Insights into the HIV-1 Latent Reservoir and Strategies to Cure HIV-1 Infection

Bai, Ruojing; Lv, Shiyun; Wu, Hao; Dai, Lili

doi:https://doi.org/10.1155/2022/6952286

Disease Markers

On this page

Abstract Introduction Conclusions Conflicts of Interest References Copyright Related Articles

Review Article | Open Access

Volume 2022 | Article ID 6952286 | https://doi.org/10.1155/2022/6952286

Insights into the HIV-1 Latent Reservoir and Strategies to Cure HIV-1 Infection

Ruojing Bai,^1,2Shiyun Lv,^1,2Hao Wu ,¹and Lili Dai¹

Academic Editor: Meng-Hao Huang

Received07 Nov 2021

Revised07 Feb 2022

Accepted09 May 2022

Published31 May 2022

Abstract

Since the first discovery of human immunodeficiency virus 1 (HIV-1) in 1983, the targeted treatment, antiretroviral therapy (ART), has effectively limited the detected plasma viremia below a very low level and the technique has been improved rapidly. However, due to the persistence of the latent reservoir of replication-competent HIV-1 in patients treated with ART, a sudden withdrawal of the drug inevitably results in HIV viral rebound and HIV progression. Therefore, more understanding of the HIV-1 latent reservoir (LR) is the priority before developing a cure that thoroughly eliminates the reservoir. HIV-1 spreads through both the release of cell-free particles and by cell-to-cell transmission. Mounting evidence indicates that cell-to-cell transmission is more efficient than cell-free transmission of particles and likely influences the pathogenesis of HIV-1 infection. This mode of viral transmission also influences the generation and maintenance of the latent reservoir, which represents the main obstacle for curing the infection. In this review, the definition, establishment, and maintenance of the HIV-1 LR, along with the state-of-the-art quantitative approaches that directly quantify HIV-1 intact proviruses, are elucidated. Strategies to cure HIV infection are highlighted. This review will renew hope for a better and more thorough cure of HIV infection for mankind and encourage more clinical trials to achieve ART-free HIV remission.

1. Introduction

Over 70 million people have been infected with human immunodeficiency virus 1 (HIV-1) so far since the first outbreak of the HIV-1 epidemic [1] in 1981, and since then, millions of survivors have lived with HIV-1 who are the beneficiaries of antiretroviral therapy (ART). The 2019 UNAIDS Report and World Health Organization both estimate that there are 38~70 million people living with HIV-1 infection. Of those individuals, almost 25 million have access to antiretroviral therapy (ART). Various studies have shown the half-life of the HIV-1 reservoir can range somewhere between 44 months and 13 years, and in some cohorts, no decay was observed at all. Thus, lifelong ART is required to maintain viral suppression and achieve the best health outcomes in the majority of individuals [2]. Nowadays, a number of evidence has pointed out that the risk of recurrence is related to the latent reservoir (LR) of HIV-1, also known as HIV latency, which is a pool of resting CD4+ T cells infected with replication-competent proviruses in patients treated with ART. These infected cells have stopped generating new viral particles temporally or for a long time since the treatment. Nonetheless, these infected memory CD4+ T cells which permit HIV-1 to escape from immune surveillance are the main obstacle to HIV elimination. Thus, using ART treatment to eliminate HIV is currently unrealistic.

At present, the eradication of HIV is still in need of accurate quantification of the HIV-1 LR. Although a barrage of improved assays for measuring the HIV reservoir size has been developed, there is no broad consensus on the methodology yet. Despite more than three decades of efforts, the understanding of the HIV-1 latent reservoir is not enough, and to have more understanding of it is the priority before thorough elimination of it can be achieved (a cure) and plasma viremia can be persistently inhibited after ART withdrawal (a functional cure) (Figure 1). In this review, the definition, establishment, and maintenance of the HIV-1 LR are elucidated, and standard and state-of-the-art approaches to quantify reservoir size are reviewed. Finally, current progress of the elimination of the HIV LR is highlighted.

On the left is the ART intervention on HIV-1 virus with recurrent infection after HIV-1 LR measurement to eliminate HIV-1. On the right is the strategy of eliminating HIV-1 LR carried out by persistence in long-lived memory T cell and homeostatic promotion of T cells.

2. Definition of HIV-1 LR

The HIV-1 LR is defined as a small pool of latently infected cells that persist for decades in people living with HIV (PLWH) who have received ART [3]. These cells harbor integrated and intact proviruses that do not actively produce infectious virions but can do so upon stimulation [4]. Although such cells are extremely rare (around 1 in 1 million resting CD4+ T cells), the reservoir is long-lived, with an estimated half-life of 44 months [5]. This indicates that ART alone will not eradicate the reservoir in a lifetime.

The precise nature of the HIV-1 LR remains unclear. The assessment of the transcriptional and translational status of persistent HIV proviruses in virally suppressed individuals challenges our definition of HIV latency. Whereas viral latency is often associated with transcriptional latency (i.e., the lack of transcription from the HIV promoter), an increasing number of studies have indicated that complete silencing of the HIV promoter is a rare event. Therefore, a relatively large fraction and possibly the majority of latently infected cells (cells that do not produce viral particles) may express low levels of short viral transcripts [6]. Although these abortive transcripts are frequently produced, they rarely elongate enough to generate complete or spliced transcripts [7]. Accordingly, the production of viral proteins by latently infected cells appears to be rare [8].

2.1. Establishment of the HIV-1 LR: When, Where, and How

2.1.1. When

The current consensus is that the reservoir is established in individuals immediately after HIV-1 infection and even on early ART [9]. Animal experiments show that HIV-1 LR stays in lymph nodes (LNs) and gut-associated lymphoid tissues (GALTs) within the first 72 h of mucosal simian immunodeficiency virus (SIV) infection [10]. Also, the HIV-1 LR was established in less than 10 days in a unique case who initiated preexposure prophylaxis/ART as long as 10 days after infection, and he experienced viral rebound 225 days after ART withdrawal [11]. The exact time of HIV-1 LR establishment in humans remains unclear.

2.1.2. Where

In the case where ART is not administered, the stimulated CD4+ T cells serve as the main target of HIV infection and die rapidly [12]. Only a minute fraction of these infected cells survive and become a long-lived reservoir of latently infected cells [13]. However, peripheral T cells only account for less than 2% of the total cells infected, so circulating T cells are not a unique site of HIV replication and are unlikely to represent the most favorable environment for the establishment of HIV latency. In the presence of ART, these reservoirs are particularly spread in GALTs and LNs [14] relative to the spleen, liver, lung, central nervous system, and bone marrow [15]. Lymphoid tissues may especially represent a favorable environment for the establishment of viral latency. It is not surprising that HIV-infected cells are found in multiple tissues after years of ART [16].

Currently, imaging the persistent tissue reservoir in living people on ART is not possible. Recently, a study of tissues collected from 6 postmortem PLHIV patients revealed that HIV proviruses existed in all 28 tissues examined wherein the blood and the lymphoid system serve as the main vectors for virus dissemination throughout the body [16]. Besides, HIV-1 DNA is highly enriched in CD4+ tissue-resident memory T (TRM) cells in the female genital tract (particularly the cervix) [17] and the male genital tract which may be a tissue reservoir where macrophages are enriched [18]. Macrophages enriched in these tissues may serve as potential viral sanctuaries. However, whether reproductive tracts are tissue reservoirs remains poorly understood.

