TY - JOUR
AU - Riley, James L
AB - Abstract HIV-infected individuals successfully controlling viral replication via antiretroviral therapy often have a compromised HIV-specific T-cell immune response due to the lack of CD4 T-cell help, viral escape, T-cell exhaustion, and reduction in numbers due to the withdrawal of cognate antigen. A successful HIV cure strategy will likely involve a durable and potent police force that can effectively recognize and eliminate remaining virus that may emerge decades after an individual undergoes an HIV cure regimen. T cells are ideally suited to serve in this role, but given the state of the HIV-specific T-cell response, it is unclear how to best restore HIV-specific T-cell activity prior initiation of a HIV cure strategy. Here, we review several strategies of generating HIV-specific T cells ex vivo that are currently being tested in the clinic and discuss how infused T cells can be part of an HIV cure strategy. human-immunodeficiency-virus, antiretroviral therapy, latency reversing agent, T-cell receptor, chimeric antigen receptor, T-cell exhaustion, ex vivo T-cell expansion HIV induces profound loss of CD4 T cells throughout all compartments of the body, increasing the susceptibility to AIDS-related opportunistic infections [1]. However, in the era of effective antiretroviral therapy (ART), successfully treated human immunodeficiency virus (HIV)-infected individuals are expected to have a normal lifespan characterized by low levels of viremia and restored CD4 T-cell counts. As the field moves to cure HIV, a very small subset of cells that harbor latent, replication-competent virus has now become the target of therapeutic intervention [2, 3]. Many current strategies propose to awaken the viral reservoir in the hope that the immune system, namely HIV-specific CD8 T cells (CTLs), will eradicate these cells. Unfortunately, despite effective ART, CTL responses are generally compromised and are ill-prepared to eliminate cells whose latent HIV has become activated. This review will examine why adoptive T-cell therapy is an attractive approach to restore the HIV-specific T-cell response and will highlight approaches, summarized in Figure 1 and Table 1, that have been previously or are currently being tested in the clinic. Figure 1. Open in new tabDownload slide Cartoon depicting current adoptive T-cell therapies for human immunodeficiency virus (HIV) infection. Top (purple): Natural T cells from HIV-infected or seronegative individuals are stimulated ex vivo with HIV peptide pool targeting conserved regions of HIV. The expanded cell product can be infused as a preventative vaccine or as part of an HIV cure strategy. Bottom right (yellow): T cells are gene-engineered to express HIV-specific T-cell receptors (TCRs) that effectively controls HIV replication. Most major histocompatibility complex (MHC) class I restricted TCRs would have to be affinity enhanced in order to function in CD4 T cells. This strategy would only be effective in individuals harboring the correct MHC allele and, presumably, several populations of unique HIV-specific TCR-expressing T cells would need to be infused to prevent viral escape. Bottom left (green): T cells are gene-engineered to express a chimeric antigen receptor (CAR) that provides HLA-independent targeting HIVEnv. Shown here is a CAR that uses CD4 or single chain antibody (scFv) to bind HIVENV. Each of these approaches can work in CD4 and CD8 T cells and can be linked to costimulatory domains to further enhance the potency, expansion, and survival of these CAR T-cell products in vivo. Figure 1. Open in new tabDownload slide Cartoon depicting current adoptive T-cell therapies for human immunodeficiency virus (HIV) infection. Top (purple): Natural T cells from HIV-infected or seronegative individuals are stimulated ex vivo with HIV peptide pool targeting conserved regions of HIV. The expanded cell product can be infused as a preventative vaccine or as part of an HIV cure strategy. Bottom right (yellow): T cells are gene-engineered to express HIV-specific T-cell receptors (TCRs) that effectively controls HIV replication. Most major histocompatibility complex (MHC) class I restricted TCRs would have to be affinity enhanced in order to function in CD4 T cells. This strategy would only be effective in individuals harboring the correct MHC allele and, presumably, several populations of unique HIV-specific TCR-expressing T cells would need to be infused to prevent viral escape. Bottom left (green): T cells are gene-engineered to express a chimeric antigen receptor (CAR) that provides HLA-independent targeting HIVEnv. Shown here is a CAR that uses CD4 or single chain antibody (scFv) to bind HIVENV. Each of these approaches can work in CD4 and CD8 T cells and can