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. Author manuscript; available in PMC: 2025 Jul 1.
Published in final edited form as: Curr Opin HIV AIDS. 2024 May 1;19(4):169–178. doi: 10.1097/COH.0000000000000858

Recent advances on anti-HIV CAR-T cell treatment to provide sustained HIV remission

Hang Su 1, April Mueller 1, Harris Goldstein 1,2
PMCID: PMC11981014  NIHMSID: NIHMS1986206  PMID: 38695148

Abstract

Purpose of review

Successful sustained remission of HIV infection has been achieved after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation for treatment of leukemia in a small cohort people living with HIV (PLWH). This breakthrough demonstrated that the goal of curing HIV was achievable. However, the high morbidity and mortality associated with bone marrow transplantation limits the routine application of this approach and provides a strong rationale for pursuing alternative strategies for sustained long-term antiretroviral therapy (ART)-free HIV remission. Notably, long-term immune-mediated control of HIV replication observed in elite controllers (ECs) and post-treatment controllers (PTCs) suggests that potent HIV-specific immune responses could provide sustained ART-free remission in PLWH. The capacity of chimeric antigen receptor (CAR)-T cells engineered to target malignant cells to induce remission and cure in cancer patients made this an attractive approach to provide PLWH with a potent HIV-specific immune response. Here, we review the recent advances in the design and application of anti-HIV CAR-T cell therapy to provide a functional HIV cure.

Recent findings

HIV reservoirs are established days after infection and persist through clonal expansion of infected cells. The continuous interaction between latently infected cells and the immune system shapes the landscape of HIV latency and likely contributes to ART-free viral control in ECs. CAR-T cells can exhibit superior antiviral activity as compared to native HIV-specific T cells, particularly because they can be engineered to have multiple HIV specificities, resistance to HIV infection, dual costimulatory signaling, immune checkpoint inhibitors, stem cell derivation, CMV TCR coexpression, and tissue homing ligands. These modifications can significantly improve the capacities of anti-HIV CAR-T cells to prevent viral escape, resist HIV infection, and enhance cytotoxicity, persistence, and tissue penetration. Collectively, these novel modifications of anti-HIV CAR-T cell design have increased their capacity to control HIV infection.

Summary

Anti-HIV CAR-T cells can be engineered to provide potent and sustained in vitro and in vivo antiviral function. The combination of anti-HIV CAR-T cells with other immunotherapeutics may contribute to long-term HIV remission in PLWH.

Keywords: HIV remission, HIV reservoirs, CD8+ T cells, anti-HIV CAR-T cells

INTRODUCTION

Sustained HIV remission

In 2022, approximately 1.3 million people became newly infected with human immunodeficiency virus (HIV) world-wide, increasing the total number to approximately 85.6 million people infected with HIV since the first report of acquired immune deficiency syndrome (AIDS) in the U.S. in 1981 (1, 2). Among them, approximately 40.4 million (47%) of these individuals have died from HIV-related diseases (2). The development of antiretroviral therapy (ART), particularly combinational ART which targets different steps in the HIV replication cycle, has enabled long-term survival of people living with HIV (PLWH) (3). However, despite long-term reduction of HIV to undetectable levels, the resurgence of viremia soon after the cessation of ART demonstrated that years of successful suppression of active viral replication did not cure HIV infection (4). HIV cure was prevented by the presence of HIV reservoirs consisting of latent HIV-infected cells distributed throughout the body which survive despite standard or intensified ART and are capable of producing infectious virus and reintroducing HIV infection after the cessation of ART (5). The potential for HIV cure was first demonstrated in 2008 by the description of a PLWH, later known as “The Berlin Patient”, who was cured of HIV after receiving two allogeneic hematopoietic stem cell transplants (allo-HSCTs) to treat his leukemia. Importantly, the donor was homozygous for the CCR5Δ32 mutation which rendered the progeny CD4 T cells resistant to R5-tropic HIV infection (6). The Berlin patient continued to be HIV free in the absence of ART after the allo-HSCT transplant until his unfortunate passing in 2020 (7, 8). This case designation by the transplant location, was followed for subsequent PLWH HIV cures that were designated as the “London” (9), “City of Hope” (10), “New York” (11), and “Düsseldorf” (12) patients. Recently, the “Geneva patient” was reported to be cured of HIV, but in contrast to the other cures, he received the transplant from a CCR5 wild type donor (13). Previous cases where allo-HSCT from CCR5 wild type donors resulted in sustained ART-free remission were ultimately followed by viral rebound (14). Although the significant morbidity and mortality of allo-HSCT prevents its routine application as a cure for HIV, these cases highlighted an alternative and safer pathway towards HIV cure by downregulating expression of CCR5 in donor cells, either through direct in vivo gene editing (15), or adoptive transfer of ex vivo gene-edited effector cells (16).