2.1.3. How

There are two models for the establishment of the HIV-1 LR. First, as CD4+ TRM cells are the predominant population [12], the activation-to-quiescence transition using a defined cocktail of cytokines, including tumor growth factor-beta (TGF-β), interleukin-10 (IL-10), and IL-8, probably provides an opportunity for the establishment of HIV latency and allows the persistence of latently infected cells [19]. In the immune microenvironment, checkpoint molecules expressed on T cells are the immunosuppressive factors that significantly repress T cell activation and contribute to HIV-1 latency, of which PD-1, LAG-3, and TIGIT are the known markers to block HIV-1 persistence during ART [20–22]. More studies have explained the active role of PD-1 that blocks HIV transcription [23, 24]. Of note, the coculture of monocytes or myeloid dendritic cells (mDCs) with activated HIV-infected T cells augments the transition to a postactivation state of latency, indicating the potential cell-to-cell contact during the establishment of HIV latency [25, 26].

The two means for the establishment of viral latency consist of direct infections in CD4+ TRM cells and cell-to-cell transmission between infected and uninfected CD4+ TRM cells. Although the inefficient infection in CD4+ TRM cells can be blocked during the HIV replication cycle, the indirect cell-to-cell transmission gives way to HIV-1 latency [27]. Besides, soluble factors are also contributors to HIV-1 latency in resting CD4+ T cells. For instance, IL-7, for T cell homeostasis, regulates the activity of the restriction factor SAMHD1 and exacerbates the vulnerability of CD4+ TRM cells to HIV-1 [28, 29]. Similarly, the chemokines CCL19 and CCL20 participating in cell trafficking from other tissues to LNs and GALTs may increase the possibility of HIV infection in CD4+ TRM cells via modifying the actin cytoskeleton to allow the nucleus of HIV-1 DNA to enter a LR of quiescent integrated HIV-1 DNA [30]. The sites of CD4+ TRM cell recruitment may impact HIV-1 susceptibility: CD4+ T cells derived from lymphoid organs (the spleen and tonsil), subjected to moderate-level activation, benefit from the establishment of the HIV LR [31].

3. Maintenance of the HIV-1 LR

Several studies over the past decade have reported that such clonal expansions of latently infected cells—the duplication of partial and near-full-length HIV genomes and/or integration sites—are the key mechanism of maintenance of the HIV reservoir [32–34]. The infected cells in clones in samples of patients undergoing ART may differ from each other [35]. The following mechanisms explain the heterogeneity [36]: (a) antigen-driven clonal proliferation of infected cells [37], (b) homeostatic proliferation of infected cells [38], and (c) HIV integration-induced cell proliferation [39]. Although the first mechanism is a major driver of the maintenance of the HIV reservoir as confirmed by most researchers, the effect of the coexistence of the other two mechanisms cannot be excluded [36, 40]. Therefore, clonal expansion of latently infected cells contributes to the maintenance of the HIV-1 LR.

4. Measurement of the HIV-1 LR

Despite clinically efficacious ART, replication-competent HIV-1 persists as latent proviral DNA capable of rekindling viral replication after ceasing ART. Therapies to eliminate latent HIV-1 are being developed for a complete cure. Accurate assays to quantify intact or rebound-competent HIV-1 are critical to this effort. Four challenges obstruct the precise quantification of the HIV-1 LR. The gravest one is that in ART-treated PLWH with mutations and/or deletions, HIV-1 proviruses produce defective mutants which are unable to replicate. However, not all intact genomes (without defective mutations or deletions) can produce virions after induction. It is more of an occasional incidence of latently infected cells. Finally, most HIV reservoirs that reside in tissues cannot be accurately sampled with current specimen-collection approaches [41–44].

The conventional quantification of HIV, the gold standard VOA assay, can merely detect the transcribed replicates of totiviruses; therefore, this technique underestimates reservoir levels. However, PCR analysis for total HIV DNA or Alu-Gag PCR also quantitates a large amount of defective HIV DNA fragments and thereby overestimates reservoir levels. Bruner et al. developed a new method, the intact proviral DNA assay (IPDA), to amplify HIV fragments and the Env gene using droplet digital PCR (ddPCR). HIV DNAs used for the amplification of are limited to those whose 3 ends are defective, and only the DNAs used for the amplification of Env have defective 5 ends. Double-positive HIV DNA amplified using IPDA is intact HIV DNA, which not only corroborates the results from the VOA assay but also compensates for the flaw of the PCR assay that can yield false-positive results due to defective viral fragments. Based on these studies, reservoirs of potential intact HIV DNA and those of defective HIV DNA hold completely different traits and effectively overcome the three challenges mentioned above (the fourth challenge is an objective existence).

IPDA for HIV DNA quantification using ddPCR targets multiply regions of proviral DNA to exclude deleted and hypermutated proviruses. The ddPCR is the third-generation PCR technique, which partitions samples into 20,000 droplets, and each droplet contains an independent reaction system and tremendously reduces interference from background nucleic acid molecules during PCR amplification. Therefore, it is competent in the quantification of low-copy nucleic acid molecules of interest. The ddPCR technique uses the ratio of positive to negative droplets among the 20,000 droplets to calculate the copy number of target nucleic acid molecules, without the use of standard substances for standard curves. Here is the specific principle: an amplicon is added at the packaging signal and the conserved site in the env sequence, respectively, excluding 90% of deficiency; at the same time, a mutant protein is added to bind to the amplified loci of env, excluding 95% of most frequent mutations. As a result, double-positive DNA fragments can be identified as intact proviral DNA. Meanwhile, two amplicons with the same distance as that of the reference RPP30 gene in another hole are designed for shearing, control (the strand break of DNA between two amplicons during DNA extraction will reduce the double-positive number detected and there by the results could be underestimated), and cell quantification. By this means, the size of reservoirs can be calculated.

IPDA is optimal for high-throughput analysis in large interventional or observational clinical studies. For instance, a recent longitudinal cohort analysis has evaluated the decay rate of intact and defective proviruses in a large number of patients by using this technique [45]. Another study using this measurement found no relationship between heroin or cocaine use and the reservoir size [46]. This technique offers competitive advantages of 97% elimination of defective proviruses, only about 1.5-fold overestimation of the LR size, simpler operation, lower cost, and greater speed than traditional QVOA. Nonetheless, sequence polymorphisms in some patients, the requirement for alternative primers or proteins, and within-clade diversity dependence obstruct the efficient amplification so the provirus inducibility cannot be accurately quantified.

5. Elimination of the HIV-1 LR

5.1. Strategies Targeting the HIV-1 Replication Cycle

5.1.1. Early ART

Early initiation of ART is aimed at reducing virus diversification since the diagnosis of HIV infection can prevent damage of immune function as much as possible, minimize HIV-related complications in treated individuals, and prevent human-to-human transmission by lowering viremia [47]. Early ART initiation currently cannot achieve an HIV cure in adults or mothers; however, the infants can be the beneficiaries of the early interventions. As these early interventions reshape the association between the virus and the immune system, HIV infection can be ultimately controlled after ART withdrawal in a certain proportion of patients that have received ART at an early stage. This population accounts for approximately 5–10% of all HIV-infected individuals, who become posttreatment controllers achieving ART-free viral remission [48, 49].

