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

2020; Mary Ann Liebert, Inc.; Volume: 32; Issue: 1-2 Linguagem: Inglês

10.1089/hum.2020.252

1557-7422

Joseph M. McCune, Emily H. Turner, Adam Jiang, Brian Doehle,

Innovation and Socioeconomic Development

Human Gene TherapyVol. 32, No. 1-2 CommentariesOpen AccessCreative Commons licenseBringing Gene Therapies for HIV Disease to Resource-Limited Parts of the WorldJoseph M. McCune, Emily H. Turner, Adam Jiang, and Brian P. DoehleJoseph M. McCune*Correspondence: Dr. Joseph M. McCune, HIV Frontiers, Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation, 500 5th Avenue North, Seattle, WA 98109-4636, USA. E-mail Address: mike.mccune@gatesfoundation.orgHIV Frontiers, Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation, Seattle, Washington, USA.Search for more papers by this author, Emily H. TurnerHIV Frontiers, Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation, Seattle, Washington, USA.Search for more papers by this author, Adam JiangHIV Frontiers, Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation, Seattle, Washington, USA.Search for more papers by this author, and Brian P. DoehleHIV Frontiers, Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation, Seattle, Washington, USA.Search for more papers by this authorPublished Online:18 Jan 2021https://doi.org/10.1089/hum.2020.252AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionDespite 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). Although 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 coreceptor, 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.4,5Ongoing 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, generation of effective antiviral CD8+ T cell responses, and knockout of the viral coreceptor, 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 toward 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 (Fig. 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," that is, 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 reinfection blocked.Figure 1. The vision for the HIV Frontiers Program.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) before reinfusion.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 betsTo 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 among 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 broadly neutralizing antibodies [bNAbs], induction of a durable T cell response against HIV, and CCR5 knockout), 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 consortiumIn this program, a consortium of academic laboratories has been established to define the biology of the rebound-competent reservoir of HIV in vivo and, in particular, to discover circulating nonviral biomarkers that can be used to monitor it over time. A strategically focused, multidisciplinary team effort is carrying out studies in people living with HIV (PLHIV) in resource-limited parts of the world, as well as in nonhuman 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 nonviral biomarkers for the rebound-competent reservoir will be discovered in the nonhuman primate, crossvalidated in the human, and assessed for their ability to define the size and quality of the rebound-competent reservoir while on antiretroviral therapy (ART), and the time to viral rebound once ART is discontinued.Of note, the HIV Frontiers Program presupposes 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.The Need for an HIV CureEven though dramatic advances have been made in the diagnosis, treatment, and prevention of HIV infection, the pandemic continues unabated. Especially in countries that are resource limited, alarming rates of new infections persist, and it is unlikely that sufficient funds will become available for universal testing, treatment, and follow-up care. Even should funding emerge, life-long adherence to suppressive ART is difficult for many. In the worst-case scenario, funding for treatment and care will remain the same or even diminish, and with an anticipated "youth bulge" and increasing resistance to ART,1 an uncontrolled epidemic may possibly even grow.6,9To avoid this, we must stop acquisition of HIV by those at risk. One way to do this is by primary prevention, for example, with a vaccine, long-lasting pre-exposure prophylaxis, voluntary medical male circumcision, barrier methods, and structural and behavioral changes. Another way is to prevent transmission from PLHIV, for example, by an intervention that lowers the circulating viral load to a point at which transmission is unlikely (e.g., 3 years) reduces viral load to 1 year) viral remission in some,19 possibly because an indirect CD8+ T cell "vaccinal effect" is induced when bNAb/HIV immune complexes are internalized by antigen-presenting cells.37,38Immune modulationTo further enhance durable T cell immunity, a number of approaches are being pursued to reverse the immune dysfunction induced by progressive HIV disease. Thus, immune checkpoint blockers such as pembrolizumab (anti-PD1) and ipilimumab (anti-CTLA4) are being evaluated for their ability to augment HIV-specific functional immune responses,39–41 vedolizumab (anti-α4β7) for its ability to reduce trafficking of susceptible CD4+ T cells to the gut HIV reservoir,42 and the IL-15 superagonist ALT-803/N-803 for its ability to improve trafficking of CD8+ T cells to lymphoid tissue B cell follicles.43,44 A variety of other agents (e.g., sirolimus, an IL-21 superagonist, and anti-IFNα/β receptor antibodies) are also being tested for their ability to reduce HIV-associated inflammation, hoping to thereby improve HIV-specific immune responses.45–47Targeting the HIV replication cycleThese approaches are designed to either inhibit infection of CD4+ target cells (e.g., by transplantation of bone marrow stem cells from a CCR5Δ32 donor, knockout of the endogenous CCR5 