Appreciating the tremendous difficulty to completely eradicate HIV and provide a sterilizing cure as described in the above cases, researchers have been actively pursuing a more attainable functional cure of HIV where virus remains suppressed by host immune system in the absence of ART, also referred as sustained HIV remission. Indeed, sustained ART-free HIV remission has been achieved in a small group of PLWH that can be further categorized into two groups based on whether initial ART was administered; post-treatment controllers (PTCs) (17) and elite controllers (ECs) (18). Following the model of these unique cases, researchers have invested intensive efforts on the advancement of novel immunotherapeutics to mobilize host immune system to reproduce the success of HIV controllers for the broader population of PLWH (19).

HIV reservoir: the major roadblock for achieving sustained HIV remission

In ART-treated PLWH, HIV persists in cells as either replication-competent or defective provirus. While the cells containing replication-competent proviruses are considered the true HIV reservoirs that can produce infectious viral progeny, they consist of less than 10% of the total cells containing proviruses (20). Nevertheless, despite being replication-defective, some proviruses display active transcription/translation manifested as nonsuppressible residual viremia and production of non-infectious virus-like particles. This can contribute to ongoing inflammation and immune activation/exhaustion, increasing the frequency of non-AIDS associated comorbidity and mortality (21–23). HIV reservoirs are established within days of infection with the bulk of the reservoir formed close to the initiation of ART (24–26). The rapid formation of a significant reservoir soon after infection makes it nearly impossible to prevent viral resurgence after ART cessation, necessitating life-long ART. However, early ART intervention can effectively limit the size and diversity of HIV reservoirs compared to deferred treatment, thereby lowering the threshold of viral clearance (27). HIV reservoirs possess a long half-life of approximately 44 months, as measured by both conventional cell culture-based quantitative viral outgrowth assay (QVOA) and modern droplet digital polymerase chain reaction (ddPCR)-based intact proviral DNA assay (IPDA) (4, 28). Interestingly, the apparent “stability” of HIV reservoirs is an outcome of the constant replacement of cells containing proviruses with cells containing identical proviral sequences due to the proliferation of latently infected cells (29–31). Indeed, evidence has shown that different subpopulations of HIV reservoirs can sustain, wax, and wane throughout years of ART after constant encounter with antigenic stimuli and immune surveillance (31). However, despite these variations, HIV reservoir size is maintained or even increased in certain PLWH despite years of ART (28, 32, 33). A major challenge preventing viral eradication is that latent infected cells do not produce viral proteins and only a fraction can be induced to express viral proteins, preventing their detection by the immune system (34). In virally suppressed PLWH, the quantity of intact HIV proviruses measured by IPDA was over 50-fold higher than the amount of inducible intact HIV proviruses measured by QVOA after T cell stimulation (20). This may partially explain the inability of latency reversal agents (LRAs) tested so far in PLWH to reduce HIV reservoirs (35). The broad distribution of HIV reservoirs throughout multiple anatomical sites further complicates viral clearance by the immune system (36, 37). While clonal HIV sequences were observed to be shared between tissues (38), the physical barrier and different immune environment among tissues, especially central nervous system (CNS), may limit therapeutical access and cause viral compartmentalization (39–41). Therefore, more sophisticated distribution systems ensuring the delivery of therapeutics to all tissues harboring HIV sanctuary need to be pursued (42, 43).