During long-term ART, much of the reservoir derive from the cells that are infected just before treatment initiation. It is arguable that in the preintervention period, the putative reservoir is unstable [50, 51]. This implies that during early ART, the rapidly changing immune environment shifts the balance toward a state in which HIV latency can be achieved. Presumably, the massive reduction in HIV-1-associated inflammation and T cell activation reduces the turnover of the reservoir, leading to the generation of longer-lived cells harboring intact genomes. Immune stimulation under the cover of ART (preferably with the coadministration of a therapy that induces the killing of infected cells) might work best during this window of opportunity.

5.1.2. Transplantation

There are two studies of two patients (from Berlin and London) who underwent allogeneic stem cell transplantations from CCR5132/132 donors who achieved an HIV-1 cure. After monitoring their plasma viremia for 10 and 2 years, respectively, negative results were found after ART withdrawal [52, 53]. These studies reported the depletion of the HIV-1 LR during pretransplant conditioning, and the reservoirs were replaced with donor cells with Delta 32 CCR5 deletion to confer resistance to R5-tropic HIV-1 infection [54]. As there are a lack of CCR5132/132 donors, diagnosis delay of HIV infection in most cases, and massive expenditure, HIV cure for most patients is unrealistic. Therefore, silencing, the basic principle of HIV-1 cured, or HIV-1 LR elimination is the priority.

5.1.3. Gene Editing

Recent years have seen the emergence of several gene editing tools, such as CRISPR Cas9 and zinc-finger nucleases (ZFN). These techniques are potent in enhancing host resistance or disrupting viral latency through the silencing of integrated provirus in the host, which paves the way for an HIV-1 cure. These strategies offer the precise correction of sequences in a genome. Different from LRAs, they can produce desired outcomes without a physiological impact throughout the body. Notably, as several studies reported off-target effect, the safety of these methods must be evaluated before the clinical application. [55] So far, the only clinical study has achieved Delta 32 CCR5 deletion using ZFN-targeted editing to help patients gain partial genetic resistance to R5-tropic HIV-1 infection [56]. Most studies focus on the efficacy of CRISPR-Cas9 because of its simple operation. Some studies have performed CCR5 or CXCR4 ablation in CD4+ TRM cells using CRISPR-Cas9 to protect cells against CCR5 or CXCR4 tropic HIV-1 infection [57–59]. To specifically knockout or silence the HIV-1 proviral genome, which is the premise of HIV-1 LR elimination, is feasible with CRISPR Cas9 therapy [60, 61]. Besides, by targeting other domains of the HIV-1 proviral genome, the resultant indels in these domains introduced by NHEJ-mediated repair can result in frameshift mutations to deactivate the provirus [62, 63]. This strategy, in combination with a novel drug delivery system, was successfully performed in mouse models [64]. During the viral replication cycle, though multiple editable sites can be targeted in the HIV-1 proviral genome using a CRISPR-Cas9 strategy, therefore, more options for quasispecies diversity are provided; the lack of adequate viral vectors or lipid compounds is a barrier to effective delivery [65]. Considering that there is a substantial number of LNs, GALTs, and other tissues with HIV-1 LR, the elimination of the reservoirs is a project that has to be exerted with such great effort that current strategies can hardly make it.

5.1.4. Shock and Kill

The shock and kill strategy was put forward by Siliciano and Deeks in 2012. It is a combination strategy using latency-reversing agents (LRAs) in immunotherapeutic treatment (e.g., T cell vaccines) to shock and kill intervention activated cells via reactivating them, thereby reducing the size of the LR and preventing viremia rebound [66, 67]. Since the single use of either constituent merely shows limited clinical benefit, the combination strategy is yet to be tested, leaving its efficacy to be in doubt. However, its flaws are currently known as toxic side effects and systemic immune response alongside HIV-1 latency reversal.

The commonly used LRAs can be assigned to six groups by pharmacological mechanisms: histone posttranslational modification modulators, nonhistone chromatin modulators, NF-κB stimulators, TLR agonists, extracellular stimulators, and a miscellaneous category of unique cellular mechanisms [68]. The nonspecific histone deacetylase inhibitors (HDACIs) characterized to acetylate the histone of integrated proviral promoters in vitro are the most prominent at present. Clinical trials for the promising HDACI candidates, including vorinostat, disulfiram, and romidepsin, reported that these HDACIs effectively induced viral replication and killed activated cells harboring HIV once the immune system was activated [69–71].

Inspired by a current finding that some of the latently infected CD4+ T cells are HIV-specific, efforts have been made to develop cost-effective and safe HIV-specific vaccines to reverse HIV latency [72, 73]. HIV vaccines reactivate HIV-specific latently infected cells to eliminate them via stimulated cytotoxic T lymphocytes (CTLs) [74], thus offering a near-complete representation of viral quasispecies and an enhanced killing effect of the shock and kill strategy [67]. The shock effect can be enhanced using a latency-reversing intervention with the involvement of other immune cells. For instance, GS-9620 (a TLR-7 agonist) can reactivate HIV-infected CD4+ TRM cells probably through IFN-γ release from plasmacytoid dendritic cells [75]. Despite those reported effective results, some studies had inconsistent results and reported that these strategies have nonsignificant effect on diminishing the size of the HIV reservoir in patients [76, 77]. Some studies even reported adverse effect on immune response after the administration of these strategies [78, 79]. Some scholars from the University of Pennsylvania proposed that the research and development of COVID-19 vaccine will help promote the research and development of HIV vaccine. These undesirable results may be ascribed to insufficient killing effect, so extensive studies using strategies with improved killing effects are being developed, including employing broadly neutralizing antibodies and immune checkpoint inhibitors [80], as shown in the details below.

5.1.5. Block and Lock

There are some data indicating that the HIV genome that becomes preferentially enriched in intergenic regions becomes hypermethylated over time through multiple mechanisms, resulting in less HIV expression [31]. This evolution of proviral distribution reflects the survival of cells with defective HIV viruses and that of the viruses in regions of the genome that promotes “deep latency.” A relatively novel cure strategy, namely, block and lock, by contrast, aimed at reinforcing latency (“block”) rather than inducing latency reversal, has been proposed to prevent viremia rebound following ART discontinuance [81, 82]. To illustrate it in detail, transcriptional gene silencing (TGS) by promoter targeting small interfering RNAs (siRNAs) can rapidly recruit chromatin remodelers to repress HIV-1 transcription [81]. To enhance or maintain the HIV-1 latency, the targeted inhibition of the HIV-1 positive regulator Tat is employed so that the viral replication cycle can be blocked (“lock”) at the transcriptional level [82]. Clinical studies about other potential HIV-silencing techniques are in progress. Among the potential candidates, inhibitors of mammalian target of rapamycin (mTOR) have been justified as effective [83]. Their therapeutic efficacy and safety have been validated in clinical studies.

Though the efficacy of “shock and kill” approach is uncertain, evidence has pointed out that it can remarkably diminish the LR size and is expected to achieve ART-free HIV remission.

5.1.6. Strategies That Target the Immunity

(1) Therapeutic Vaccination. Therapeutic vaccination enhances the host immune response to HIV-1, thus eradicating the HIV-1 LR or diminishing viremia rebound as a cure. This way leverages vaccine inoculation during sustained ART-mediated viral suppression. During ART interruption, the time to viral rebound, the size of the LR, and the profile of the host immune response are detected to confirm the efficacy of HIV-1 vaccination.

