Bringing Gene Therapies for HIV Disease to Resource-Limited Parts of the World

Despite the fact that 59% of people living with HIV (PLHIV) currently achieve viral suppression on antiretroviral therapy (ART), recent gains in controlling the global HIV/AIDS epidemic may be threatened: key HIV incidence rates are declining only modestly, the sustainability of programs to expand ART remains unclear, and the "youth bulge" in sub-Saharan Africa contributes to a growing at-risk population.1 Although much effort has been devoted to prevention interventions, these face major technical and/or implementation challenges. A complementary approach is a safe, effective, and durable intervention that completely eliminates HIV infection ("eradication") or that suppresses viremia in the absence of ART ("remission") (both of these states are referred to as an "HIV cure" herein). Though a daunting goal, the scientific basis is clear: long-term remission if not eradication has been observed in the "Berlin patient"2 as well as the "London patient"3 following transplantation of bone marrow progenitor cells lacking the viral co-receptor, CCR5; and durable remission occurs in tens of thousands of PLHIV (so-called "Elite Controllers"), some of whom ("Exceptional Elite Controllers") may have eliminated their infections through natural immunity.4,5 Ongoing work over the past decade suggests that HIV cure might be induced by some interventions, alone or in combination, including provision of broadly neutralizing antibodies (bNAbs), generation of effective antiviral CD8+ T cell responses, and knock-out of the viral co-receptor, CCR5.6 Little is known, however, about the nature and vulnerabilities of the rebound-competent viral reservoir that persists despite ART and about the immunologic control of virus in the absence of ART; today's "best bets," in other words, must still be viewed as long shots. Initiated by the Bill & Melinda Gates Foundation in 2019, the HIV Frontiers Program aims to move work on HIV cure towards interventions that will ultimately be available to all, most especially those in resource-limited parts of the world where the prevalence of disease is high (Figure 1). It starts with the premise that the journey will be long (15-25 years) and that it will ultimately yield a "single-shot cure," i.e., a product that is delivered percutaneously ("in vivo") in a single encounter, safely and effectively modifying selected cells in the body so that viral replication and spread are suppressed and re-infection blocked. This aspirational goal is likely to be realized through a series of progressive interventions that move from combination therapies provided over a longer duration of time to those in which cells are modified outside of the body ("ex vivo") prior to re-infusion.7 The work will build on current knowledge to advance through a series of technical and practical hurdles while also gathering new knowledge to best design a curative intervention for HIV and to determine whether and how it might be used. To get to the point of having a "single-shot cure" for HIV in hand, two interlocking areas of focus are being pursued: Current Best Bets: To minimize the expected time to impact, investments are being made in all of the necessary elements of a "single-shot" HIV cure in parallel. As a critical enabler, the Program is leveraging the considerable interest and resources in biotech/pharma companies that are now developing ex vivo genetic and cell-based interventions; uniquely amongst ongoing efforts, it intends to shift the emphasis of such interventions to delivery in vivo, an approach that is much more likely to benefit those in resource-limited parts of the world. Early forms of the "single-shot" cure would tap current "best bets" (i.e., administration of two or more bNAbs, induction of a durable T cell response against HIV, and CCR5 knock-out), quickly pivoting to others should they arise, and asking the questions: can these interventions be delivered efficiently and safely to appropriate cell populations in vivo; if so, can they be associated with methods to detect their failure; and, importantly, is there a viable pathway for product development and distribution in sub-Saharan Africa? Incremental steps are being taken to maximize the likelihood of success, with development and validation of novel approaches for targeting and editing selected populations of cells (e.g., hematopoietic stem cells, CD4+ T stem central memory cells, and B cells) in vivo. At the outset, this work is taking advantage of genetic "cures" for sickle cell disease that are now in hand, with early results indicating that substantial clinical benefit can be obtained with even incomplete correction of the hemoglobin S genotype (either by editing the hemoglobin S allele or by upregulating hemoglobin F) in hematopoietic stem cells ex vivo.8 Successful efforts to modify hematopoietic stem cells in vivo to result in similar corrections might form a pathway to the in vivo introduction of modifications aimed at HIV cure. If successful, the ultimate product will be an inexpensive composition that is easily and safely delivered, and designed to effect a durable HIV cure for all; en route, interventions providing benefit for those with sickle cell disease (as well as other hemoglobinopathies) should predictably arise. The HIV Reservoirs Consortium: In this program, a consortium of academic labs has been established to define the biology of the rebound-competent reservoir of HIV in vivo and, in particular, to discover circulating non-viral biomarkers that can be used to monitor it over time. A strategically focused, multidisciplinary team effort is carrying out studies in PLHIV in resource-limited parts of the world as well as in non-human primate models that recapitulate relevant aspects of human HIV infection and in which the reservoir can be systematically perturbed with interventions that could not be used in humans. Using state-of-the-art assays, it is hoped that circulating non-viral biomarkers for the rebound-competent reservoir will be discovered in the non-human primate, cross-validated in the human, and assessed for their ability to define the size and quality of the rebound-competent reservoir while on ART and the time to viral rebound once ART is discontinued. Of note, the HIV Frontiers Program pre-supposes the will to assume and to share significant risk. Substantial new financial resources and a sustained commitment will be required to pursue the multiple components of a "single-shot" HIV cure in parallel and to simultaneously launch the HIV Reservoirs Consortium. Such resources and commitment will not arise from a single source; rather, partnerships must be formed and strategic priorities set. This review will outline some of the steps that are being taken to reach these goals.