be linked to costimulatory domains to further enhance the potency, expansion, and survival of these CAR T-cell products in vivo. Table 1. Approaches to HIV-Specific Adoptive T-Cell Therapy Approach . Ex Vivo Expanded HIV-Specific T Cells . HIV-Specific TCR Redirected T-Cell Therapy . HIV-Specific CAR Redirected T-Cell Therapy . Genome editing No genome editing Site-specific TCR/CAR integrate via dsDNA break and homology-directed repair using AAV donor template Retroviral/lentiviral transduction with vector containing TCR/CAR To date, no serious adverse events reported due to genotoxicity caused by engineering T cells Cell expansion Multipeptide stimulation via autologous APCs Polyclonal T-cell stimulation using artificial APCs or anti-CD3/CD28 antibody-coated beads Antigen recognition Ex vivo expanded HIV-specific T cells react to a variety of distinct HIV-derived epitopes Responses are restricted to the individual’s HLA haplotype TCR transgenic T cells recognize a single epitope comprising 8–11 amino acids derived from a conserved region in the HIV genome CARs recognize infected cells independent of HLA/peptide presentation Antigen recognition moiety of the CAR (CD4- or scFv-based) targets HIVENV expressed on the cell surface HIV escape Constrains virus escape by restoring broad T-cell responses Latent HIV may harbor preexisting mutations that render infected cells insensitive to therapy Target conserved region in the genome where mutations likely impair viral fitness Infusion of T cells with multiple specificities will further constrain virus escape Affinity-enhanced TCRs may limit virus escape but could result in off-target toxicity Escape from CD4-based CAR likely imposes a fitness loss as mutations that abrogate CD4 binding will compromise viral entry scFv-based CARs will likely select for resistant virus much like the infusion of neutralizing antibodies CAR T cells expressing unique HIV-specific scFvs will likely be required to prevent escape HIV accessory proteins HIVNEF and HIVVPU prevent the surface expression of HLA molecules Reduction in peptide-HLA complexes on infected cell surface impairs TCR T-cell recognition and killing CAR T cells recognize infected cells independent of HLA and are not affected by HIV-induced HLA downregulation Function and exhaustion Failure to control HIV after ART cessation will impair TCR T-cell function due to persistent exposure to viral antigen Collapse of CD4 T-cell help from depletion of HIV-specific CD4 T cells will further impair the function of infused TCR T cells Integration of costimulatory domains (ie, 4-1BB) augments CAR T-cell function and susceptibility to exhaustion CD4- and scFv-based CAR T cells are susceptible to infection but can become resistant (ie, by genetic disruption of HIV coreceptor CCR5) Approach . Ex Vivo Expanded HIV-Specific T Cells . HIV-Specific TCR Redirected T-Cell Therapy . HIV-Specific CAR Redirected T-Cell Therapy . Genome editing No genome editing Site-specific TCR/CAR integrate via dsDNA break and homology-directed repair using AAV donor template Retroviral/lentiviral transduction with vector containing TCR/CAR To date, no serious adverse events reported due to genotoxicity caused by engineering T cells Cell expansion Multipeptide stimulation via autologous APCs Polyclonal T-cell stimulation using artificial APCs or anti-CD3/CD28 antibody-coated beads Antigen recognition Ex vivo expanded HIV-specific T cells react to a variety of distinct HIV-derived epitopes Responses are restricted to the individual’s HLA haplotype TCR transgenic T cells recognize a single epitope comprising 8–11 amino acids derived from a conserved region in the HIV genome CARs recognize infected cells independent of HLA/peptide presentation Antigen recognition moiety of the CAR (CD4- or scFv-based) targets HIVENV expressed on the cell surface HIV escape Constrains virus escape by restoring broad T-cell responses Latent HIV may harbor preexisting mutations that render infected cells insensitive to therapy Target conserved region in the genome where mutations likely impair viral fitness Infusion of T cells with multiple specificities will further constrain virus escape Affinity-enhanced TCRs may limit virus escape but could result in off-target toxicity Escape from CD4-based CAR likely imposes a fitness loss as mutations that abrogate CD4 binding will compromise viral entry scFv-based CARs will likely select for resistant virus much like the infusion of neutralizing antibodies CAR T cells expressing unique HIV-specific scFvs will likely be required to prevent escape HIV accessory proteins HIVNEF and HIVVPU prevent the surface expression of HLA molecules Reduction in peptide-HLA complexes on infected cell surface impairs TCR T-cell recognition and killing CAR T cells