IAS Towards an HIV Cure Symposium: Workshop Summary
The fourth annual Towards a Cure symposium, organised by the International AIDS Society (IAS) before the large summer conferences was held this year on 18-19 July 2015 in Vancouver.
The programme for these workshops is abstract-driven based on the most important cure-related research that will be included in the IAS main conference.
Although most of the data at the Cure workshop is embargoed until it is presented in the main conference, the following plenary talks set the main themes to watch.
Recent Progress in Cure Research
An overview by Dan Kuritzkes, currently leading research as head of the adult ACTG trials network set the context for the workshop with an update of the progress over the seven since the successful proof of concept case of the Berlin patient.
Even though attempts to reproduce the Berlin results with other autologous stem cell transplants have unfortunately not been successful, he suggested that perhaps either these recent cases were too advanced when treated or that the original case was just especially lucky in ways we have yet to understand.
Although reversing latently infected CD4 cells is now recognised as a necessary step for cure research, even if this is achieved, we know that on its own this will not be sufficient to produce a cure.
The talk reviewed limited success of latency revering strategies including use of HDAC inhibitors and gene therapy and raised important ethical issues of needing additional interventions when recommending treatment interruptions for people treated during earlier stages after infection. Many researchers see this as the key population in whom cure strategies are most likely to work but yet they risk acute seroconversion if they stop treatment.
Community Involvement in Cure Research
In the second plenary, long-time HIV positive activist Matt Sharp, expanded on cure research from a personal perspective from early involvement in community responses in San Francisco in the 1980s through to achieving five year follow-up after having been an early participant in the first zinc finger nuclease-based gene therapy safety study: while his CD4 cells have doubled, there is little understand of the clinical implications and ageing takes him into unchartered waters as a subject for research.
Diagnosed in 1988 and recently having celebrated his 60th birthday, Matt gave a calm, steady and sober evaluation of being part of a community response that included fellow activists Martin Delaney (in whose name much of the US public cure research programme is named after) and Bob Munk, the popular long-time activist whose death in the week before the conference left many of us saddened after a long and inspiring fight against progressively debilitating HIV-related complications.
Matt spoke of the difficulties of having to still educate and explain -- to media, HIV positive people and even activists -- community myths and misunderstandings about cure research and how a new community educational resource (avac.org/CUREiculum) may help others to do this.
For the future, cure research needs to be central to campaign such as gettingtozeroSF.org and this will require increased funding to overcome the challenges of sustainability of global universal ARV access.
Broadly Neutralising Monoclonal Antibodies (bNAb's) as Treatment
A review of the treatment potential of bNAbs was given by John Mascola from the US NIAID/NIH Vaccine Research Centre that included the background, opportunities and recent data from the VRC01 trial.
Although monoclonal antibodies have a long history as potential HIV therapeutic interventions, most notably with ibalizumab and PRO140 -- both of which have been in development for many years -- more recently developed compounds both cover a broader neutralising range and have significantly greater potency.
The first property is essential in order to avoid escape mutations that with single mAb's will develop resistance similar to monotherapy with antiretrovirals -- emphasising the importance of using combination therapy with monoclonal antibodies. The second is needed to enable lower doses to be used -- also with longer half-lives -- in order to bring manufacturing costs within reach of practical use.
Data was presented for VRC01 (see the MOBS03 bridging session at 11 am on Monday in the main IAS 2015 programme) which together with 3BNC117 is also being studied as a potential prevention intervention in people at high risk of HIV.
Although still in early stages of development, future research has the potential to further increase potency by 10-100 fold, extending dosing to perhaps only require injections every 3 to 6 months and to manufacture bNAb's with characteristics that reduce the risk of resistance.
Immune Recognition After Reversal of Latency
With multiple several advances in the approach of activating the reservoir of latently infected CD4 cells, Marcus Altfied from the Heinrich-Pette Institute reviewed the problem of generating an effective immune response. Not only are current immune responses unable to respond to newly activated latent cells, which themselves might persist for much longer than previously expected, but activation itself can be an incomplete process, stalling at several earlier stages prior to productively producing new virus.
This session reviewed the kinetics of antigen expression and included new data on using NK cell activity.
Engineering CD4 T Cells
The plenary talk on approaches to engineering T cells was given by James Riley from the University of Pennsylvania who stressed the potential for gene therapy to improve on CD4 responses which in the context of cure research will need to be sustained for decades if ART is to be stopped.
In addition to the history of this field from early studies in 1996 that included antisense molecules targeting integrated proviral DNA, this talked focused on the use of zinc finger nuclease (ZFN) and Sangamo compound SB-728 that modifies and reinfuses CD4 cells to carry CCR5 deletions.
A new compound C34 is building on this technology with the aim of producing a greater percentage of HIV resistant cells with the hope that this will have a greater impact on viral suppression.
Strategies for Viral Reactivation and Predictors of Post Treatment Controllers
The important concern for whether biomarkers can be sufficiently predictive to guide selection of appropriate participants for research studies that involve a treatment interruption (TI) was reviewed by Sarah Fidler from Imperial College London, who also outlined important cure-related studies starting in the UK.
This included results from the UK SPARTAC study (Short Pulse ART at Seroconversion) presented at CROI 2015 (Abstract LB111) that showed that high pre-treatment levels of PD-1, TIM-3 or Lag-3 (but not at time of TI) were predictive of time to viral rebound after the interruption.
Two new studies in the UK include the prospective HEATHER cohort of HIV seroconvertors who start ART within 3 months of diagnosis and the RIVER study that is using integrase-based ART plus prime-boost vaccine plus multiple doses of the HDAC inhibitor vorinostat with a primary endpoint of reduction in total HIV DNA.