CD8+ T cells: the cornerstone for achieving sustained HIV remission

CD8+ T cells play a crucial role in the adaptive immune system by mediating defense of the host against endogenous and exogenous pathogens, including HIV, through major histocompatibility complex (MHC)-dependent cytotoxic activity (44) and MHC-independent noncytotoxic responses (45). An HIV-specific CD8+ T cell response is rapidly mobilized in response to the emergence of viremia and plays an important role in markedly reducing the plasma viral load from peak viremia. Notably, the magnitude of CD8+ T cell responses is inversely correlated with the HIV set point (46). During sexual transmission in SIV-infected rhesus macaques, mucosal HIV infection is established by about 1 week, which is prior to the detection of HIV in the peripheral blood and the development of HIV-specific CD8+ T cell responses (47). This temporal gap between the time of HIV exposure and detection of viremia, termed the eclipse period of infection, can extend to greater than 2 weeks in PLWH (48). Consequently, ART initiated during the earliest stage of infection after the onset of viremia fails to cure HIV because it is too late after local viral reservoirs are established (24, 25). There is also delayed quantitative and functional development of CD8+ T cells following initial HIV amplification in untreated PLWH (46) which may be further blunted by early ART intervention (48). ART initiation during hyperacute HIV infection may also inhibit the differentiation as well as memory formation of polyfunctional HIV-specific CD8+ T cells that could confer viral control after ART interruption in the PTCs (49). Correspondingly, the PTCs identified are often PLWH that generally initiate ART between 1 to-3 months post HIV exposure but not during the earliest Fiebig stages (25, 50, 51). During untreated chronic infection, HIV-specific CD8+ T cells are overwhelmed by viral antigens, overexpressing inhibitory immunoreceptors such as programmed cell death protein 1 (PD-1), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and lymphocyte Activation Gene-3 (LAG-3), becoming anergic and prone to apoptosis which is not fully reversed by ART (52). The precise mechanisms responsible for the interplay between CD8+ T cells, HIV reservoirs, and the shaping of the landscape of viral latency during ART has not been fully determined. In ART-treated macaques, depletion of CD8+ T cells caused limited impact on SIV dynamics, suggesting that other immune factors may compensate and contribute to viral control such as autologous antibodies and NK cells (53–55). However, upon ART interruption, CD8+ T cells play a key role on the control of HIV viral rebound (53). The induction of highly potent CD8+ T cells during ART is a promising but unrealized strategy to limit HIV reservoirs and facilitate viral remission after ART is discontinued. A possible solution may be derived from ECs, the small group of PLWH who can naturally maintain viral control in the absence of ART, by producing potent CD8+ T cells targeting highly conserved HIV epitopes irrespective of HLA alleles (56). Induction of functional CD8+ T cell responses combined with the state-of-art mRNA delivery system used to generate COVID-19 vaccines holds great potential for next round of HIV vaccine development to induce immune responses to mediate sustained control of HIV infection (57, 58).

ANTI-HIV CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELLS

In addition to generating HIV-specific T cell responses by in vivo or ex vivo HIV peptide activation and expansion (59, 60), HIV-specific T cells capable of killing infected cells can be genetically engineered to express defined T cell receptors (TCRs) specific for highly conserved HIV sequences (61). The predominant molecular engineering approaches that have been used are to transduce T cells with lentiviral vectors (LVs) encoding HIV-specific TCRs or HIV envelope-specific CARs. While expression of HIV-specific TCRs can endow CD8+ T cells with potent antiviral capacity, its capacity to lyse infected cells is dependent on the presentation of HIV peptides by MHC molecules whose expression can be downregulated by HIV Nef (62) and Vpu (63), especially during chronic infection. Downregulation of MHC molecules by HIV can be circumvented by CARs binding HIV antigens independent of MHC. Furthermore, the addition of defined costimulatory signaling domains to the TCR signaling domains of the CAR significantly enhanced the functional activity and potency of CAR-T cells revolutionizing cancer therapy (64). A recent side-by-side comparison between TCR- and CAR-T cell-mediated suppression of HIV infection in primary T cells demonstrated that even with affinity enhancement, antigen upregulation, and disruption of MHC downregulation, the HIV killing activity of HIV-specific CAR-T cells was more potent than that of HIV-specific TCR-mediated T cells (65). It is likely that the potency of the CAR-T construct could be further increased by incorporating a costimulatory signal domain that was not provided in the present study. The superior HIV control by CAR-T cells may be due to their capacity to rapidly induce active caspase 3 in infected cells, a central component of cellular apoptosis. Interestingly, the faster release of caspase 3 but not necessarily a higher level was observed after CAR-T cell treatment as compared to TCR-T cell therapy, indicating that robust HIV control by CAR-T cells was achieved not only through potent viral killing but also through prevention of viral spread. Multiple groups have demonstrated that the efficient viral targeting and killing by CAR-T cells can be further increased using several strategies outlined (Fig. 1).