recognize infected cells independent of HLA and are not affected by HIV-induced HLA downregulation Function and exhaustion Failure to control HIV after ART cessation will impair TCR T-cell function due to persistent exposure to viral antigen Collapse of CD4 T-cell help from depletion of HIV-specific CD4 T cells will further impair the function of infused TCR T cells Integration of costimulatory domains (ie, 4-1BB) augments CAR T-cell function and susceptibility to exhaustion CD4- and scFv-based CAR T cells are susceptible to infection but can become resistant (ie, by genetic disruption of HIV coreceptor CCR5) Abbreviations: AAV, adeno-associated virus; APC, antigen presenting cell; ART, antiretroviral therapy; CAR, chimeric antigen receptor; dsDNA, double-stranded DNA; HIV, human immunodeficiency virus; scFv, single-chain variable fragment; TCR, T-cell receptor. Open in new tab Table 1. Approaches to HIV-Specific Adoptive T-Cell Therapy Approach . Ex Vivo Expanded HIV-Specific T Cells . HIV-Specific TCR Redirected T-Cell Therapy . HIV-Specific CAR Redirected T-Cell Therapy . Genome editing No genome editing Site-specific TCR/CAR integrate via dsDNA break and homology-directed repair using AAV donor template Retroviral/lentiviral transduction with vector containing TCR/CAR To date, no serious adverse events reported due to genotoxicity caused by engineering T cells Cell expansion Multipeptide stimulation via autologous APCs Polyclonal T-cell stimulation using artificial APCs or anti-CD3/CD28 antibody-coated beads Antigen recognition Ex vivo expanded HIV-specific T cells react to a variety of distinct HIV-derived epitopes Responses are restricted to the individual’s HLA haplotype TCR transgenic T cells recognize a single epitope comprising 8–11 amino acids derived from a conserved region in the HIV genome CARs recognize infected cells independent of HLA/peptide presentation Antigen recognition moiety of the CAR (CD4- or scFv-based) targets HIVENV expressed on the cell surface HIV escape Constrains virus escape by restoring broad T-cell responses Latent HIV may harbor preexisting mutations that render infected cells insensitive to therapy Target conserved region in the genome where mutations likely impair viral fitness Infusion of T cells with multiple specificities will further constrain virus escape Affinity-enhanced TCRs may limit virus escape but could result in off-target toxicity Escape from CD4-based CAR likely imposes a fitness loss as mutations that abrogate CD4 binding will compromise viral entry scFv-based CARs will likely select for resistant virus much like the infusion of neutralizing antibodies CAR T cells expressing unique HIV-specific scFvs will likely be required to prevent escape HIV accessory proteins HIVNEF and HIVVPU prevent the surface expression of HLA molecules Reduction in peptide-HLA complexes on infected cell surface impairs TCR T-cell recognition and killing CAR T cells recognize infected cells independent of HLA and are not affected by HIV-induced HLA downregulation Function and exhaustion Failure to control HIV after ART cessation will impair TCR T-cell function due to persistent exposure to viral antigen Collapse of CD4 T-cell help from depletion of HIV-specific CD4 T cells will further impair the function of infused TCR T cells Integration of costimulatory domains (ie, 4-1BB) augments CAR T-cell function and susceptibility to exhaustion CD4- and scFv-based CAR T cells are susceptible to infection but can become resistant (ie, by genetic disruption of HIV coreceptor CCR5) Approach . Ex Vivo Expanded HIV-Specific T Cells . HIV-Specific TCR Redirected T-Cell Therapy . HIV-Specific CAR Redirected T-Cell Therapy . Genome editing No genome editing Site-specific TCR/CAR integrate via dsDNA break and homology-directed repair using AAV donor template Retroviral/lentiviral transduction with vector containing TCR/CAR To date, no serious adverse events reported due to genotoxicity caused by engineering T cells Cell expansion Multipeptide stimulation via autologous APCs Polyclonal T-cell stimulation using artificial APCs or anti-CD3/CD28 antibody-coated beads Antigen recognition Ex vivo expanded HIV-specific T cells react to a variety of distinct HIV-derived epitopes Responses are restricted to the individual’s HLA haplotype TCR transgenic T cells recognize a single epitope comprising 8–11 amino acids derived from a conserved region in the HIV genome CARs recognize infected cells independent of HLA/peptide presentation Antigen recognition moiety of the CAR (CD4- or scFv-based) targets HIVENV expressed on the cell surface HIV escape Constrains virus escape by restoring broad T-cell responses Latent HIV may harbor preexisting mutations that render infected cells insensitive to therapy Target conserved