Edited by: Maria Salgado, IrsiCaixa, Spain
Reviewed by: Markus Haug, Norwegian University of Science and Technology, Norway; Vicente Planelles, The University of Utah, United States
This article was submitted to Clinical Microbiology, a section of the journal Frontiers in Cellular and Infection Microbiology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The major barrier to HIV cure is a population of long-lived cells that harbor latent but replication-competent virus, are not eliminated by antiretroviral therapy (ART), and remain indistinguishable from uninfected cells. However, ART does not cure HIV infection, side effects to treatment still occur, and the steady global rate of new infections makes finding a sustained ART-free HIV remission or cure for HIV-seropositive individuals urgently needed. Approaches aimed to cure HIV are mostly based on the “shock and kill” method that entails the use of a drug compound to reactivate latent virus paired together with strategies to boost or supplement the existing immune system to clear reactivated latently infected cells. Traditionally, these strategies have utilized CD8+ cytotoxic lymphocytes (CTL) but have been met with a number of challenges. Enhancing innate immune cell populations, such as γδ T cells, may provide an alternative route to HIV cure. γδ T cells possess anti-viral and cytotoxic capabilities that have been shown to directly inhibit HIV infection and specifically eliminate reactivated, latently infected cells
The road to developing a complete cure for HIV is fraught with potholes and dead ends. Clearing cellular and anatomical reservoirs provides a unique set of challenges. Latent virus is able to evade immune responses by integrating into the host genome of resting CD4+ T cells and entering a state of dormancy. Despite the cessation of new virion production, viral persistence is maintained by clonal expansion of HIV-infected cells (Chomont et al.,
The majority of current LRAs reactivate viral transcription through induction of the canonical NF-κB pathway. NF-κB is a host transcription factor that interacts with the HIV LTR and has been shown to be a powerful driver of the viral replication cycle (Nabel and Baltimore,
Harnessing the natural antiviral CTL immune response has been the most investigated strategy for the “shock and kill” approach (Borrow et al.,
Additionally, the use of γδ T cells could offer a novel therapeutic avenue that may overcome some of the challenges facing traditional αβ T cell strategies. γδ T cells possess a range of antiviral function including cytolytic activity against HIV-infected cells (Wallace et al.,
The γδ T cell lineage is a unique subset of innate-like T lymphocytes that offer an attractive alternative to conventional αβ T cells, which predominate in current cell-based immunotherapies. Since their discovery in the 1980's, γδ T cells have been shown to contribute to tumor surveillance, fighting infectious disease, and autoimmunity (Tanaka,
Human γδ T cells account for 0.5–10% of circulating T cells and are classified into two major subpopulations based on the δ chain usage, Vδ1 and Vδ2 T cells. Smaller subpopulations expressing Vδ3 and Vδ5 share a degree of similar functions as Vδ1 T cells but the extent of their involvement in immunity is unknown (Takihara et al.,
Vδ1 T cells are capable of recognizing self-antigen lipids presented within the MHC-like CD1 protein family, but the specific ligand they recognize remains unknown. In contrast, Vδ2 T cell ligand has been extensively characterized. Vδ2 T cells undergo activation following recognition of low-molecular-weight phosphorylated compounds referred to as phosphoantigens (P-Ags) (Jomaa et al.,
γδ T cells are further characterized by a diverse set of membrane bound receptors and cytokine production capability that denotes a high degree of polyfunctionality as regulatory and effector cells (Vantourout and Hayday,
Most γδ T cells express the NK cell receptors, DNAM-1 and NKG2D, the latter of which acts as a co-stimulatory signal upon recognition of stress markers MICA, MICB, and ULBPs. Activation through this pathway has a 2-fold effect resulting in the secretion of pro-inflammatory cytokines TNF-α and IFN-γ as well as direct cytolytic activity mediated by the release of perforins and granzymes (Wu et al.,
When assessing γδ T cells' prospect as a novel HIV cure therapeutic, it is crucial to understand the effects of both HIV pathogenesis and ART on γδ T cell populations. Pauza et al. have recently reviewed the initial studies of γδ T cell dysregulation in the context of HIV disease progression and treatment (Pauza et al.,
Although the Vδ2:Vδ1 inverted frequencies are never restored, early initiation of ART has been shown to partially restore the loss of γδ T cell function in HIV-seropositive individuals. Casetti et al. found that introducing treatment during primary infection reconstitutes Vδ1 T cell direct cytotoxic capabilities but antiviral chemokine production of CCL4 (MIP-1β) remains dampened despite early intervention. Moreover, both Vδ2 T cell cytotoxic function and pro-inflammatory cytokine production appear to be negatively impacted early on and are unable to be recovered regardless of the timing of ART (Casetti et al.,
