Hiv And The Immune System – Center of Molecular Inflammation Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Norway
A major obstacle to HIV treatment is the population of long-lived cells harboring latent but highly infectious virus, which is not eliminated by antiretroviral therapy (ART) and remain undifferentiated from uninfected cells. However, ART does not cure HIV, the side effects of treatment are still present, and the constant global increase in new infections makes it urgent to find ART- free HIV eradication or treatment of HIV-seropositive patients. The approach to HIV treatment is often based on “shock and kill” which involves the use of a combination of drugs to reactivate the latent virus together with strategies to stimulate or supplement the virus. immune system to eliminate latent infections. Traditionally, these strategies have used CD8+ cytotoxic lymphocytes (CTL) but have encountered many problems. Enhancing the immune system, such as γδ T cells, may provide another way to treat HIV. γδ T cells have antiviral and cytotoxic properties that have been shown to directly inhibit HIV infection and specifically eliminate replicating, latently infected cells in vitro. In particular, their anatomical and MHC-recognition antigen-independent access to the immune system can overcome many of the obstacles faced by CTL strategies. In this review, we discuss the role of γδ T cells in immunity and HIV infection as well as their current use in cancer treatment strategies. We present these data as a way to consider the use of γδ T cells for HIV treatment strategies and highlight some important insights that need to be investigated.
Hiv And The Immune System
The road to a complete cure for HIV is lined with potholes and dead ends. Clearing cellular reservoirs and anatomical reservoirs presents special challenges. Latent virus can suppress the immune response by integrating into the host’s genome on resting CD4 + T cells and entering a state of quiescence. Despite the cessation of new virion production, the risk of infection is controlled by the clonal expansion of the HIV virus (Chomont et al., 2009; Lee et al., 2020). Additional complications include immunosuppression or difficult-to-reach anatomical sites such as the central nervous system, colon, or secondary lymphoid tissue where the infection can develop. antiretroviral therapy (ART) (Barton et al., 2016; Bronnimann et al., 2018; Denton et al., 2019; McManus et al., 2019). To date, HIV treatment has only been successful in two HIV-seropositive patients who also have myeloid leukemia or Hodgkin’s lymphoma. Two individuals received stem cell transplants with a homozygous mutation in the CCR5 gene (CCR5Δ32/Δ32), a chemokine receptor that facilitates infection (Gero Hütter et al., 2009; Gupta et al., 2019). However, this method is unlikely to be feasible for widespread use. A safer, more efficient method, called “shock and kill” has been the focus of research for the past 15 years (Sengupta and Siliciano, 2018). This strategy is based on the use of combination drugs, or latency-reversing agents (LRAs), to reactivate the virus after treatment to improve the immune system. can eliminate HIV replication (Deeks, 2012; Barton et al. , 2013; Archin et al., 2014). A recent review by Kim et al. visit the local and regional authorities now during the various stages of the investigation (Kim et al., 2018). LRAs are grouped according to their main target in the body. Epigenetic modifiers include histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), DNA methyltransferase inhibitors (DNMTi), bromodomain inhibitors (BRDi), and protein kinase C (PKC) agonists (Margolis et al., 2016). Non-epigenetic LRAs include agonists for the endosomal pattern recognition receptors TLR7, TLR8 and TLR9, which have been shown to cause infection and prevent HIV infection in the immune system (Offersen et al. , 2016; Lim et al., 2018; Meas et al., 2020). Unfortunately, within these categories, only a handful of drugs have advanced to animal studies or human clinical trials. These include the HDACis vorinostat, panobinostat, and romidepsin, the PI3K/Akt inhibitor disulfiram, the PKC agonists bryostatin and ingenol, and the TLR9 agonist MGN1703. With the exception of bryostatin, all of these compounds resulted in an increase in viral mRNA levels, although this was not accompanied by viral suppression (Kim et al., 2018). Therefore, the possibility of shock and killing strategies depends on the discovery and development of new LRAs with different methods of action and may focus on other methods. experience
Aids Vs. Autoimmune Diseases