region in the genome where mutations likely impair viral fitness Infusion of T cells with multiple specificities will further constrain virus escape Affinity-enhanced TCRs may limit virus escape but could result in off-target toxicity Escape from CD4-based CAR likely imposes a fitness loss as mutations that abrogate CD4 binding will compromise viral entry scFv-based CARs will likely select for resistant virus much like the infusion of neutralizing antibodies CAR T cells expressing unique HIV-specific scFvs will likely be required to prevent escape HIV accessory proteins HIVNEF and HIVVPU prevent the surface expression of HLA molecules Reduction in peptide-HLA complexes on infected cell surface impairs TCR T-cell recognition and killing CAR T cells recognize infected cells independent of HLA and are not affected by HIV-induced HLA downregulation Function and exhaustion Failure to control HIV after ART cessation will impair TCR T-cell function due to persistent exposure to viral antigen Collapse of CD4 T-cell help from depletion of HIV-specific CD4 T cells will further impair the function of infused TCR T cells Integration of costimulatory domains (ie, 4-1BB) augments CAR T-cell function and susceptibility to exhaustion CD4- and scFv-based CAR T cells are susceptible to infection but can become resistant (ie, by genetic disruption of HIV coreceptor CCR5) Abbreviations: AAV, adeno-associated virus; APC, antigen presenting cell; ART, antiretroviral therapy; CAR, chimeric antigen receptor; dsDNA, double-stranded DNA; HIV, human immunodeficiency virus; scFv, single-chain variable fragment; TCR, T-cell receptor. Open in new tab EVIDENCE OF T-CELL–MEDIATED CONTROL OF HIV REPLICATION In rare instances, asymptomatic HIV-infected individuals known as elite controllers (ECs) spontaneously suppress virus replication (<50 RNA copies/mL of blood) and maintain CD4 T cells (>350 cells/μL blood) in the absence of ART [4, 5]. Slower disease progression in ECs is predominately associated with the induction and maintenance of polyfunctional CTLs restricted to particular HLA class I alleles, including HLA-B57 and HLA-B27 [6–8], indicating that properly targeted T cells can durably control HIV replication. Moreover, landmark studies employing rhesus macaques that similarly control pathogenic simian immunodeficiency virus (SIV) infection demonstrate that in vivo depletion of CD8 T cells results in virus reemergence and systemic infection [9], further supporting that CD8 T cells can actively patrol the body and control infection but stop short of eradicating latent reservoirs. Therefore, a major goal of therapeutic strategies that seek to bolster the HIV-specific T-cell response is to reconstitute protective CTL responses, similar to those observed in ECs, in the vast majority of individuals who fail to naturally control HIV replication. WHY DO WE NEED TO RESTORE HIV-SPECIFIC T CELLS TO BETTER ENABLE HIV CURE STRATEGIES? HIV employs several mechanisms to avoid immune clearance contributing to the long-term persistence of infected cells. For instance, the HIV genome rapidly accumulates mutations leading to the outgrowth of virus escape variants that render infected cells insensitive to CTL-mediated recognition and killing [10, 11]. Even in the presence of ART, escape mutations dominate the provirus DNA landscape [12] and, combined with the low frequency of CTLs that persist as a result of waning cognate antigen [13], likely contributes to the failed clearance of the latent reservoir. Moreover, despite ART suppressing HIV replication to nearly undetectable levels, treatment does not reconstitute immune function to the same extent as seronegative individuals. Indeed, residual CTLs present during ART maintain a skewed memory phenotype [14], express greater levels of activation markers [15, 16], and display features of exhaustion characterized by surface expression of inhibitory receptors [17], concomitant with reduced proliferative capacity, cytokine secretion, and cell-mediated cytotoxicity [18]. Lastly, the level of CD4 T cells is not fully restored after initiating ART, and therapeutic strategies aimed to reinvigorate HIV-specific CD4 T cells may be of paramount importance, given the critical role these cells maintain in promoting the optimal antiviral function of other lymphocytes. Taken together, in the vast majority of individuals successfully treated with ART, HIV-specific T cells poorly persist, are functionally compromised, and often target HIV variants that are no longer present. EX VIVO EXPANSION AND ADOPTIVE TRANSFER OF T CELLS FROM PEOPLE LIVING WITH HIV The term adoptive immunotherapy denotes the transfer of immunocompetent cells for the treatment of cancer, autoimmunity, or infectious disease [19]. Adoptive immunotherapy can