Multifarious immunotherapeutic approaches to cure HIV-1 infection.
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ABSTRACT:
SUBMITTER: Imami N
PROVIDER: S-EPMC4635699 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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Project description:Purpose of reviewA serious effort has begun to develop therapies that may be capable of eradicating established HIV infection in man. Because of the biological complexity of HIV infection that persists despite potent antiretroviral therapy, it is widely believed that if such therapies can be developed they will involve complex, multimodality approaches. We highlight some of the recent studies in this effort.Recent findingsAn inhibitor of histone deacetylase has been demonstrated to disrupt latency in man, and new histone deacetylase inhibitors have been identified. Other potential targets, such as histone methyltransferase, protein kinase C, and BRD4, have been recently studied. Model systems, both in primary cells and in animal models, are beginning to be validated. In the clinic, immune-based therapies to aid in the clearance of persistent infection are also being tested.SummaryIt is too early to know what combination eradication therapies for HIV infection will look like in the future, but candidate therapies and model systems to perform preclinical validation are beginning to take shape.
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Project description:Current strategies aimed to cure HIV infection are based on combined efforts to reactivate the virus from latency and improve immune effector cell function to clear infected cells. These strategies are primarily focused on CD8+ T cells and approaches are challenging due to insufficient HIV antigen production from infected cells and poor HIV-specific CD8+ T cells. ?? T cells represent a unique subset of effector T cells that can traffic to tissues, and selectively target cancer or virally infected cells without requiring MHC presentation. We analyzed whether ?? T cells represent a complementary/alternative immunotherapeutic approach towards HIV cure strategies. ?? T cells from HIV-infected virologically suppressed donors were expanded with bisphosphonate pamidronate (PAM) and cells were used in autologous cellular systems ex vivo. These cells (a) are potent cytotoxic effectors able to efficiently inhibit HIV replication ex vivo, (b) degranulate in the presence of autologous infected CD4+ T cells, and (c) specifically clear latently infected cells after latency reversal with vorinostat. This is the first proof of concept to our knowledge showing that ?? T cells target and clear autologous HIV reservoirs upon latency reversal. Our results open potentially new insights into the immunotherapeutic use of ?? T cells for current interventions in HIV eradication strategies.
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Project description:Therapeutic approaches towards a functional cure or eradication of HIV have gained renewed momentum upon encouraging data emerging from studies in SIV monkey models and recent results from human clinical studies. However, a multitude of questions remain to be addressed, including how to deal with the latent viral reservoir, how to boost the host immune response to the virus and what the hurdles are to reach relevant viral compartments in the body. Advances have been made especially with regard to identifying agents that can reactivate the latent virus in vivo and boost the cellular and humoral immunity, but it remains largely unclear whether any of these strategies can awaken a sufficiently large fraction of the viral reservoir and whether the boosted immunity can prevent rapid viral replication once antiretroviral treatments are stopped.
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Project description:Purpose of reviewCombination antiretroviral therapy (ART) has enabled tremendous progress in suppressing HIV replication in infected patients. However, ART alone cannot eradicate HIV and its latent, persisting reservoirs. Novel approaches are needed to eradicate the virus or achieve functional cure in the absence of ART.Recent findingsAdoptive T-cell therapies were initially tested in HIV-infected individuals with limited efficiency. Benefiting from new and improved methodologies, an increasing array of CAR T-cell therapies has been successfully developed in the cancer immunotherapy field, demonstrating promising new avenues that could be applied to HIV. Numerous studies have characterized various HIV-specific CAR constructs, types of cytolytic effector cells, and CAR-expressing cells' trafficking to the reservoir compartments, warranting further in-vivo efforts. Notably, the ability of CAR cells to persist and function in low-antigen environments in vivo, that is, in ART-suppressed patients, remains unclear.SummaryDespite promising results in preclinical studies, only a handful of clinical trials have been initiated worldwide. Several obstacles remain prior to successful application of HIV-specific CAR T-cell therapies in patients. In this review, we survey the current state of the field, and address paths towards realizing the goal of an efficacious HIV CAR T-cell product.
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Project description:Today HIV infection cannot be cured due to the presence of a reservoir of latently infected cells inducing a viral rebound upon treatment interruption. Hence, the latent reservoir is considered as the major barrier for an HIV cure. So far, efforts to completely eradicate the reservoir via a shock-and-kill approach have proven difficult and unsuccessful. Therefore, more research has been done recently on an alternative block-and-lock functional cure strategy. In contrast to the shock-and-kill strategy that aims to eradicate the entire reservoir, block-and-lock aims to permanently silence all proviruses, even after treatment interruption. HIV silencing can be achieved by targeting different factors of the transcription machinery. In this review, we first describe the underlying mechanisms of HIV transcription and silencing. Next, we give an overview of the different block-and-lock strategies under investigation.
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Project description:Gut mucosal damage, associated with Human Immunodeficiency Virus-1 (HIV) infection, is characterized by depletion in CD4+ T cells and persistent immune activation as a result of early epithelial barrier disruption and systemic translocation of microbial products. Unique approaches in studying both HIV infection in human patients and Simian Immunodeficiency Virus (SIV) infection in rhesus macaques have provided critical evidence for the pathogenesis and treatment of HIV/AIDS. While there is vast resemblance between SIV and HIV infection, the development of gut dysbiosis attributed to HIV infection in chronically infected patients has not been consistently reported in SIV infection in the non-human primate model of AIDS, raising concerns for the translatability of gut microbiome studies in rhesus macaques. This review outlines our current understanding of gut microbial signatures across various stages of HIV versus SIV infection, with an emphasis on the impact of microbiome-based therapies in restoring gut mucosal immunity as well as their translational potential to supplement current HIV cure efforts.
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Project description:Despite the ability of antiretroviral therapy to minimize human immunodeficiency virus type 1 (HIV-1) replication and increase the duration and quality of patients' lives, the health consequences and financial burden associated with the lifelong treatment regimen render a permanent cure highly attractive. Although T cells play an important role in controlling virus replication, they are themselves targets of HIV-mediated destruction. Direct genetic manipulation of T cells for adoptive cellular therapies could facilitate a functional cure by generating HIV-1-resistant cells, redirecting HIV-1-specific immune responses, or a combination of the two strategies. In contrast to a vaccine approach, which relies on the production and priming of HIV-1-specific lymphocytes within a patient's own body, adoptive T-cell therapy provides an opportunity to customize the therapeutic T cells prior to administration. However, at present, it is unclear how to best engineer T cells so that sustained control over HIV-1 replication can be achieved in the absence of antiretrovirals. This review focuses on T-cell gene-engineering and gene-editing strategies that have been performed in efforts to inhibit HIV-1 replication and highlights the requirements for a successful gene therapy-mediated functional cure.
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