HIV-1 vaccines only trigger narrow CTL response to specific HIV-1 proteins (e.g., gag) after inoculation. CTL escape mutants can be enhanced due to a weaker efficacy since the mutation happens during primary infection [84, 85]. Therefore, HIV-1 vaccine is seemingly more reliable as it triggers a broader anti-HIV-1 immune response. Some researchers stated that they would fabricate dendritic cell- (DC-) based vaccines using autologous DCs cocultured or transfected with inactivated HIV-1 to stimulate CD4+ TRM cells to boost immune responses [86, 87]. Interestingly, a study reported that a combination of HIV-1 vaccines and Tat-based immunization, a “block and lock” strategy, continually suppressed the proviral reservoir followed by the recovery of immune function. This suggests that therapeutic vaccination can boost the immune response in HIV-1 infection clearances [88].

Currently, HIV-1 vaccines have not yet induced sustained HIV-1 remission. Among these studies, a study by Davenport et al. expressed their concern that although the most efficacious vaccines could block 80% of viral reactivation, viremia rebound could quickly occur in these patients in less than five weeks after ART withdrawal [89]. This indicates that HIV-1 vaccination cannot thoroughly eliminate the latent HIV-1 reservoir, which means it is insufficient to overcome viral rebound and further cure HIV-1 infection. To make up for this shortcoming, in contrast to using HIV-1 vaccination separately, a proper combination of strategies, such as shock and kill, targeted to suppress viral rebound can be more effective in the treatment. Two clinical studies have adopted and validated this combination protocol (gag-based vaccination followed by HDCAI latency reversal); however, plasma viremia has been redetected in less than two weeks after that [90, 91].

5.1.7. Broadly Neutralizing Antibodies (bNAbs)

Immunotherapies are popular as the HIV antagonists directly target cells expressing the HIV envelop proteins that interact with the lymphocyte cell-surface molecule CD4 so the latent HIV reservoir can be eliminated. Some studies reported that bNAbs targeting specific envelope glycoproteins probably suppress virus replication in vivo [92, 93] by blocking the entry and spreading of virus. Theoretically, bNAbs can trigger host-mediated cytotoxicity by binding themselves to envelope proteins expressed on the surface of infected immune cells that have already been stimulated, thereby reducing the active reservoir. Whether the infected cells are killed in vivo remains unproven, though indirect evidence suggests that it may have some effect [94].

Some early proof-of-concept studies about several strategies aimed at enhancing PTC were being completed. Even if bNAbs cannot directly clear the latent cellular reservoirs of HIV infection, it has been postulated that they achieve this for highly immunogenic antibody-antigen response and thus might stimulate potent HIV-specific immune response and achieve post-ART control [95].

Hindered by the barriers to HIV-1 vaccine development and HIV-1 eradication and remission, passive transfer of monoclonal HIV-1 neutralizing antibodies is another option. The small-molecule drugs bNAbs featuring longer half-lives currently being used not only have an attractive price but also stimulate the immune response directly and exert a robust killing effect on the latently infected cells. By this means, the course of HIV-1 infection can be shortened. As of now, several clinical trials have used various bNAbs and successfully verified the efficacy of suppressing and controlling viremia rebound [96].

5.1.8. Chimeric Antigen Receptor T (CAR-T) Cells

CAR-T cell therapy has been employed to treat B cell malignancies [97–99], and there is evidence that reveals its potential in treating HIV-1 infection. For eliminating latently infected cells, autologous T cells can be engineered to express a unique CAR to confer HIV-1 antigen specificity. Patients who receive CAR-T cell therapy can directly raise the CTL response to cells expressing the disease epitope [100], so CAR-T cell therapy can eliminate latently infected cells with HIV-1-associated antigen through the killing effect of CTLs, aiding in the control of the virus without ART. Some in vitro experiments using CAR-T cell therapy have ascertained a satisfactory efficacy of anti-HIV-1 CAR-T cells [101, 102]. An animal experiment based on mouse models where the mouse cells were infected with HIV-1 showed the effective eradication of HIV-1 infected cells [103]. Notably, preclinical studies ascertained that bNAb-based CAR-modified CD8+ T cell therapy is possible as a cure; however, it needs to be validated by high-quality clinical studies. At present, CAR T-cell therapy is flawed with CAR T cell expansion, persistence, off-target effect, and severe cytokine release syndrome (sCRS). More work is needed to address these issues.

5.1.9. Immune Checkpoint Blockers

The definition of immune checkpoints is a large sum of regulatory pathways that potently suppress the immune activity, particularly the T cell activity; the associations between immune checkpoints, immune exhaustion, and impaired function have been proven (reviewed by Wykes and Lewin) [104]. CD4+ T cells in the peripheral circulation and lymphoid tissues express high levels of immune checkpoint markers, including programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and other markers that adhere to the membrane to exert the killing effect on HIV once activated [22, 105, 106]. Expressions of immune checkpoints are upregulated in HIV-specific CD4+ and CD8+ T cells when HIV-specific immunity is activated in untreated and treated cases and ex vivo. The single or combined use of antibodies against these markers can enhance the upregulation [21]. In this way, the HIV LR can be reduced [104]. The upregulated checkpoints in latently infected T cells incorporate PD1/PD-L1 and CTLA-4 as the main components. These markers are worthy of research on drug delivery or HIV-1 clearance [107–109]. In vitro studies on the efficacy of immune checkpoint blockers claimed that the HIV-1 LR could be inhibited via the IC-mediated manner, and in vivo studies also confirmed its effect of promoted latency reversal. These results show the anti-HIV-1 potential of immune checkpoint inhibitors [23, 24, 110].

6. Combination Therapy for HIV-1 Infection

At present, no single treatment can eliminate HIV-1 LRs, nor even remission. Combination strategies can minimize the LR level with the host immune system defending against latent infection efficiently after treatment. Most ongoing studies on HIV-1 cures designed to assess their safety and relevant mechanism remain in preclinical and transitional phases. Clinical trials for assessment of combination approaches are getting more and more attention [111], and more efficacious combination strategies are expected to achieve a complete cure or remission [91, 112].

7. Conclusions

Some progress in HIV-1 cure development has been made, such as reduced HIV-1 mortality and HIV-1 LR measurement. But there is still a long way to go for the research and development of HIV-1 elimination and remission as preexisting measurement cannot guarantee 100% accurate quantitation of the HIV-1 LR at each stage, and current therapies cannot achieve complete clearance due to the persistent LR.

The past decade has witnessed many strategies proposed as a cure, among which the shock and kill therapy is the most promising. Validation studies of the shock and kill strategy reported neither decrease nor increase in the time to viral rebound, and the virus reactivation still existed in vivo. Hence, the enhancement of the killing effect against the HIV-1 LR and alternative methods, such as therapeutic vaccination and immune boosters against HIV-1 infection via augmenting immune-mediated control of HIV-1 after ART withdrawal, is required. Regarding novel methods, such as immune checkpoint inhibitors, gene editing tools, and CAR-T cell therapy, their efficacy needs to be verified in more clinical studies. These approaches have renewed hope for an HIV-1 cure. Posttreatment complications, such as adverse effects weakening immune response, pose challenges in patient compliance and precise assessments of the therapeutic efficacy. The complexity of LR quantification is associated with the inherent variability of the HIV-1 genome, the low incidence of latently infected cells, and the abundance of defective proviruses.