locus, and/or expression of antagonists that prevent viral entry into potential target cells)6,48,49 or to reverse latency and increase transcription of HIV (e.g., by provision of latency reversal agents such as histone deacetylase inhibitors, Toll-like receptor agonists, or disulfiram),50 thereby effecting virus- or immune-mediated cytolysis of infected cells ("kick-and-kill"). Conversely, it might be possible to "block-and-lock" the viral genome, for example, by inhibition of Tat with didehydro-cortistatin A or with the use of interfering RNAs to silence the viral promoter or cause degradation of complementary viral mRNA.6,45 Finally, gene editing strategies (e.g., with CRISPR/Cas9 and the Brec1 recombinase) are being employed to activate or inactivate the integrated proviral genome in situ.51,52Data about the impact of some, if not all, of these approaches should be forthcoming in the next 2–4 years from a diverse array of interventional and observational studies that are now ongoing, although at an early stage and with a narrow demographic of participants and small sample sizes.14Limitations of Current Funding MechanismsAlthough HIV cure research has attracted substantial resources and much energy since it was formally launched over a decade ago,53 there has been little consideration given to interventions that might be used in resource-limited parts of the world and no coordinated plan to discover circulating nonviral biomarkers to qualitatively and quantitatively define the rebound-competent reservoir in those on or discontinuing ART. Given the absence of such biomarkers and the presence of other daunting technical challenges as well as concerns about short-term return on investment, biotech/pharma has more or less shied away from this work and the few companies with serious programs will not be easily able to prioritize products for resource-limited countries.Meanwhile, even though the NIH and organizations such as amfAR have devoted considerable resources to academic laboratories to discover and develop cures for HIV and to more deeply study the biology of the rebound-competent reservoir, the incentive structure of academia is not well suited for the sustained support of multidisciplinary team efforts of high risk, particularly those not also associated with a downstream profit motive that might attract the attention of biotech/pharma. In aggregate, the motivating factors and resources required to bring curative interventions for HIV to resource-limited parts of the world would appear to require new models for discovery, innovation, and risk-sharing partnership.Strategy of the HIV Frontiers ProgramThe HIV Frontiers Program has been devised as a first step toward building these models. It aims to take a comprehensive approach toward developing an effective, durable, safe, and affordable single-shot HIV cure that could be used anywhere in the world, envisioning two interlocking areas of focus: one that would explore the Current Best Bets for HIV cure and another that would create an HIV Reservoirs Consortium to understand the biology of the rebound-competent reservoir and circulating nonviral biomarkers of it.Current Best BetsAchieving a single-shot HIV cure requires integration of four key elements (Fig. 2): (1) design of the cure, (2) in vivo delivery and durability of the design, (3) detection of the loss of remission, and (4) distribution of the intervention in sub-Saharan Africa. Rather than to await the definition of the best design for a curative intervention and to then pursue the remaining elements, the HIV Frontiers Program is advancing all in parallel. This approach is motivated by the goal of minimizing the expected timeline to impact and enabled by existing commercial interest in cell targeting and editing, diagnostics, and curing sickle cell disease.54 Indeed, we view the extension of promising ex vivo gene therapies for sickle cell disease to people in need in sub-Saharan Africa as an imperative; this exercise may also serve as a pathfinder for analogous in vivo gene therapy approaches for an HIV cure.Figure 2. The key elements of the HIV Frontiers Program.Although research on in vivo cellular and genetic modifications is at a very early stage, the following projections can now be reasonably made:DesignIf the design of a broadly applicable HIV cure remains elusive, it is nonetheless possible to imagine (as described in more detail in Lewin et al.7) that there will be an evolutionary progression of curative target product profiles, moving over time from combination therapies to ex vivo gene therapies to in vivo gene therapies. Modeling of the epidemic in sub-Saharan Africa, where transmission rates remain high, suggests that an optimal curative intervention should not only suppress (or eliminate) the rebound-competent reservoir within affected individuals but also prevent infection upon re-exposure to virus.9Among the approaches described above, those that now look most promising for use in resource-limited parts of the world include interventions that provide a durable effect without repeated administration, for example, extended provision of multiple bNAbs or of eCD4, and/or the induction of a long-lasting and effective antiviral immune response. Given the examples of the "Berlin patient" and the "London patient" as well as intriguing preliminary data with directed CCR5 knockout in peripheral blood cells, interventions ablating this locus might also be pursued.These and many other approaches are being advanced, alone or in combination, into human clinical trials, data from which should be forthcoming in the next several years to more completely inform the best design for an HIV cure. Notably, however, most of these trials are being conducted in a narrow demographic (mostly older white men living in the United States, Europe, and