A number of conferences and workshops related to HIV cure research have taken place over the past several months, many of which can be viewed or learned about online. Links and some brief reports from four events are provided below.
Promising Approaches to HIV Remission and Cure
HIV cure research was the chosen topic for the Harvard University Center for AIDS Research (CFAR) annual symposium, held on October 23rd. The organizers have created a YouTube playlist featuring all presentations and panel discussions from the event.
5th Conference on Cell & Gene Therapy for HIV Cure
The only conference that specifically focuses on cell and gene therapy in HIV cure research was launched in 2014 under the auspices of the defeatHIV Collaboratory at the Fred Hutchinson Cancer Research Center in Seattle. The meeting has quickly become established as the key annual get together for this area of the cure research field. The 5th conference took place from August 22-23 in Seattle; the agenda is available on the event website and videos of presentations are now being added to the defeatHIV YouTube channel (a playlist is available for day 1).
Fred Hutch News published two stories about the conference, the first highlighting the work of keynote speaker Dr. Robert Siliciano and the second covering presentations and a workshop focused on strategies to make gene therapies more affordable and globally accessible.
The latter workshop was co-organized by the well-known HIV researcher Mike McCune, who is now leading the HIV Frontiers program at Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation. McCune recently co-authored a commentary in the journal EBioMedicine outlining how an accessible gene therapy might theoretically contribute to achieving an HIV cure.
A significant step toward making the hope of accessible gene therapies a reality was announced by the Bill & Melinda Gates Foundation and the National Institutes of Health (NIH) on October 23rd. The two research behemoths have joined forces to launch an initiative that will invest at least $100 million over the next four years to develop affordable, gene-based cures for sickle cell disease (SCD) and HIV.
In tandem with the Cell & Gene Therapy conference, defeatHIV’s indefatigable Community Engagement Project Manager Michael Louella organized a public event at the Seattle Library co-hosted by DeAunte' Damper, the LGBTQ Chair of the Seattle King County NAACP. Discussants included the researcher Carl June, gene therapy trial participants Matt Sharp and Matt Chappell, and defeatHIV Community Advisory Board members Tranisha Arzah and Manuel Venegas. Video is available on the Seattle Channel and the defeatHIV YouTube channel.
Finding and Characterizing HIV Reservoirs
A second example of collaboration between the Bill & Melinda Gates Foundation and the NIH in the area of cure research was a workshop on finding and characterizing HIV reservoirs, held July 30-31 on the NIH campus. Thanks to the wonders of the NIH videocast system, the entire meeting can be viewed online (see day 1 and day 2).
Particularly recommended is a tour de force presentation by Robert Siliciano, one of the first researchers to identify the HIV reservoir. Siliciano highlighted the recent shift in understanding of how the HIV reservoir persists despite antiretroviral therapy (ART). Initially, there were suspicions that continuing low-level viral replication in tissues (sometimes referred to as “sanctuary sites”) was playing a role, but it has now become apparent that—in his words— “the vast majority of cells in the reservoir are not generated by direct infection but by proliferation of previously infected cells.”
Siliciano also discussed a new assay developed in his laboratory that attempts to simplify the detection of the replication-competent HIV reservoir. In a study published in Nature earlier this year (now available free in PMC), Siliciano’s group described their approach to assessing the intactness of HIV DNA proviruses, which they’ve named the intact proviral DNA assay (IPDA).
In the workshop presentation, Siliciano showed unpublished data from Gregory Laird indicating that the decay of the HIV reservoir in people on ART is the same (~44 months) when measured with the IPDA or the far more cumbersome and expensive quantitative virus outgrowth assay (QVOA). He noted, however, that the IPDA also revealed outliers around the average value – some study participants had precipitous declines in their HIV reservoir, while others showed increases (likely the result of proliferation of latently infected CD4 T cells).
IAS HIV and HBV Cure Forum/IAS 2019
In recent years, the International AIDS Society (IAS) has scheduled symposiums on HIV cure research immediately preceding their main annual conference (which alternates between the International AIDS Conference and the IAS Conference on HIV Science). The theme differs at each event, and in 2019 the focus was on parallels between the efforts to cure HIV and hepatitis B (HBV).
A detailed report from the meeting was published on October 22nd in the open access Journal of Virus Eradication. Oral and poster abstracts are also available from the same journal. Slide presentations are posted on the IAS website for the event.
Among the presentations:
Maria Pino described research in the SIV/macaque model suggesting that the approved multiple sclerosis treatment fingolimod (trade name Gilenya) can cause retention of cytotoxic T cells in lymphoid tissue and reduce the reservoir of virus DNA in T follicular helper cells (some of the work was published in PLoS Pathogens on October 18th). A subset of macaques administered fingolimod at the time of ART initiation showed evidence of a delayed and lower magnitude viral load rebound after an analytical treatment interruption.
There is considerable interest in the prospects for Gilead Sciences toll-like receptor 7 (TLR-7) agonist vesatolimod in HIV, due to encouraging results in macaques. Preliminary data from a phase I trial in people on ART were presented by Sharon Riddler from the University of Pittsburgh School of Medicine. The compound appeared safe and there was evidence of immune-stimulating activity at doses over 6mg. The ultimate aim is to study vesatolimod in combination with other interventions such as broadly neutralizing antibodies.
One question that the trial didn’t address is whether responses to vesatolimod might be different in women compared to men. A decade ago the research group of Marcus Altfeld reported evidence of sex differences in responsiveness to TLR7 agonists, and female sex was associated with greater induction of interferon-stimulated gene expression in a previous trial of vesatolimod as a treatment for hepatitis B.
Out of 48 participants in the dose-escalating HIV trial, only five were women, and three of the six dose groups included only men. It will be important for future studies to investigate whether sex influences the response to vesatolimod in people with HIV. An ongoing trial is evaluating vesatolimod in HIV controllers who have started ART, but demographic information on participants is not yet available.
Sharon Lewin from the Doherty Institute in Australia described a new effort that is underway to develop a “target product profile” (TPP) for an HIV cure with particular focus on global accessibility, and the formation of a related “HIV Cure Acceleration for Africa” (HCAAP) working group. These plans grew out of a summit hosted by the IAS in partnership with the Annenberg Trust at Sunnylands.
A presentation at the main IAS 2019 conference that drew attention was delivered by Xu Yu from Massachusetts General Hospital. Yu highlighted cases of extreme elite control of HIV that may represent clearance of all replication-competent viruses, focusing in particular on a long-term elite controller referred to as the “San Francisco patient.” Recently, an article in Leapsmag by Bob Roehr revealed the individual to be Loreen Willenberg, who is renowned among activists for her key role in promoting elite controller research via the Zephyr Foundation. Official IAS 2019 video of Yu’s presentation is not available, but a partial recording is posted to the defeatHIV Facebook page.
Links to cure-related IAS 2019 sessions are appended below.
Stem cell and genome editing for HIV cure (plenary session, presentation starts at 0:31:40)
Paula Cannon, University of Southern California, United States
New and old players in HIV replication
HIV transcription: The sound of silence
What is the cure, why do we need it and how do we get there?
Keep control: Elite and post-treatment controllers
Hide and seek: Reservoirs and strategies to target them
Research by and for whom? Community engagement in research
HIV remission and control trials
Kill the enemy: CTL and NK cells
Paediatric HIV infection: It's never too early
Comments