Instead of emphasizing on single-agent strategies, the combined use of synergistic anti-HIV-1 agents (e.g., LRAs plus HIV-1 vaccination) is more likely to remarkably reverse the HIV-1 LR and achieve the ultimate goal of long-term ART-free viral remission.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

UNAIDS, “UNAIDS data,” 2019, https://www.unaids.org/en/resources/documents/2019/2019-UNAIDS-data.
View at: Google Scholar
M. R. Gardner, “Promise and progress of an HIV-1 cure by adeno-associated virus vector delivery of anti-HIV-1 biologics,” Frontiers in Cellular and Infection Microbiology, vol. 10, article 176, 2020.
View at: Google Scholar
J. K. Wong, M. Hezareh, H. F. Gunthard et al., “Recovery of replication-competent HIV despite prolonged suppression of plasma viremia,” Science, vol. 278, no. 5341, pp. 1291–1295, 1997.
View at: Google Scholar
J. N. Blankson, D. Persaud, and R. F. Siliciano, “The challenge of viral reservoirs in HIV-1 infection,” Annual Review of Medicine, vol. 53, no. 1, pp. 557–593, 2002.
View at: Publisher Site | Google Scholar
J. D. Siliciano, J. Kajdas, D. Finzi et al., “Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4⁺ T cells,” Nature Medicine, vol. 9, no. 6, pp. 727-728, 2003.
View at: Publisher Site | Google Scholar
S. A. Yukl, P. Kaiser, P. Kim et al., “HIV latency in isolated patient CD4+ T cells may be due to blocks in HIV transcriptional elongation, completion, and splicing,” Science Translational Medicine, vol. 10, no. 430, article eaap 9927, 2018.
View at: Google Scholar
K. G. Lassen, J. R. Bailey, and R. F. Siliciano, “Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4⁺ T cells in vivo,” Journal of Virology, vol. 78, no. 17, pp. 9105–9114, 2004.
View at: Publisher Site | Google Scholar
M. Pardons, A. E. Baxter, M. Massanella et al., “Single-cell characterization and quantification of translation-competent viral reservoirs in treated and untreated HIV infection,” PLoS Pathogens, vol. 15, no. 2, article e1007619, 2019.
View at: Publisher Site | Google Scholar
J. Ananworanich, A. Schuetz, C. Vandergeeten et al., “Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection,” PLoS One, vol. 7, no. 3, article e33948, 2012.
View at: Publisher Site | Google Scholar
J. B. Whitney, A. L. Hill, S. Sanisetty et al., “Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys,” Nature, vol. 512, no. 7512, pp. 74–77, 2014.
View at: Publisher Site | Google Scholar
T. J. Henrich, H. Hatano, O. Bacon et al., “HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: an observational study,” PLoS Medicine, vol. 14, no. 11, article e1002417, 2017.
View at: Google Scholar
X. Wei, S. K. Ghosh, M. E. Taylor et al., “Viral dynamics in human immunodeficiency virus type 1 infection,” Nature, vol. 373, no. 6510, pp. 117–122, 1995.
View at: Google Scholar
D. Finzi, J. Blankson, J. D. Siliciano et al., “Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy,” Nature Medicine, vol. 5, no. 5, pp. 512–517, 1999.
View at: Google Scholar
L. Leyre, E. Kroon, C. Vandergeeten et al., “Abundant HIV-infected cells in blood and tissues are rapidly cleared upon ART initiation during acute HIV infection,” Science Translational Medicine, vol. 12, no. 533, p. 3491, 2020.
View at: Publisher Site | Google Scholar
J. K. Wong and S. A. Yukl, “Tissue reservoirs of HIV,” Current Opinion in HIV and AIDS, vol. 11, no. 4, pp. 362–370, 2016.
View at: Publisher Site | Google Scholar
A. Chaillon, S. Gianella, S. Dellicour et al., “HIV persists throughout deep tissues with repopulation from multiple anatomical sources,” The Journal of Clinical Investigation, vol. 130, no. 4, pp. 1699–1712, 2020.
View at: Publisher Site | Google Scholar
J. Cantero-Pérez, J. Grau-Expósito, C. Serra-Peinado et al., “Resident memory T cells are a cellular reservoir for HIV in the cervical mucosa,” Nature Communications, vol. 10, no. 1, p. 4739, 2019.
View at: Publisher Site | Google Scholar
Y. Ganor, F. Real, A. Sennepin et al., “HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy,” Nature Microbiology, vol. 4, no. 4, pp. 633–644, 2019.
View at: Publisher Site | Google Scholar
C. Dobrowolski, S. Valadkhan, A. C. Graham et al., “Entry of polarized effector cells into quiescence forces HIV latency,” MBio, vol. 10, no. 2, article e00337-19, 2019.
View at: Google Scholar
R. Banga, F. A. Procopio, A. Noto et al., “PD-1⁺ and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals,” Nature Medicine, vol. 22, no. 7, pp. 754–761, 2016.
View at: Google Scholar
G. M. Chew, T. Fujita, G. M. Webb et al., “TIGIT marks exhausted T cells, correlates with disease progression, and serves as a target for immune restoration in HIV and SIV infection,” PLoS Pathogens, vol. 12, no. 1, article e1005349, 2016.
View at: Publisher Site | Google Scholar
R. Fromentin, W. Bakeman, M. B. Lawani et al., “CD4⁺ T cells expressing PD-1, TIGIT and LAG-3 contribute to HIV persistence during ART,” PLoS Pathogens, vol. 12, no. 7, article e1005761, 2016.
View at: Google Scholar
V. A. Evans, R. M. Van Der Sluis, A. Solomon et al., “PD-1 contributes to the establishment and maintenance of HIV-1 latency,” AIDS (London, England), vol. 32, no. 11, pp. 1491–1497, 2018.
View at: Google Scholar
R. Fromentin, S. DaFonseca, C. T. Costiniuk et al., “PD-1 blockade potentiates HIV latency reversal ex vivo in CD4⁺ T cells from ART-suppressed individuals,” Nature Communications, vol. 10, no. 1, pp. 1–7, 2019.
View at: Publisher Site | Google Scholar
N. A. Kumar, K. Cheong, D. R. Powell et al., “The role of antigen presenting cells in the induction of HIV-1 latency in resting CD4⁺ T-cells,” Retrovirology, vol. 12, no. 1, pp. 1–16, 2015.
View at: Google Scholar
S. D. Rezaei, H. K. Lu, J. J. Chang, A. Rhodes, S. R. Lewin, and P. U. Cameron, “The pathway to establishing HIV latency is critical to how latency is maintained and reversed,” Journal Of Virology, vol. 92, no. 13, article e02225-17, 2018.
View at: Publisher Site | Google Scholar
H. M. Baldauf, X. Pan, E. Erikson et al., “SAMHD1 restricts HIV-1 infection in resting CD4⁺ T cells,” Nature Medicine, vol. 18, no. 11, pp. 1682–1688, 2012.
View at: Google Scholar
M. Coiras, M. Bermejo, B. Descours et al., “IL-7 induces SAMHD1 phosphorylation in CD4+ T lymphocytes, improving early steps of HIV-1 life cycle,” Cell Reports, vol. 14, no. 9, pp. 2100–2107, 2016.