be considered as a strategy aimed at replacing, repairing, or enhancing the biological function of a damaged tissue or system by means of autologous or allogeneic cells. The first successful infusion of ex vivo expanded, polyclonal CD4 T cells that enabled a high degree of engraftment was performed by activating T cells from HIV-infected individuals with artificial antigen presenting cells (aAPCs) composed of magnetic beads coated with anti-CD3 and anti-CD28 antibodies, which through the downregulation of CCR5 and upregulation of β-chemokines permitted robust expansion in the absence of viral outgrowth [20–22]. A dose escalation protocol was performed in which individuals were administered treatments at 6-week intervals, beginning with an initial infusion of 3 × 109 cells, followed by a second infusion of approximately 1 × 1010, and then a third infusion of 3 × 1010 cells. The infused cells were > 95% CD4+, did not contain detectable replication-competent HIV, and had a Th1-like cytokine profile. In total, 8 patients were given 51 infusions of expanded CD4 T cells with minimal adverse events [23]. Together, these clinical results indicate that the infusion of CD4 T cells propagated with bead-based aAPCs are safe and have the capacity for prolonged engraftment. Due to the limited number of study subjects and short follow-up time, the statistical significance of whether autologous CD4 T-cell infusions provided a clinical benefit could not be measured. Nonetheless, HIV-infected individuals trended to maintain near-normal CD4 T-cell counts with decreased expression of CCR5, and exhibited improved recall response to antigens, suggesting that this strategy has the potential to limit or correct the immunodeficiency induced by HIV. Importantly, in this strategy, the ex vivo activation and propagation of T cells selects for the fittest cells with the greatest expansion potential and function, thereby eliminating defective and exhausted T cells [24]. Since these initial studies, efforts have instead focused on the adoptive transfer of HIV-specific T cells as opposed to polyclonal T cells with unknown specificities. Next, we describe 3 approaches employing antigen-specific T cells that have been tested in the clinic. EX VIVO EXPANDED, NATURAL HIV-SPECIFIC T CELLS PROVIDE A NON-GENE MODIFIED MEANS TO RESTORE THE HIV-SPECIFIC T-CELL RESPONSE Several studies have infused ex vivo expanded, natural antigen-specific T cells into humans that target viral infections including cytomegalovirus (CMV), Epstein-Barr virus (EBV), and HIV [25]. CMV-specific CTLs isolated from major histocompatibility complex (MHC)-identical bone marrow donors were ex vivo expanded and administered to 14 allogeneic bone marrow transplant recipients. Each individual recovered CMV-specific CTL activity and these cells persisted in vivo for up to 12 weeks [26]. In a similar study, investigators administered allogeneic donor-derived EBV-specific CD8 and CD4 T cells, genetically marked with the neomycin resistance gene, to 6 recipients of T-cell–depleted bone marrow allografts. Gene-marked T cells were responsive to in vivo and ex vivo challenge with EBV, and persisted at low frequencies for as long as 18 months after infusion [27]. Moreover, in the context of HIV infection, treatment of 1 patient with CTLs targeting a single epitope in HIVNEF selected for virus escape variants [28]. In all of these studies, the vast majority of T cells failed to durably engraft, which has limited the study of long-term effects of virus-specific T-cell immunotherapy. Nonetheless, these pioneering studies laid a strong foundation that adoptively transferred T cells exert immune pressure that could control viral replication. More recently, polyclonal HIV-specific CTLs have been generated from HIV-infected and seronegative individuals after ex vivo stimulation with peptide mixes that comprise the most conserved regions of the HIV genome. This approach meets good manufacturing practice standards and does not require T-cell genome engineering; as such there is no risk of genotoxicity. Furthermore, because these mature T cells underwent normal development in the body, it is unlikely that there will be any off-target reactivity by infusing more of these natural T cells. However, a potential disadvantage of this approach is that HIV has developed effective measures to escape natural T-cell responses so it is unclear whether increasing the frequency of HIV-specific T cells, even when targeting conserved regions of the virus, will ultimately control virus replication. Currently, a clinical trial (NCT03485963) is underway infusing multi-HIV–specific T cells into individuals to test the safety and feasibility of this approach. Notably, this clinical trial is designed to test whether these