaque models prevent CD4 depletion and immune dysfunction but fails to elicit broadly neutralizing antibodies (bNAbs). In new experiments, Debré showed that specific substitutions within the 3S peptide motif can induce antibodies, which not only inhibit NKp44L expression and deleterious NK cytotoxicity but broadly neutralize HIV, providing a rational for a therapeutic vaccine reducing HIV reservoir.
Lara Vojnov from Madison, USA, gave a very interesting presentation showing that the majority of freshly sorted SIV-specific CD8+ T cells cannot suppress viral replication in SIV-infected macrophages. These data have recently been published (http://www.ncbi.nlm.nih.gov/pubmed/22318140) and raise the possibility that while AIDS virus-infected macrophages only constitute a small percentage of all virus-infected cells, they may be relatively resistant to CD8+ T cell-mediated lysis and continue to produce virus over long periods of time.
Key words: ANRS, HIV eradication, HIV persistence, HIV reservoirs, IAS, VISCONTI, towards an HIV cure