Australia).14 It will accordingly be crucial to test the hypothesis that curative interventions in this demographic will be of benefit to others, especially those in resource-limited parts of the world.Delivery and durabilityAlthough many of the above "best bets" are being provided by ex vivo manipulation of cells (e.g., in the case of CCR5 knockout) or repeated administration of GMP-grade protein (e.g., in the case of bNAbs), rapid and sustained advances in the fields of cellular and genetic therapy, now being pursued by many companies, suggest that most could instead be introduced by in vivo targeting and editing of long-lived cells (Fig. 3). By example, bNAbs might be delivered to long-lived B cells as self-replicating mRNA or by stable modification of the immunoglobulin locus itself, and CCR5 might be knocked out in bone marrow-resident hematopoietic stem cells or circulating T stem central memory cells. Importantly, durable immune responses might also be generated upon induction of a "vaccinal effect" by immune complexes formed between bNAbs and HIV, or by provision of appropriate vaccines to antigen-presenting cells.Figure 3. Critical considerations in the discovery, development, and clinical application of therapies targeting and editing long-lived cells in vivo.To introduce such modifications in vivo, it will be necessary to design vectors that can carry the appropriate editing systems to selected target cells after percutaneous (e.g., intravenous or intramuscular) administration. Active work in this area55–57 has already highlighted the capabilities of viral (e.g., AAV and lentiviral) vectors as well as ligand-directed lipid nanoparticles, ribonucleoprotein complexes, synthetic nucleocapsids, and exosomes; given commercial opportunities in areas like oncology, it is inevitable that even more options will surface in the future.As a first step, the HIV Frontiers Program is investing in studies to ask the question: can multilineage hematopoietic stem cells, mobilized or not, be targeted by viral or nonviral vectors in vivo (e.g., in humanized mouse models and nonhuman primates) and then edited to assume new functional traits (e.g., upregulation of hemoglobin F in the case of sickle cell disease)? We envision that these proof-of-concept experiments would likely have carryover impact for modification of such cells for purposes of HIV cure (e.g., introduction of genes encoding bNAbs), while also providing valuable information about the targeting and editing of other long-lived cell populations of interest, for example, T stem central memory cells and B cells.DetectionAnticipating that methods conferring lifelong remission will take years if not decades to perfect, it will be necessary in the interim to develop methods by which viral rebound can be reliably detected. Efforts are already being made to develop inexpensive home test kits that can be used by the individual, some of which are able to detect low viral loads (839 copies/mL) with a single finger prick.58 These efforts could be extended in the future to develop approaches to viral detection that are even more simple, affordable, and accurate. We also envision that they will be vastly accelerated if it is possible to define circulating nonviral biomarkers of the rebound-competent reservoir (see The HIV Reservoirs Consortium section).DistributionIt is unlikely that any approach involving cell targeting and editing in vivo will move into sub-Saharan Africa until and unless there are compelling reasons to believe that it will safely provide benefit to those in need. The most immediate motivation will be promising data for the cure of sickle cell disease. As mentioned above, several ex vivo approaches toward a genetic cure of sickle cell disease are now in hand, each of which is being pursued by for-profit US-based companies and the NIH. Early results indicate that substantial clinical benefit can be obtained with even incomplete correction of the hemoglobin S genotype (either upon editing the hemoglobin S allele or by upregulation of hemoglobin F).Working in collaboration with these efforts, the technical envelope for in vivo delivery of analogous interventions will be explored, first in the United States and then in sub-Saharan Africa. Successful validation of targeting and editing approaches in sub-Saharan Africa (which would be its own reward) would provide early confidence that similar technical, clinical, regulatory, and introduction approaches could be taken toward HIV cure, where links between proposed target modifications and clinical success are now less certain.We have also considered it important to initiate—sooner than later—a vigorous discussion about the ultimate implementation of curative interventions for HIV and sickle cell disease into sub-Saharan Africa. To this end, plans have been made to launch the HIV Cure Africa Acceleration Partnership, a multidisciplinary public–private partnership designed to catalyze and promote HIV cure research through engagement of diverse stakeholders and community members, convening them at an early stage to accelerate the design, socialization, implementation, and rapid adoption of HIV cure products.59 We imagine that it—or a similar public–private partnership—might also serve to advance curative interventions for sickle cell disease.The HIV Reservoirs ConsortiumTo be maximally effective and practical, interventions to cure HIV must be designed to suppress the rebound-competent reservoir of HIV over a relatively long period of time, for example, by engaging an immune response that destroys and/or prevents viral spread from cells harboring rebound-competent viral genomes. As in the case of staging in the treatment of cancer, it is possible that—depending on the absolute size of the reservoir and its disposition among cell types and organs of the body—di