cells can reduce the size of the latent reservoir in the presence of ART, rather than the ability to delay or control viral rebound during an analytical treatment interruption. T-CELL RECEPTOR GENE THERAPY REDIRECTS T CELLS TO HIV-INFECTED CELLS Rather than expanding naturally derived HIV-specific T cells via ex vivo peptide stimulation, researchers have gene-engineered polyclonal T cells to express specific T-cell receptors (TCRs) to restore the HIV-specific T-cell response. A large number of HIV-specific T-cell responses, especially those targeting epitopes within HIVGAG, correlate with viral control [29], suggesting that these responses limit viral replication and/or force HIV to mutate into a less fit state. In principle, the TCR sequences from these effective T-cell responses can be identified, placed into a gene transfer vector, and introduced into T cells. These redirected TCR transgenic T cells then can be expanded and adoptively transferred back into the individual, thereby reconstituting the HIV-specific immune response. However, there are several issues with this approach that have limited clinical testing. For instance, this therapy is HLA-restricted and only individuals expressing a certain HLA allele have the potential to realize therapeutic benefit. Unfortunately, a majority of HIV-specific T cells that associate with enhanced control of infection are enriched in ECs, and are restricted to relatively rare HLA alleles, including HLA-B27 and HLA-B57. As a result, the focus has shifted to uncovering TCRs that are restricted by common HLAs such HLA-A2 [30]. However, natural HLA-A2 restricted HIV-specific T cells are not associated with viral control [29], so efforts have been made to affinity-enhance these TCRs to exert greater control of HIV replication [31]. In 2009, a clinical trial was initiated (NCT00991224) to test the ability of affinity-enhanced TCRs to reconstitute the HIV-specific immune response. Recruitment was challenging given that HLA-A2, which is overrepresented in the Caucasian population, is not as prevalent in the HIV-infected community. Indeed, approximately 40 individuals were screened to identify a total of 4 HLA-A2+ people of which only 2 individuals consented to be on the trial. Unfortunately, a tragic incident involving the death of an individual treated with T cells expressing a cancer-specific (MAGE-A3) TCR that was affinity enhanced using a similar process to the HIV-specific TCR led to the suspension of this clinical trial before anyone received the affinity-enhanced TCR. The 2 individuals who did receive a low dose of the non-affinity–enhanced TCR experienced no serious adverse events during the course of the study, but it was not determined whether the therapy had any beneficial effect. Thus, the clinical utility of TCR-engineered T cells remains unknown. HIV-SPECIFIC CARS AS A MEANS TO CONTROL HIV REPLICATION Between 1995 and 2005, several clinical trials evaluated the therapeutic efficacy of adoptively transferred chimeric antigen receptor (CAR) T cells for HIV infection. Retroviral transduction of T cells with an HIV-specific CAR redirected specificity by expressing CD4, the natural ligand of the HIVENV glycoprotein, as the extracellular antigen-binding moiety fused to the CD3-ζ chain (termed CD4ζCAR). Although the infusion of CD4ζCAR T cells did not improve disease outcome after ART cessation, these first in-human studies demonstrated the safety and feasibility of ex vivo adoptive T-cell gene therapy [32–34]. In the intervening years, the cancer immunotherapy field has advanced the design and manufacturing of CAR T cells [35], culminating in the Food and Drug Administration approval of 2 CD19-targeted therapies for treatment refractory B-cell malignancies [36]. This success has driven significant interest in adapting new CAR technologies for alternative disease indications, including reinvigorating CAR T-cell therapy for HIV infection [37]. Recently, the CD4ζCAR was reengineered through a series of modifications to both the expression system and CAR design by applying lessons learned from the cancer field [38]. To enhance CAR surface expression, a lentiviral vector that used the EF-1α promoter to drive CAR expression was employed instead of the murine retroviral backbone under the control of the PGK promoter. Further changes included swapping the CD4 transmembrane and hinge domains for CD8α to promote CAR dimerization, and inclusion of costimulatory domains to potentiate in vivo T-cell proliferation and function. The step-wise alterations and iterative functional tests lead to the development of an optimized CD4ζCAR containing the 4-1BB costimulatory domain. When expressed in CD8 T cells, these cells exhibited superior in vitro antiviral activity compared to T cells