In addition to altering γδ T cell frequencies, HIV infection modulates the expression of NK cell-like and potentially other receptors, directly modifying their cytotoxic capabilities (Poccia et al.,
Implementation of an allogeneic adoptive cell therapy. (1)
One of the advantages of using γδ T cells is that they can be easily manipulated
In addition to
Specific targeting and activation of γδ T cell effectors. The transduction of HIV-specific αβ TCRs or chimeric antigen receptors (CAR) combined with the unique antigen recognition of γδ T cells could reduce off-target toxicity issues. Target-specific activation of γδ T cells can lead to the exertion of cytotoxic functions through a number of different mechanisms: (i) direct cytolysis of malignant or infected cells through the release of cytotoxic granules containing perforin and other granzymes; (ii) Induction of apoptosis by Fas Ligand and TRAIL death receptors; and (iii) antibody-dependent cellular cytotoxicity (ADCC) triggered by binding of the Fcγ receptor CD16 to the constant region of IgG antibody-coated targets. In addition to secreting pro-inflammatory cytokines interferon-γ (IFN-γ) and tumor-necrosis factor-α (TNF-α), γδ cells also produce CC-chemokines that inhibit CCR5-dependent entry of HIV virions into CD4+ T cells. Created with
Due to Vδ2 T cells susceptibility to CCR5-mediated cell death and direct infection, the allogeneic adoptive cell therapy would require either finding CCR5Δ32 homozygous healthy individuals or
Manipulation of CCR5 expression. The expression of CCR5 leaves Vδ2 T cells susceptible to direct infection as well as activation of the p38-mediated cell death signaling pathway. (1) Ablation of the CCR5 gene could confer a degree of resistance to effector subsets prior to adoptive transfer generating (2) HIV-resistant γδ T cells. Traditional gene editing strategies have utilized zinc-finger nucleases or transcription activator-like effector nucleases (TALENs) to recognize and cleave specific genomic sequences. More recently, focus has shifted to the use of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated protein 9 (Cas9) that rely on a small single guide RNA that is complementary to the target gene sequence. Created with
Although the anti-HIV capacity of γδ cells to inhibit viral replication is well-documented (Wallace et al.,
The study of allogeneic γδ T cell transfer to treat chronic disease is still in its infancy but there have been recent developments in the cancer field. Haploidentical hematopoietic stem cell transplantation markedly improved survival rates of patients with hematologic cancers (Godder et al.,
These studies provide the possibility that allogeneic transfer may be a safe, feasible treatment for certain cancers. Whether this applies to relatively healthier ART-treated individuals will require direct studies to sufficiently assess safety and efficacy for HIV cure. Nevertheless, as a byproduct of the cancer trials, untethering from strict HLA-matching engenders the possibility of generating an off-the-shelf repository of γδ T cells to treat disease. Improvements to
It is important to determine how these compounds impact the cytotoxic capacity of effector cells in HIV-seropositive individuals. Epigenetic modifiers, belonging to the same categories as current LRAs, have been shown to affect γδ T cell or NK cell functions. Current information about the impact of HDACis on γδ T cells is limited and comes from cancer studies using Valproic acid (Bhat et al.,
A number of fundamental questions that require investigation will need to be answered prior to the clinical implementation of γδ T cells in HIV therapy. How do γδ T cells recognize HIV infected cells? Do allogeneic γδ T cells specifically target and kill reactivated latently infected cells similar to autologous cells? Will the Vδ2 subpopulation alone be sufficient or will both subpopulations be required to maximize efficacy of an allogeneic approach? Additionally, what is the ideal cytotoxic phenotype for clearing reactivated latently infected cells and how will this phenotype be produced through
Targeted therapy utilizing the potent cytotoxic capabilities of γδ T cells is a compelling avenue of research that has broad implications in treating a variety of diseases. Extensive focus within the field of cancer continues to produce a steady stream of innovations that may boost the efficacy of γδ T cell therapies. Advances in latency reversal combined with the allogeneic transfer of expanded effector γδ T cells could provide a dynamic two-prong strategy to cure persistent HIV infection. While our recent work showed the feasibility of using γδ T cells to specifically target and kill HIV infected cells (Garrido et al.,
All authors have contributed to writing, editing, and reviewing the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Authors would like to thank the HIV-seropositive donors for their contribution to science.