20th International AIDS Conference - Melbourne, Australia

TUAA01 Defining and Targeting Residual Virus on cART
  Oral Abstract Session : Track A
Venue: Room 203-204
Time: 22.07.2014, 14:30 - 16:00
Co-Chairs: Sarah Palmer, Australia
Christine Rouzioux, France

Alternative RNA splicing in latently infected T cells generates chimeric cellular:HIV mRNAs with the potential to generate Tat and reactivate infection
S. Sonza1, J. Jacobson1, T. Mota1, M. Lee1, J. Howard1, S. Lewin2,3, D. Purcell1
1University of Melbourne, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia, 2Alfred Hospital, Infectious Diseases Unit, Melbourne, Australia, 3Monash University, Department of Infectious Diseases, Melbourne, Australia

Ultra-deep barcoded SIVmac239 to identify and quantify viral reservoirs and recrudescent viremia
C. Fennessey, C. Reid, B. Keele
Frederick National Laboratory, AIDS and Cancer Virus Program, Frederick, United States

Co-localization of follicular SIV-specific CD8 T cells with Tfh in the germinal centers of chronically SIV infected rhesus macaques is associated with enhanced viral control
G. Mylvaganam, V. Velu, R.R. Amara
Emory University, Yerkes National Primate Research Center, Decatur, United States

A population of CD8 T cells is located in germinal centers that is functionally capable of mediating bispecific antibody mediated killing of HIV-infected T cells
C. Petrovas1, S. Ferrando-Martinez1,2,3, A. Pegu1, K. Boswell1, M. Asokan1, D. Ambrozak1, D. Kotlyar1, F. Docobo3, M. Leal3, E. Ruiz-Mateos3, R. Koup1
1Vaccine Research Center, Bethesda, United States, 2HGU Gregorio Maranon, Madrid, Spain, 3HU Virgen dle Rocio/IBiS/US, Sevilla, Spain

Possible clearance of transfusion-acquired nef-deleted attenuated HIV-1 infection by a long-term non-progressor with CCR5 Delta32 heterozygous and HLA-B57/DR13 genotype
J. Zaunders1,2, W.B. Dyer3,4, M. Churchill5, M.L. Munier2, P. Cunningham1, K. Suzuki1,2, B. Wang6, K. McBride2, P.R. Gorry7, N.K. Saksena6, N. Seddiki8, K. Koelsch2, J.S. Sullivan9, D.A. Cooper1,2, S. Riminton10, J. Learmont4, A.D. Kelleher1,2
1St Vincent's Hospital, Sydney, Centre for Applied Medical Research, Darlinghurst, Australia, 2University of New South Wales, Kirby Institute, Kensington, Australia, 3University of Sydney, Sydney Medical School, Sydney, Australia, 4Australian Red Cross Blood Service, Sydney, Australia, 5Burnet Institute, HIV Neuropathogenesis Laboratory, Melbourne, Australia, 6University of Sydney, Westmead Millenium Institute, Sydney, Australia, 7Burnet Institute, HIV Molecular Pathogenesis Laboratory, Melbourne, Australia, 8Universite Paris-Est Creteil, INSERM U 955, Paris, France, 9Children's Cancer Institute Australia, Sydney, Australia, 10Concord Hospital, Clinical Immunology, Sydney, Australia

The HDAC inhibitor romidepsin is safe and effectively reverses HIV-1 latency in vivo as measured by standard clinical assays
O.S. Søgaard1, M.E. Graversen1, S. Leth1, C.R. Brinkmann1, A.-S. Kjær1, R. Olesen1, P.W. Denton1, S. Nissen1, M. Sommerfelt2, T.A. Rasmussen1, L. Østergaard1, M. Tolstrup1
1Aarhus University Hospital, Dept. of Infectious Diseases, Aarhus, Denmark, 2Bionor Pharma, Oslo, Norway

Moderated discussion

Powerpoints presentations
Alternative RNA splicing in latently infected T cells generates chimeric cellular:HIV mRNAs with the potential to generate Tat and reactivate infection - Secondo Sonza

The HDAC inhibitor romidepsin is safe and effectively reverses HIV-1 latency in vivo as measured by standard clinical assays - Ole Schmeltz Søgaard

Rapporteur report

Track A report by Renee van der Sluis

This session provided a platform for researchers from various backgrounds to present studies related to identifying and targeting the viral reservoir. The overall aim of the session was to gain a better understanding of what viruses persist, where they persist and what strategies can be used to eliminate them.


