Plenary talks at IAS Cure Workshop

1 August 2015. Related: Conference reports, Cure-related research, IAS Cure 2015.

Simon Collins, HIV i-Base

The following article summarises the plenary talks at this annual cure research workshop.

Recent progress in cure research

An overview by Dan Kuritzkes, currently leading research as head of the adult ACTG trials network set the stage for the workshop with an update of the progress over the seven years since the successful proof of concept case of the Berlin patient. [1]

Kuritzkes noted that attempts to reproduce the results with other autologous stem cell transplants from CCR5-deficient donors have unfortunately not been successful, perhaps either these cases were too advanced when treated, or conversely, the original case was just lucky. The most worrying possibility is that the mutation that renders cells deficient for CCR5 also affects the efficacy of stem cell transplantation, but it is not yet clear if that may be the case.

Although reversing HIV latency 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 the limited successes of latency revering strategies including use of HDAC inhibitors and gene therapy and raised important ethical issues of the need for 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 and an increase in HIV reservoir size 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. [2]

This ranged 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 understanding of the clinical implications and ageing takes him into uncharted 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 (who 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 after a long and inspiring fight against progressively debilitating HIV-related complications left many of us saddened).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 campaigns such as “gettingtozeroSF.org” and this will require increased funding to overcome the challenges of the sustainability of global universal ARV access.

Broadly neutralising monoclonal antibodies (bNAb’s) as treatment

John Mascola from the US NIAID/NIH Vaccine Research Centre gave a review of the treatment potential of bNAbs that included the background, opportunities and recent data from the VRC01 trial. [3]

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 have both a broader neutralising range and have significantly greater potency.

The first property is essential in order to avoid escape mutations that with single mAbs will lead to 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, extend dosing to perhaps only require injections every 3 – 6 months and to manufacture bNAbs with characteristics that reduce the risk of resistance.

Immune recognition after reversal of latency

With multiple advances in the approach of activating HIV in the reservoir of latently infected CD4 cells, Marcus Altfied from the Heinrich-Pette Institute reviewed the problem of generating an effective immune response to facilitate elimination of these cells. [4]

Not only are current immune responses typically unable to respond to CD4 cells in which latent HIV has been activated – which themselves might persist for much longer than previously expected – but activation itself can be an incomplete process, stalling at several earlier stages before 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 genetically engineering T cells was given by James Riley from the University of Pennsylvania. Dr Riley stressed the potential for gene therapy to improve on HIV-specific CD4 responses which, in the context of cure research, will need to be sustained for decades if ART is to be stopped. [5]

As well as the history of this field from early studies in 1996 that included antisense molecules targeting HIV, 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 approach that targets an HIV fusion inhibitor protein, C34, to the CXCR4 co-receptor (to ensure that the inhibitor is present at or near the site of HIV entry into CD4 cells) 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 question of 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. [6]

This review included results from the UK SPARTAC study (Short Pulse ART at Seroconversion) presented at CROI 2015 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. [7]

Two new studies in the UK include the prospective HEATHER cohort of HIV seroconverters who start ART within 3 months of diagnosis and the RIVER study that is using integrase inhibitor-based ART plus prime-boost vaccine plus multiple doses of the HDAC inhibitor vorinostat with a primary endpoint of reduction in total HIV DNA.

Thanks to Richard Jefferys for editorial comments.

References:

Unless stated otherwise, references are plenary talks in the Programme to the IAS Towards and HIV Cure Symposium, 18-19 July 2015, Vancouver.

http://www.iasociety.org/What-we-do/Towards-an-HIV-Cure/Events/2015-Symposium

1. Kuritzkes D. Progress and Challenges in HIV Cure Research,
2. Sharp M. Community Involvement in HIV Cure-related Research: Not Just Guinea Pigs.
3. John Mascola J. HIV-1 broadly neutralizing antibodies: Potential role in HIV treatment approaches.
4. Altfeld M. Immune recognition following latency reversal.
5. Riley J. Engineering T cells to functionally cure HIV-1 infection.
6. Fidler S. CHERUB: Collaboration in HIV Eradication in the UK; Predictors of PTC and Viral Reactivation Strategies.
7. Hurst J et al. Biomarkers to Predict Viral Rebound at Antiretroviral Therapy Interruption in SPARTAC. CROI 2015, 23-26 February 2015, Seattle. Late breaker oral abstract 111LB.
   http://www.croiconference.org/sessions/biomarkers-predict-viral-rebound-antiretroviral-therapy-interruption-spartac