Figure 1.

Figure 1.

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Recent advances on anti-HIV CAR-T cell design. (I) To restrict HIV escape and protect CAR-T cells from HIV infection: (A) Multispecific CD4-based bi- and tri-specific CARs were engineered, including bispecific CD4-MBL-CAR with an additional N-terminal of CCR5 regions (trispecific), and bispecific CD4-m36.4-CAR (Bi-DuoCAR) with an additional gp41-derived C-peptide fusion inhibitor C46 (Tri-DuoCAR). (B) Targeted insertion of CARs into the coreceptor CCR5 locus using mRNA-delivered megaTAL nuclease or CRISPR-Cas9 to disrupt CCR5 gene expression, preventing HIV infection of the transduced CAR-T cells. (II) To enhance CAR-T cell cytotoxicity: (C) CD28 and 4–1BB costimulatory signaling domains were incorporated into one 3rd generation CAR or two separate CARs in Dual-CAR-T cells. (D) CAR-T cells were engineered to be resistant to exhaustion and provide sustained antiviral activity by the introduction of immune checkpoint inhibitors, such PD-1 expression inhibitors through short hairpin RNA (shRNA) constructs, PD-1 “sink” binders, or secreted PD-1 inhibitor. (III) To improve CAR-T cell persistence and tissue penetration: (E) Exogenous HIV envelope-expressing cells were administered to bind the CAR and stimulate CAR-T cell expansion. (F) Anti-HIV-CAR-T cells were generated that also expressed CMV antigen-specific TCRs to enable CAR-T cell expansion through CMV vaccine stimulation. (G) CAR-T cells engineered were generated from T memory stem cells (TSCM) and hematopoietic stem and progenitor cells (HSPCs) which displayed high capacity of proliferation and enhanced longevity. In addition, CAR-expressing HSPCs migrated to tissue compartments and differentiated into B-, T-, and myeloid-lineage CAR-expressing cells. (H) CAR-T cells were engineered with tissue homing receptors, such as CXCR5, that directed CAR-T cells to tissue HIV reservoirs. MBL, carbohydrate recognition domain of mannose binding lectin. M36.4, an scFv-derived heavy chain-only antibody specific for the co-receptor binding region.

Restrict HIV escape and protect CAR-T cells from viral infection

A major mechanism by which HIV escapes T cell mediated responses is by generating immune escape mutants. The use of CD4 as the binder for the CAR-T cell may prevent immune evasion. Because the CD4 receptor is indispensable for HIV Env binding and entry into the host cells, viral mutations in gp120 reducing binding to the CD4 binder would also reduce the infectivity. However, a potential deleterious effect of expressing the CD4 binder on CD8 T cells is that it would render these CAR-T cells susceptible to HIV infection and subsequent elimination. To overcome this sequela, bi- and tri-specific CARs were engineered to target variable regions of HIV Env peptide. The Berger group employed CD4 binding site and carbohydrate recognition domain of mannose binding lectin (MBL) for a bispecific CAR design (66) and an additional N-terminal domain of coreceptor CCR5 to make the trispecific CAR (67). Using an alternative approach, Anthony-Gonda and colleagues developed the duoCAR architecture which incorporates a CD4 binding site (mD1.22) with an scFv-derived heavy chain-only co-receptor binding region (m36.4) and added a gp41-derived C-peptide fusion inhibitor (C46) as the third antiviral motif (68, 69). Both groups reported that the bi- and tri-specific CAR-T cells provided broader coverage, enhanced cytotoxic effects against HIV infection, and protected the cells from HIV infection as compared to CAR-T cells expressing only the CD4 binder. The duoCAR-T cell therapy is currently being evaluated in an ongoing phase I/IIa clinical trial with PLWH (NCT04648046).