Most of the LRAs now reactivate the virus by disrupting 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 potent driver of the replication cycle (Nabel and Baltimore, 1987; Hiscott et al., 2001). This approach is not limited to infectious diseases and therefore the toxicity of the immune system is still a concern (Bratland et al., 2011). An immunogenic effect of LRA on different effector immune cell subsets has also been reported, presenting an additional challenge when trying to reconstitute the entire immune system (Garrido et al., 2016; Walker -Sperling et al., 2016). Despite these concerns, combined LRAs have been shown to induce synergism and potentially suppress T-cell activation. Darcis et al. showed an increase in efficacy across multiple latency models in vitro and ex vivo when one of the PKC agonists bryostatin or ingenol was paired with the bromodomain inhibitor JQ1. Building on this work, Albert et al. found both an increase in efficiency and a decrease in activation when bryostatin is paired with HDACis (Darcis et al., 2015; Albert et al., 2017). In addition, modulation of the non-canonical NF-κB pathway by other mitochondrial-derived activator of caspase (SMAC) mimetics can contribute to the interest in shock and kill strategies. (Pache et al., 2015). Induction of this pathway results in increased NF-κB-driven transcription, thus potentially avoiding the side effects seen with LRAs in the past. Recently, the SMAC mimetic AZD5582 was shown to induce effective HIV protection from deep anatomical reservoirs of humanized mice and nonhuman primates. These studies, although very promising, require further analysis and testing in humans (Sampey et al., 2018; Nixon et al., 2020). These reversible latency improvements must be combined with balanced antiretroviral therapy to effectively eradicate and eliminate chronic HIV infection.
The use of the immune system CTL immune system is the most investigated shock and kill approach (Liv et al., 1994; Santra et al., 2010). This is highlighted by the development of HIV-specific ex vivo expanded T cells (HXTC) that can recognize multiple viral epitopes. HXTCs have been shown to be safe for transplantation in humans but have little effect on disease clearance in the absence of replication (Sung et al., 2018). Unfortunately, some LRAs including HDACis and PKC agonists may have an effect on CTL function that requires further investigation (Clutton and Jones, 2018). The extent to which these effects occur in vivo and among other classes of LRAs is the subject of current clinical studies. In addition, CTL-based strategies are still struggling with problems caused by the escape of the virus, the immune system, and the inability to enter the body. anatomical reservoirs, including the B-cell follicle (Day et al., 2006; Connick et al., 2007; Deng et al. , 2015). Other strategies using NK cells have begun to be explored, and their potential as an anti-HIV agent has recently been reviewed (Desimio et al., 2019).
In addition, the use of γδ T cells may provide new therapeutic approaches that may overcome some of the challenges faced by αβ T cell strategies. γδ T cells have many antiviral properties including cytolytic activity against HIV (Wallace et al., 1996). In particular, our group showed that Vδ2 T cells from ART-treated HIV-infected individuals target and kill reactivated autologous HIV-infected CD4+ T cells in vitro, creating the first proof-of- suggesting the potential of Vδ2 T cells to be used in an immunotherapeutic approach to HIV treatment (Garrido et al., 2018). Additional evidence from our recent work suggests a correlation of γδ T-cell cytotoxic capacity with a lower rate of reactivation of HIV in culture. regulation of resting CD4+ T cells from ART-suppressed HIV-seropositive individuals (James et al., 2020). In addition, activated γδ T cells induce adjuvant immune responses including HIV-specific T cell responses (Poccia et al., 2009). The therapeutic use of γδ T cells to treat HIV is still less studied compared to cancer, but the first findings combined with the investigation of their biology more research is needed on their ability to prevent disease.
The γδ T cell is a special type of innate-like T lymphocytes that have an attractive alternative to the conventional αβ T cells, which are currently controlled by cell-based immunotherapies. Since their discovery in the 1980s, γδ T cells have been shown to be useful in tumor detection, disease fighting and autoimmunity (Tanaka, 2006; Kabelitz, 2011; Vantourout and Hayday , 2013; Silva-Santos et al., Law 201. al.., 2015; et al., 2017). Their definition is a T cell receptor (TCR) that has distinct γ and δ chains that recognize nonpeptidic antigens in the absence of
Immune Checkpoint Blockade In Hiv
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