View at: Google Scholar
M. J. Pace, E. H. Graf, L. M. Agosto et al., “Directly infected resting CD4+ T cells can produce HIV Gag without spreading infection in a model of HIV latency,” PLoS Pathogens, vol. 8, no. 7, article e1002818, 2012.
View at: Google Scholar
P. U. Cameron, S. Saleh, G. Sallmann et al., “Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton,” Proceedings of the National Academy of Sciences, vol. 107, no. 39, pp. 16934–16939, 2010.
View at: Publisher Site | Google Scholar
L. Chavez, V. Calvanese, and E. Verdin, “HIV latency is established directly and early in both resting and activated primary CD4 T cells,” Plos Pathogens, vol. 11, no. 6, article e1004955, 2015.
View at: Google Scholar
L. B. Cohn, I. T. Silva, T. Y. Oliveira et al., “HIV-1 integration landscape during latent and active infection,” Cell, vol. 160, no. 3, pp. 420–432, 2015.
View at: Publisher Site | Google Scholar
K. B. Einkauf, G. Q. Lee, C. Gao et al., “Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy,” The Journal of Clinical Investigation, vol. 129, no. 3, pp. 988–998, 2019.
View at: Google Scholar
M. R. Pinzone, D. J. VanBelzen, S. Weissman et al., “Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion,” Nature Communications, vol. 10, no. 1, p. 728, 2019.
View at: Publisher Site | Google Scholar
Z. Wang, E. E. Gurule, T. P. Brennan et al., “Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane,” Proceedings of the National Academy of Sciences, vol. 115, no. 11, pp. E2575–E2584, 2018.
View at: Publisher Site | Google Scholar
M. Kim and R. F. Siliciano, “Reservoir expansion by T-cell proliferation may be another barrier to curing HIV infection,” Proceedings of the National Academy of Sciences, vol. 113, no. 7, pp. 1692–1694, 2016.
View at: Publisher Site | Google Scholar
P. Mendoza, J. R. Jackson, T. Y. Oliveira et al., “Antigen-responsive CD4⁺ T cell clones contribute to the HIV-1 latent reservoir,” Journal of Experimental Medicine, vol. 217, no. 7, article e20200051, 2020.
View at: Google Scholar
N. N. Hosmane, K. J. Kwon, K. M. Bruner et al., “Proliferation of latently infected CD4⁺ T cells carrying replication-competent HIV-1: potential role in latent reservoir dynamics,” Journal of Experimental Medicine, vol. 214, no. 4, pp. 959–972, 2017.
View at: Google Scholar
F. Maldarelli, X. Wu, L. Su et al., “Specific HIV integration sites are linked to clonal expansion and persistence of infected cells,” Science, vol. 345, no. 6193, pp. 179–183, 2014.
View at: Google Scholar
S. Sunshine, R. Kirchner, S. S. Amr et al., “HIV integration site analysis of cellular models of HIV latency with a probe-enriched next-generation sequencing assay,” Journal of Virology, vol. 90, no. 9, pp. 4511–4519, 2016.
View at: Google Scholar
T.-W. Chun, D. C. Nickle, J. S. Justement et al., “Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy,” The Journal of Infectious Diseases, vol. 197, no. 5, pp. 714–720, 2008.
View at: Publisher Site | Google Scholar
J. D. Estes, C. Kityo, F. Ssali et al., “Defining total-body AIDS-virus burden with implications for curative strategies,” Nature Medicine, vol. 23, no. 11, pp. 1271–1276, 2017.
View at: Google Scholar
Y. C. Ho, L. Shan, N. N. Hosmane et al., “Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure,” Cell, vol. 155, no. 3, pp. 540–551, 2013.
View at: Publisher Site | Google Scholar
G. Pantaleo, C. Graziosi, J. F. Demarest et al., “HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease,” Nature, vol. 362, no. 6418, pp. 355–358, 1993.
View at: Google Scholar
M. J. Peluso, P. Bacchetti, K. D. Ritter et al., “Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy,” JCI Insight, vol. 5, no. 4, article e132997, 2020.
View at: Publisher Site | Google Scholar
G. D. Kirk, J. Astemborski, S. H. Mehta et al., “Nonstructured treatment interruptions are associated with higher human immunodeficiency virus reservoir size measured by intact proviral DNA assay in people who inject drugs,” The Journal of Infectious Diseases, vol. 223, no. 11, pp. 1905–1913, 2021.
View at: Publisher Site | Google Scholar
Z. M. Ndhlovu, S. W. Kazer, T. Nkosi et al., “Augmentation of HIV-specific T cell function by immediate treatment of hyperacute HIV-1 infection,” Science Translational Medicine, vol. 11, no. 493, article aau0528, 2019.
View at: Google Scholar
G. Namazi, J. M. Fajnzylber, E. Aga et al., “The control of HIV after antiretroviral medication pause (CHAMP) study: posttreatment controllers identified from 14 clinical studies,” The Journal of Infectious Diseases, vol. 218, no. 12, pp. 1954–1963, 2018.
View at: Publisher Site | Google Scholar
A. Sáez-Cirión, C. Bacchus, L. Hocqueloux et al., “Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI study,” PLoS Pathogens, vol. 9, no. 3, article e1003211, 2013.
View at: Google Scholar
M. R. Abrahams, S. B. Joseph, N. Garrett et al., “The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation,” Science Translational Medicine, vol. 11, no. 513, article aaw5589, 2019.
View at: Google Scholar
J. Brodin, F. Zanini, L. Thebo et al., “Establishment and stability of the latent HIV-1 DNA reservoir,” eLife, vol. 5, article e18889, 2016.
View at: Publisher Site | Google Scholar
R. K. Gupta, S. Abdul-Jawad, L. E. McCoy et al., “HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation,” Nature, vol. 568, no. 7751, pp. 244–248, 2019.
View at: Publisher Site | Google Scholar
G. Hütter, D. Nowak, M. Mossner et al., “Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation,” New England Journal of Medicine, vol. 360, no. 7, pp. 692–698, 2009.
View at: Google Scholar
R. Liu, W. A. Paxton, S. Choe et al., “Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection,” Cell, vol. 86, no. 3, pp. 367–377, 1996.
View at: Google Scholar
M. L. Kimberland, W. Hou, A. Alfonso-Pecchio et al., “Strategies for controlling CRISPR/Cas9 off-target effects and biological variations in mammalian genome editing experiments,” Journal of Biotechnology, vol. 284, pp. 91–101, 2018.
View at: Google Scholar
P. Tebas, D. Stein, W. W. Tang et al., “Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV,” NEJM, vol. 370, no. 10, pp. 901–910, 2014.
View at: Publisher Site | Google Scholar
Q. Wang, S. Chen, Q. Xiao et al., “Genome modification of CXCR4 by Staphylococcus aureus Cas9 renders cells resistance to HIV-1 infection,” Retrovirology, vol. 14, no. 1, pp. 1–12, 2017.