An alternative approach to protect CD4-expressing CAR-T cells from HIV infection is to suppress their expression of CCR5 by targeted insertion of the anti-HIV-CAR construct to disrupt the CCR5 locus. This was achieved through precise nuclease digestion within the genomic CCR5 sequence followed by homology-directed integration of the CAR into the CCR5 locus delivered by an adeno-associated virus (AAV)-vector. Hale et al. disrupted CCR5 with an mRNA-delivered megaTAL nuclease followed by insertion of a CAR construct using the PGT145 broadly neutralizing antibody (bNAb) that targets the N-glycans V1/V2 loop as a binder (70). Recently, Rothemejer et al. applied CRISPR-Cas9 to disrupt the CCR5 region with a CAR construct using the 10–1074 bNAb that targets the N-glycans V3 loop as a binder (71). Both studies demonstrated disruption of the CCR5 gene that conferred the engineered CD4-CAR-T cells with resistance to HIV infection, while CD8-CAR-T cells maintained potent in vitro cytotoxic activity. The major limitation of this strategy was that only 10% to 15% of primary T cells expressed the CCR5-deficient CAR using this transduction method, which is much lower as compared to the efficiency of non-targeted delivery of CAR constructs into T cells by lentiviral vectors.

Enhance cytotoxicity of CAR-T cells against HIV infection

The functional activity of the 2nd generation CAR-T cells was markedly improved as compared to the 1st generation CAR-T cells by the addition of costimulatory signaling domains (72, 73). CD28 and 4–1BB are the most commonly utilized costimulatory signaling domains with the CD28 signal providing a faster and stronger effector responses with shorter duration, while the 4–1BB-signal generates T cells displaying a less differentiated phenotype with improved longevity but slower expansion (74, 75). Incorporating both domains in a 3rd generation CAR may provide the CAR-T cells with the optimum balance of functionality and persistence. Maldini et al. cotransduced T cells with LVs encoding CD4-CD28-CAR and CD4–4-1BB-CAR to generate Dual-CAR-T cells expressing both CD4-CD28-CAR and CD4–4-1BB-CAR which displayed potent effector activity and proliferative potential (76). Interestingly, Dual-CAR-T cells that expressed CD28 and 4–1BB on separate CARs also exhibited superior HIV-mediated cellular expansion and persistence as compared to CAR-T cells expressing both costimulatory signaling domains on the same CAR, possibly due to the membrane proximity of the CD28 domain on the latter (77). The major limitation of this strategy of cotransduction with two LVs is the inefficiency by which cells were successfully transduced by both LVs which resulted in a low yield of the Dual-CAR-T cells. This can be overcome by designing a LV architecture that contains 2 separately expressed CARs attached to different costimulatory regions as described (68). Liu et al. administered bNAb-based CD28/4–1BB signaling domain CAR-T cells engineered with additional triple immune checkpoint inhibitors (PD-1, Tim-3, and Lag-3) to ART-treated PLWH. They observed that CAR-T therapy successfully reduced the levels of cell-associated RNA and intact HIV DNA, as well as delayed viral rebound (78). The Zhu group blocked PD1 activity in a 2nd generation CAR through either a PD-1 “sink” (79) or a secreted PD-1 inhibitor (80) and reported that PD-1-suppressed CAR-T cells displayed superior antiviral function both in vitro and in humanized mice as compared to non-PD-1-suppressed CAR-T cells.