expressing the original clinical trial CAR or an HLA-B57 restricted TCR derived from an EC. Moreover, optimized CD4ζCAR T cells demonstrated remarkable expansion kinetics in humanized mice, concomitant with reduced rebound viremia and protection of CD4 T cells from HIV-induced destruction after ART cessation. As a result of these promising findings, a phase I clinical trial (NCT03617198) is underway employing this reengineered CAR to treat HIV infection. Other groups have developed alternative strategies to target HIVENV, including CARs that express extracellular single-chain variable fragments (scFvs) derived from HIV-specific broadly neutralizing antibodies (bNabs) [38–41]. scFv-based targeting moieties could provide direct advantages over CD4-based CARs, such as exhibiting greater binding affinity for HIVENV either through natural antibody affinity maturation or artificial design, and their ability to engage functionally important regions in HIVENV that are outside of the CD4 binding site (CD4bs) [19]. However, to become a widely applicable therapy, scFv-based CARs will likely need to overcome HIV escape, where latent reservoirs may already harbor mutations that render infected cells insensitive to recognition by scFvs. HIV escape is less of a concern for CD4-based CAR T-cell therapy, given mutations within the CD4bs that abrogate binding to CD4 would impose a significant replicative fitness cost to the virus [42]. An effort to reconcile these different targeting moieties lead to the development of bispecific CARs, which fuse together an scFv with domains 1 and 2 of CD4 into the same construct [43]. In this orientation, a single CAR can engage multiple sites within HIVENV, likely increasing avidity and further constraining the mutational space HIV uses to escape. In comparison to HIV-specific TCR-based therapy, CAR T cells may be uniquely poised to combat HIV infection [19]. HIV-specific CARs target virus-infected cells by binding to surface-expressed HIVENV, which by nature redirects T-cell specificity independent of surface peptide/HLA presentation, and thus is applicable to a broader population. As such, CAR T-cell recognition of infected cells is unaffected by HIV-associated downregulation of HLA by the viral accessory proteins Nef and Vpu [44, 45]. Furthermore, the ability to integrate costimulatory signals into the CAR, such as 4-1BB, may significantly augment both the function of these cells to bypass T-cell exhaustion caused by chronic antigen exposure [46], as well as boost their long-term persistence to target the stable, latent reservoir that persists after decades of suppressive ART. Although CAR T cells can be engineered to overcome many virus-mediated immune-escape mechanisms, HIV infection still poses challenges specific for CAR T cells. An important barrier to successful CAR T-cell therapy may be infection of CD4- and scFv-based CAR T cells. Data from in vitro assays and HIV-infected humanized mice demonstrates the susceptibility of these cells to infection [38, 47], fearing that CAR T cells themselves can contribute to viremia and potentially overwhelm CAR T-cell–mediated control over virus replication. As a result, numerous groups have developed strategies to protect CD4 T cells from HIV infection, which through further engineering could be applied to CAR T cells. The most attractive approach includes methods to inhibit HIV fusion and prevent subsequent entry into the host cell. For instance, zinc finger, megaTAL, and CRISPR/Cas9 nucleases have been used for site-specific disruption of the HIV coreceptors CCR5 and CXCR4 [48–50], leading to resistance to infection from diverse HIV strains. Moreover, HIV peptides derived from the HR2 domain of HIV gp41 have been shown to inhibit virus entry when either directly anchored to plasma membrane or conjugated to surface receptors such as CXCR4 [51, 52]. When combining these tools with CAR T cells, we can expect a selective advantage under viremic conditions; however, it remains unclear how additional engineering will impact CAR T-cell function. HOW ADOPTIVELY TRANSFERRED HIV-SPECIFIC T CELLS CAN HELP ENABLE A HIV CURE Current HIV eradication approaches, such as the “shock and kill” paradigm, aim to reactivate HIV from latent reservoirs using latency reversing agents (LRAs) [53]. It is hoped that reactivated cells will die by virus-induced cytopathic effects and/or be lysed by stimulating preexisting or de novo immune responses [54]. However, LRA treatment alone has failed to measurably reduce the size of the latent reservoir in HIV-infected individuals [55–57]. These findings imply that additional immune mechanisms may be required to destroy infected cells upon latency reversal. As such, there is an opportunity for HIV-specific TCR or CAR T-cell therapy