View at: Google Scholar
W. Wang, C. Ye, J. Liu, D. Zhang, J. T. Kimata, and P. Zhou, “CCR5 gene disruption via lentiviral vectors expressing Cas9 and single guided RNA renders cells resistant to HIV-1 infection,” PLoS One, vol. 9, no. 12, article e115987, 2014.
View at: Publisher Site | Google Scholar
L. Xu, H. Yang, Y. Gao et al., “CRISPR/Cas9-mediated CCR5 ablation in human hematopoietic stem/progenitor cells confers HIV-1 resistance in vivo,” Molecular Therapy, vol. 25, no. 8, pp. 1782–1789, 2017.
View at: Google Scholar
R. Bella, R. Kaminski, P. Mancuso et al., “Removal of HIV DNA by CRISPR from patient blood engrafts in humanized mice,” Molecular Therapy - Nucleic Acids, vol. 12, pp. 275–282, 2018.
View at: Google Scholar
Q. Wang, S. Liu, Z. Liu et al., “Genome scale screening identification of SaCas9/gRNAs for targeting HIV-1 provirus and suppression of HIV-1 infection,” Virus Research, vol. 250, pp. 21–30, 2018.
View at: Google Scholar
Y. Ophinni, M. Inoue, T. Kotaki, and M. Kameoka, “CRISPR/Cas9 system targeting regulatory genes of HIV-1 inhibits viral replication in infected T-cell cultures,” Scientific Reports, vol. 8, no. 1, article 7784, 2018.
View at: Google Scholar
G. Wang, N. Zhao, B. Berkhout, and A. T. Das, “CRISPR-Cas9 can inhibit HIV-1 replication but NHEJ repair facilitates virus escape,” Molecular Therapy, vol. 24, no. 3, pp. 522–526, 2016.
View at: Publisher Site | Google Scholar
P. K. Dash, R. Kaminski, R. Bella et al., “Sequential LASER ART and CRISPR treatments eliminate HIV-1 in a subset of infected humanized mice,” Nature Communications, vol. 10, no. 1, pp. 1–20, 2019.
View at: Publisher Site | Google Scholar
Q. Xiao, D. Guo, and S. Chen, “Application of CRISPR/Cas9-based gene editing in HIV-1/AIDS therapy,” Frontiers in Cellular and Infection Microbiology, vol. 9, article 69, 2019.
View at: Google Scholar
S. G. Deeks, “Shock and kill,” Nature, vol. 487, no. 7408, pp. 439-440, 2012.
View at: Publisher Site | Google Scholar
L. Shan, K. Deng, N. S. Shroff et al., “Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation,” Immunity, vol. 36, no. 3, pp. 491–501, 2012.
View at: Publisher Site | Google Scholar
E. Abner and A. Jordan, “HIV "shock and kill" therapy: in need of revision,” Antiviral Research, vol. 166, pp. 19–34, 2019.
View at: Publisher Site | Google Scholar
G. Q. Del Prete, K. Oswald, A. Lara et al., “Elevated plasma viral loads in romidepsin-treated simian immunodeficiency virus-infected rhesus macaques on suppressive combination antiretroviral therapy,” Antimicrobial Agents and Chemotherapy, vol. 60, no. 3, pp. 1560–1572, 2015.
View at: Publisher Site | Google Scholar
M. B. Lucera, C. A. Tilton, H. Mao et al., “The histone deacetylase inhibitor vorinostat (SAHA) increases the susceptibility of uninfected CD4⁺ T cells to HIV by increasing the kinetics and efficiency of postentry viral events,” Journal of Virology, vol. 88, no. 18, pp. 10803–10812, 2014.
View at: Google Scholar
D. G. Wei, V. Chiang, E. Fyne et al., “Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing,” PLoS Pathogens, vol. 10, no. 4, article e1004071, 2014.
View at: Google Scholar
A. Demoustier, B. Gubler, O. Lambotte et al., “In patients on prolonged HAART, a significant pool of HIV infected CD4 T cells are HIV-specific,” AIDS, vol. 16, no. 13, pp. 1749–1754, 2002.
View at: Publisher Site | Google Scholar
D. C. Douek, M. R. Betts, J. M. Brenchley et al., “A novel approach to the analysis of specificity, clonality, and frequency of HIV-specific T cell responses reveals a potential mechanism for control of viral escape,” The Journal of Immunology, vol. 168, no. 6, pp. 3099–3104, 2002.
View at: Publisher Site | Google Scholar
J. Pankrac, K. Klein, and J. F. S. Mann, “Eradication of HIV-1 latent reservoirs through therapeutic vaccination,” AIDS Research and Therapy, vol. 14, no. 1, pp. 1–4, 2017.
View at: Google Scholar
A. Tsai, A. Irrinki, J. Kaur et al., “Toll-like receptor 7 agonist GS-9620 induces HIV expression and HIV-specific immunity in cells from HIV-infected individuals on suppressive antiretroviral therapy,” Journal of Virology, vol. 91, no. 8, article e02166-16, 2017.
View at: Publisher Site | Google Scholar
C. K. Bullen, G. M. Laird, C. M. Durand, J. D. Siliciano, and R. F. Siliciano, “New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo,” Nature Medicine, vol. 20, no. 4, pp. 425–429, 2014.
View at: Google Scholar
O. S. Søgaard, M. E. Graversen, S. Leth et al., “The depsipeptide romidepsin reverses HIV-1 latency in vivo,” PLoS Pathogens, vol. 11, no. 9, article e1005142, 2015.
View at: Google Scholar
S. Narasimhan, J. Coumou, T. J. Schuijt, E. Boder, J. W. Hovius, and E. Fikrig, “A tick gut protein with fibronectin III domains AIDS Borrelia burgdorferi congregation to the gut during transmission,” PLoS Pathogens, vol. 10, no. 8, article e1004278, 2014.
View at: Publisher Site | Google Scholar
M. Waibel, A. J. Christiansen, M. L. Hibbs et al., “Manipulation of B-cell responses with histone deacetylase inhibitors,” Nature Communications, vol. 6, no. 1, pp. 1–12, 2015.
View at: Google Scholar
D. H. Barouch and S. G. Deeks, “Immunologic strategies for HIV-1 remission and eradication,” Science, vol. 345, no. 6193, pp. 169–174, 2014.
View at: Google Scholar
C. Méndez, S. Ledger, K. Petoumenos, C. Ahlenstiel, and A. D. Kelleher, “RNA-induced epigenetic silencing inhibits HIV-1 reactivation from latency,” Retrovirology, vol. 15, no. 1, p. 67, 2018.
View at: Publisher Site | Google Scholar
G. Mousseau, C. F. Kessing, R. Fromentin, L. Trautmann, N. Chomont, and S. T. Valente, “The Tat inhibitor didehydro-cortistatin A prevents HIV-1 reactivation from latency,” MBio, vol. 6, no. 4, article e00465-15, 2015.
View at: Publisher Site | Google Scholar
E. Besnard, S. Hakre, M. Kampmann et al., “The mTOR complex controls HIV latency,” Cell Host & Microbe, vol. 20, no. 6, pp. 785–797, 2016.
View at: Google Scholar
R. B. Pollard, J. K. Rockstroh, G. Pantaleo et al., “Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4×: a phase 2 randomised, double-blind, placebo-controlled trial,” The Lancet Infectious Diseases, vol. 14, no. 4, pp. 291–300, 2014.
View at: Publisher Site | Google Scholar