Improve anti-HIV CAR-T cell persistence and tissue penetration

Just as decade-long cancer remission required long-term persistence of functionally active CAR-T cells (81), the achievement of HIV remission will require the infused cytotoxic CAR-T cells to be long-lived to eliminate latent HIV-infected cells soon after they get reactivated. The dogma of memory T cell hierarchy indicates that T memory stem cells (TSCM) have the highest self-renewal capacity and longevity and can differentiate into shorter-lived but more rapidly responsive central memory T cells (TCM) and effector memory T cells (TEM). Therefore, engineering TSCM or TSCM-like cells into CAR-T cells becomes an attractive strategy to generate CAR-T cells with longevity and self-renewal capacity to provide sustain in vivo persistence and activity. Arcangeli et al. compared the differential course of leukemia after treatment with naïve/ TSCM (TN/SCM)-CAR-T cells or unselected T cells (TBULK)-CAR-T cells (82). They reported that even though TN/SCM-CAR-T cells displayed reduced antitumor function in vitro, they exhibited increased antitumor activity in vivo, as compared to TBULK-CAR-T cells, likely due to their capacity for enhanced cellular expansion and persistence. Importantly, TN/SCM-CAR-T cells triggered much less cytokine release syndrome (CRS), which is a major side effect of CAR-T therapy, as compared to TBULK-CAR-T cells, likely because of their less-activated phenotype. Due to their low population in unfractionated PBMCs, obtaining sufficient TSCM for efficient CAR-T cell production has been challenging. Kranz et al. developed a simple protocol for TSCM-CAR-T cell manufacture by activating isolated naïve CD8+ T cell with a soluble anti-CD3 antibody only followed by transduction with a CAR lentivector and month-long culture with IL-7 and IL-15 (83). They were able to acquire a 2-fold enrichment of TSCM-CAR-T cells using this protocol. TSCM-enriched CAR-T cells also displayed a delayed but comparable anti-HIV response as compared to TCM/EM-enriched CAR-T cells (83). Taken together, these data support the potential benefits of generating CAR-T cells that are TSCM to provide long-term immune control.

CAR-T cells can also be generated from cells with even higher potential for self-renewal multipotent hematopoietic stem and progenitor cells (HSPCs). HSPCs are not only highly self-renewing, but also can differentiate into multiple immune cell lineages, including T cells, B cells, NK cells, and monocytes/macrophages which could contribute to immune control of HIV infection. Barber-Axthelm et al. engrafted macaques with autologous HSPC-derived CD4-CAR-T cells and maintained animals for nearly 2 years before necropsy (84). CAR-T cells were detected in the macaque lymph nodes, gastrointestinal tract, and CNS, which are all pivotal tissue sites of HIV reservoirs. In addition, CAR-T cells recovered from these tissues expressed markers of T, B, and myeloid cells, underscoring the multipotent lineages of HSPC-derived CAR-T cells. Recently, the same group performed a head-to-head comparison between PBMC- and HSPC-derived anti-HIV CAR-T cells (85). HSPC- outperformed PBMC-derived CAR-T cells on cell expansion, persistence, and tissue infiltration in both humanized mice and macaques. HSPC-derived CAR-T cells also exhibited superior HIV suppression as compared to PBMC-derived CAR-T cells in humanized mice. Taken together, these studies suggested an alternative HSPC-based CAR-T cell generation approach to improve in vivo CAR-T cell maintenance for long-term HIV control.

A major cause of the reduced persistence of anti-HIV CAR-T cell is the low level of HIV antigen present during suppressive ART reducing the stimulation of the HIV CAR-T cells. To overcome this challenge, Rust et al. successfully boosted CAR-T cell expansion by administering Env-expressed cells to CAR-T cell-treated ART-suppressed nonhuman primates which further delayed HIV rebound upon ART discontinuation (86). They also observed a recovery of CAR-T cell population after administration of a PD-1 inhibitor that facilitated HIV control. Taken together, these results support the benefits of combinational therapy with LRAs and/or immune checkpoint inhibitors to enhance CAR-T cell therapy for HIV infection. An alternative strategy to promote anti-HIV CAR-T cell proliferation is to generate the CAR-T cells in T cells expressing TCRs to a different expandable antigen. For example, Guan et al. engineered bispecific CMV-HIV-CAR-T cells through isolation, expansion, and transduction of CMV+ T cells with a bNAb-based HIV-CAR, from both CMV+ PLWH and healthy donors without HIV (87). CMV-HIV-CAR-T cells exhibited cytotoxic activity to both CMV+ and HIV+ target cells. More importantly, the CMV-HIV-CAR-T cells expanded in ART-treated humanized mice upon immunization with the CMV vaccine and prevent viremia after ART interruption. Given the prominent global prevalence of CMV, engineering bispecific CMV-HIV-CAR-T cells holds great potential on the development of long-lasting anti-HIV CAR-T cells that could be reboosted as needed (88).