to act in concert with LRAs including IL-15 superagonist [58], or stimulate toll-like receptors [59] or noncanonical NF-κB signaling [60]. Given the critical role each of these pathways have in developing cell-mediated immunity, it is likely that these approaches could synergize with CAR T cells by having an ancillary, beneficial effect on cellular function in addition to inducing viral gene expression. However, it is more than likely that multiple immune mechanisms are necessary to purge the latent reservoir. Evidence suggests that combining infusions of HIV-specific bNabs with several different classes of LRAs decreases the size of the reservoir through Fc-FcR–mediated mechanisms in humanized mice [61]. As such, bNabs could be combined with a new platform of HIV-specific CARs recently described by Herzig and colleagues [62]. These convertibleCAR T cells utilize a unique orthogonal pairing system, where T cells express a mutated form of the NKG2D extracellular domain fused to intracellular T-cell activation motifs (ie, 4-1BB/CD3-ζ). To redirect T-cell specificity, the NKG2D-CAR specially binds to soluble MicAbodies, which are HIV-specific bNabs conjugated to mutant α1-α2 domains of a MIC ligand. Notably, convertibleCAR T cells reduced the size of the inducible latent reservoir found in CD4 T cells from ART suppressed, HIV-infected individuals in vitro. Although the MicAbodies were rendered ADCC-deficient through mutations in the Fc region, it may be feasible to leave these regions intact so that MicAbodies can induce both CAR T cell- and innate-mediated effector functions. Collectively, new-generation HIV-specific CAR T-cell therapy holds great promise to work collaboratively with other interventions that engage the global HIV-specific immune response to functionally cure HIV infection. CONCLUSIONS Adoptive T-cell therapy is a promising approach to restore and augment the HIV-specific T-cell response in ART-controlled HIV-infected individuals. However, key issues need to be resolved before this approach can be used to consistently inhibit viral rebound in the absence of ART and be a key component of a strategy to cure HIV. Namely, how do we manufacture the most potent T-cell product; how can we maintain sufficient numbers of the HIV-specific T cells in the absence of antigen; and will adoptively transferred T cells traffic to all of the areas in the body in which HIV hides? The strategies that are now being tested in the clinic will provide important insight into how to improve adoptive T-cell therapy. As new approaches become available, these should also be tested in well-monitored, well-designed phase I clinical trials that employ an analytical treatment interruption. At the moment, analytical treatment interruptions appears to be the only reliable way to determine the relative efficacy of a given approach. Moreover, in these studies, it is crucial to give the adoptively transferred T cells a chance to reduce or eliminate viral replication after rebound as this may be the best way to determine the potency of a given approach. Thus, studies that restart ART once an individual has a detectable viral load will not be able to study how the adoptively transferred T cells control viral replication and miss valuable insights that could aid the design of the next clinical trial. Only through iterative well-monitored, well-designed phase 1 clinical trials of adoptively transferred HIV-specific T cells followed by robust, insightful basic science studies will we gain insight into how to best manufacture T cells to aid in the cure of HIV infection. Notes Financial support. This work was supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and National Institute on Drug Abuse (grant numbers U19AI117950 and UM1AI126620 to J. L. R.); and C. R. M. is supported by a T32 grant (grant number AI00763). Supplement sponsorship. This supplement is sponsored by the Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30 AI060354), and the Ragon Institute of MGH, MIT and Harvard. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Potential conflicts of interest. J. L. R. has filed a patent describing the construction of these HIV-specific chimeric antigen receptors. J. L. R. cofounded, and holds an equity interest in, Tmunity Therapeutics, which has the rights to license the technology described herein. 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TI - Challenges and Opportunities of Using Adoptive T-Cell Therapy as Part of an HIV Cure Strategy
JF - The Journal of Infectious Diseases
DO - 10.1093/infdis/jiaa223
DA - 2021-02-15
UR - https://www.deepdyve.com/lp/oxford-university-press/challenges-and-opportunities-of-using-adoptive-t-cell-therapy-as-part-ydhvoe7ibb
SP - S38
EP - S45
VL - 223
IS - Supplement_1
DP - DeepDyve
ER -