K. Deng, M. Pertea, A. Rongvaux et al., “Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations,” Nature, vol. 517, no. 7534, pp. 381–385, 2015.
View at: Publisher Site | Google Scholar
C. L. Gay, M. A. DeBenedette, I. Y. Tcherepanova et al., “Immunogenicity of AGS-004 dendritic cell therapy in patients treated during acute HIV infection,” AIDS Research and Human Retroviruses, vol. 34, no. 1, pp. 111–122, 2018.
View at: Google Scholar
R. T. Gandhi, D. S. Kwon, E. A. Macklin et al., “Immunization of HIV-1-infected persons with autologous dendritic cells transfected with mRNA encoding HIV-1 gag and nef: results of a randomized, placebo-controlled clinical trial,” Journal of Acquired Immune Deficiency Syndromes, vol. 71, no. 3, pp. 246–253, 1999.
View at: Google Scholar
C. Sgadari, P. Monini, A. Tripiciano et al., “Continued decay of HIV proviral DNA upon vaccination with HIV-1 tat of subjects on long-term ART: an 8-year follow-up study,” Frontiers in Immunology, vol. 10, article 233, 2019.
View at: Google Scholar
M. P. Davenport, D. S. Khoury, D. Cromer, S. R. Lewin, A. D. Kelleher, and S. J. Kent, “Functional cure of HIV: the scale of the challenge,” Nature Reviews Immunology, vol. 19, no. 1, pp. 45–54, 2019.
View at: Publisher Site | Google Scholar
G. Tapia, J. F. Højen, M. Ökvist et al., “Sequential Vacc-4x and romidepsin during combination antiretroviral therapy (cART): immune responses to Vacc-4x regions on p 24 and changes in HIV reservoirs,” Journal of Infection, vol. 75, no. 6, pp. 555–571, 2017.
View at: Google Scholar
S. Leth, M. H. Schleimann, S. K. Nissen et al., “Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony- stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial,” The Lancet HIV, vol. 3, no. 10, pp. e463–e472, 2016.
View at: Publisher Site | Google Scholar
K. J. Bar, M. C. Sneller, L. J. Harrison et al., “Effect of HIV antibody VRC01 on viral rebound after treatment interruption,” New England Journal of Medicine, vol. 375, no. 21, pp. 2037–2050, 2016.
View at: Google Scholar
P. Mendoza, H. Gruell, L. Nogueira et al., “Combination therapy with anti-HIV-1 antibodies maintains viral suppression,” Nature, vol. 561, no. 7724, pp. 479–484, 2018.
View at: Publisher Site | Google Scholar
C. L. Lu, D. K. Murakowski, S. Bournazos et al., “Enhanced clearance of HIV-1–infected cells by broadly neutralizing antibodies against HIV-1 in vivo,” Science, vol. 352, no. 6288, pp. 1001–1004, 2016.
View at: Google Scholar
J. Niessl, A. E. Baxter, P. Mendoza et al., “Combination anti-HIV-1 antibody therapy is associated with increased virus- specific T cell immunity,” Nature Medicine, vol. 26, no. 2, pp. 222–227, 2020.
View at: Publisher Site | Google Scholar
Y. Liu, W. Cao, M. Sun, and T. Li, “Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities,” Emerging Microbes & Infections, vol. 9, no. 1, pp. 194–206, 2020.
View at: Google Scholar
J. N. Brudno and J. N. Kochenderfer, “Chimeric antigen receptor T-cell therapies for lymphoma,” Nature Reviews Clinical Oncology, vol. 15, no. 1, pp. 31–46, 2018.
View at: Google Scholar
T. J. Fry, N. N. Shah, R. J. Orentas et al., “CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy,” Nature Medicine, vol. 24, no. 1, pp. 20–28, 2018.
View at: Publisher Site | Google Scholar
S. Ghorashian, A. M. Kramer, S. Onuoha et al., “Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR,” Nature Medicine, vol. 25, no. 9, pp. 1408–1414, 2019.
View at: Google Scholar
T. A. Wagner, “Quarter century of anti-HIV CAR T cells,” Current HIV/AIDS Reports, vol. 15, no. 2, pp. 147–154, 2018.
View at: Google Scholar
J. A. Sung, S. Patel, M. L. Clohosey et al., “HIV-specific, ex vivo expanded T cell therapy: feasibility, safety, and efficacy in ART-suppressed HIV-infected individuals,” Molecular Therapy, vol. 26, no. 10, pp. 2496–2506, 2018.
View at: Publisher Site | Google Scholar
M. Hale, T. Mesojednik, G. S. R. Ibarra et al., “Engineering HIV-resistant, anti-HIV chimeric antigen receptor T cells,” Molecular Therapy, vol. 25, no. 3, pp. 570–579, 2017.
View at: Google Scholar
K. Anthony-Gonda, A. Bardhi, A. Ray et al., “Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model,” Science Translational Medicine, vol. 11, no. 504, article aav5685, 2019.
View at: Google Scholar
M. N. Wykes and S. R. Lewin, “Immune checkpoint blockade in infectious diseases,” Nature Reviews Immunology, vol. 18, no. 2, pp. 91–104, 2018.
View at: Google Scholar
C. S. McGary, C. Deleage, J. Harper et al., “CTLA-4⁺PD-1⁻ memory CD4⁺ T cells critically contribute to viral persistence in antiretroviral therapy-suppressed, SIV-infected Rhesus macaques,” SIV-Infected Rhesus Macaques. Immunity, vol. 47, no. 4, pp. 776–788.e5, 2017.
View at: Publisher Site | Google Scholar
N. Chomont, M. El-Far, P. Ancuta et al., “HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation,” Nature Medicine, vol. 15, no. 8, pp. 893–900, 2009.
View at: Google Scholar
Z. Boyer and S. Palmer, “Targeting immune checkpoint molecules to eliminate latent HIV,” Frontiers in Immunology, vol. 9, article 2339, 2018.
View at: Google Scholar
C. L. Gay, R. J. Bosch, J. Ritz et al., “Clinical trial of the anti-PD-L1 antibody BMS-936559 in HIV-1 infected participants on suppressive antiretroviral therapy,” The Journal of Infectious Diseases, vol. 215, no. 11, pp. 1725–1733, 2017.
View at: Publisher Site | Google Scholar
G. Pantaleo and Y. Levy, “Therapeutic vaccines and immunological intervention in HIV infection: a paradigm change,” Current Opinion in HIV and AIDS, vol. 11, no. 6, pp. 576–584, 2016.
View at: Google Scholar
R. M. Van der Sluis, N. A. Kumar, R. D. Pascoe et al., “Combination immune checkpoint blockade to reverse HIV latency,” The Journal of Immunology, vol. 204, no. 5, pp. 1242–1254, 2020.
View at: Publisher Site | Google Scholar
B. Julg, L. Dee, J. Ananworanich et al., “Recommendations for analytical antiretroviral treatment interruptions in HIV research trials--report of a consensus meeting,” The Lancet HIV, vol. 6, no. 4, pp. e259–e268, 2019.
View at: Publisher Site | Google Scholar
J. Ananworanich and F. Barré-Sinoussi, “Is it time to abandon single intervention cure trials?” The Lancet HIV, vol. 2, no. 10, pp. e410–e411, 2015.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2022 Ruojing Bai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

779

Downloads

607

Citations