CAR-T cells can also be engineered to express chemokine receptors that will direct them to tissue compartments of latent HIV-infected cells where T cells do not usually migrate to enable increased clearing of the HIV reservoirs. Pampusch et al. designed a CXCR5-expressing anti-HIV CAR construct to provide the CAR-T cells with access to B cell follicles which are the major tissue locations of HIV reservoirs (89). Infused CXCR5-CAR-T cells migrated to the lymphoid follicles of SIV-infected macaques and achieved viral control in a subset of animals for 10 months. Unfortunately, a direct comparison between CXCR5-targeted and -untargeted CAR-T cells was not performed. Recently, the same group attempted to further enhance tissue CAR-T cell trafficking by pretreatment of anti-CD20 antibody to disrupt B cell follicles (90). They observed a higher expansion but also quicker diminishment of CAR-T cell population in the antibody-treated versus nontreated mice. In addition, the treated animals also displayed elevated plasma IL-6 levels which raised concerns about the safety of this therapeutic strategy.

CONCLUSION

Given the many consequences of life-long daily ART, including adherence, stigma, expense, side effects, drug-drug interactions, as well as the unequal access to care for many economically and socially challenged PLWH, an HIV cure is an important goal which would improve the morbidity and mortality of HIV infection for PLWH. While bone marrow transplants have led to a few cases of sterilizing cure for HIV, the high risks associated with this procedure make it more feasible to instead pursue identifying a strategy for the functional cure for HIV centered on maintaining potent and lasting antiviral immune responses. Despite the limited therapeutic effects observed in clinical trials during the early stage of CAR-T cell design and development (91), using CAR-T cell therapy to deliver a functional cure of HIV was reinvested by the improved function of second and third generation CAR-T cells and their success in providing remissions and cure for cancer. While applying advances in CAR-T cell therapy learned in cancer studies should improve the effectiveness of anti-HIV CAR-T cell therapy, treatment of HIV infection provides unique challenges, such as reduced expression of HIV antigens on infected cells and the high mutation rate of HIV which enables the rapid emergence of immune escape variants. To overcome these challenges, the addition of other therapeutic components, such as LRAs, immune modulators, bNAbs, and gene editing would enhance the capacity of anti-HIV CAR-T cell therapy to provide sustained HIV remission (92–95). Once the optimal anti-HIV CAR-T cell therapy is established, another major consideration would be to develop strategies to reduce the cost of generating and administering CAR-T cells, perhaps by developing safe vectors capable of selective in vivo transduction and conversion of T cells into anti-HIV CAR-T cells (96, 97) which may also obviate the requirement for lymphodepletion by treatment with cyclophosphamide prior to CAR-T cell treatment (98).

KEY POINTS.

  • Sterilizing HIV cure has been realized in a few individuals that received bone marrow transplant from the donors homozygous for the CCR5Δ32 mutation which confers the engrafted cells with resistance to HIV infection.

  • HIV reservoirs persist throughout infection as well as undergoing clonal expansion despite effective ART and immune surveillance, preventing ART-free HIV remission.

  • CD8+ T cells with potent antiviral activity play a major role in maintaining long-term HIV control as observed in ECs.

  • Modifications of anti-HIV CAR-T cells enhance their capacity to control HIV replication by reducing the emergence of viral immune escape mutants and increasing cytotoxicity, persistence, and tissue infiltration.

Acknowledgements

We are grateful to Drs. Boro Dropulić and Rimas Orentas at Caring Cross for their collaboration and very helpful insights and to the members of our lab.

Financial support and sponsorship

This work was funded by the NIH (R01AI145024 and 1R01AI172607 to HG) and the Einstein-Rockefeller-CUNY Center for AIDS Research (P30-AI124414).

Footnotes

Conflicts of interest

There are no conflicts of interest.

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