Dr. Sonza (Australia) provided an overview of the important role of Tat in latency. He pointed out that administration of Tat overrules most known latency mechanisms and that it can purge latent virus in cell lines.  His research demonstrated that read-through transcripts can give rise to chimeric cell:Tat RNA molecules that are translated into Tat protein via an IRES sequence in the Tat RNA. If produced in sufficient amounts, these Tat proteins could activate virus from latency. This mechanism could be used to develop novel strategies to activate latent provirus, for example by increasing background Tat levels or by introducing compounds that require a low levels of Tat for their activity.


Dr. Keele (USA) demonstrated “barcoded” SIV strains that may allow us to gain a better understanding the size and location of the viral reservoir in a non-human primate model.  One approach employing replication-competent SIVmac239 strains encoding non-synonymous mutations would allow infection with 10 unique variants to study, for example, transmission bottlenecks at mucosal sites.  To examine viruses longitudinally in the context of latent reservoirs, Dr. Keele and colleagues invented a second approach in which a synthetic swarm of viruses is generated, each carrying a unique 34 nt linker. Following infection, the linker can be used to track where viruses end up in the animal and to potentially determine which viruses rebound after cessation of cART.


The next two talks presented exciting data related to immune-mediated control of viral infection. Dr. Amara (USA) illustrated the co-localization of SIV-specific CD8+ T cells with CD4+ follicular T helper (Tfh) cells in the germinal centers. The CD8+ T cells displayed increased expression of PD1 and these cells were found more often in lymph node (LN) and rectum specimens than in blood. Interestingly, the level of PD1 expression and co-localization was linked to SIV control. Non-human primates unable to control virus replication had increased expression of PD1 and less co-localization of SIV-specific CD8+ T cells with follicular T cells compared to animals who controlled virus. These results indicate that close proximity between CD8+ T cells and Tfh cells may be beneficial to control, but high PD1 expression levels on T cells is detrimental.


Dr. Koup (USA) continued on the theme of CD8+ T cells in the context of humans. He highlighted the potential use of a bispecific antibody to redirect the cytolytic response of CD8+ T cells to HIV-infected CD4+ Tfh cells residing in the germinal centers of the LN. This bispecific antibody recruits CD8+ T cells via an anti-CD3 domain and targets infected cells using an anti-gp120 domain. Dr. Koup showed that CD8+ T cells infiltrate the germinal centers in HIV-infected LN and they have the capacity to kill infected CD4+ T cells when treated with the bispecific antibody. This approach to boost CTL killing in LNs by recruiting non-HIV specific CD8+ T cells provides a novel strategy to clear virus.


Dr. Zaunders (Australia) presented a case report of a unique patient from the Sydney Blood Bank Cohort (SBBC) who appeared to eliminate their virus. The SBBC was comprised of 9 patients infected with a delta-Nef virus via blood transfusion in the early 1980s.  Six patients were Long Term Non-Progressors, of which 3 met the criteria of Elite Controllers (EC). Samples from the EC patient discussed here harbored very low levels of HIV DNA at the time of diagnosis 15 years post-infection. Notably, HIV DNA was undetectable in samples collected from blood and gut in more recent years; however, the patient retained CD4 and CD8 T cell responses to Gag. This case differs from others in the SBBC as the subject contains 3 genetic polymorphisms associated with viral control, including protective HLA class I and HLA class II alleles, and CCR5∆32 heterozygosity. Although this is a highly unique case, it may provide clues to understand natural mechanisms of viral control and elimination of latent reservoirs.


The final talk was a late-breaker by Dr. Søgaard (Denmark), who presented the results of a clinical trial to assess the effects of romidepsin on the latent reservoir in 6 HIV-infected patients. Romidepsin is a potent HDAC inhibitor being considered for use in ‘shock and kill’ strategies to eliminate the HIV reservoir. Administration on days 0, 7 and 14 resulted in rapid histone H3 acetylation (within 1 hour) and an increase in cell associated unspliced RNA in all subjects. Notably, romidepsin induced detectable plasma viral RNA in 5 of 6 subjects after the second dose, providing the first clinical demonstration of an HDAC inhibitor that could reproducibly stimulate virus production. Unfortunately, limited activity was seen after a third dose and administration of romidepsin resulted in no change, on average, in total viral DNA measured in the 6 subjects, though one individual displayed an 80% reduction. Although more research is needed, this study provides the most compelling evidence to date that HDAC inhibitors can induce viral expression in HIV-infected patients on cART.


And with this, the session closed on a highly positive note.


    The organizers reserve the right to amend the programme.