Pathways towards human immunodeficiency virus elimination

Dash, Prasanta K.; Kevadiya, Bhavesh D.; Su, Hang; Banoub, Mary; Gendelman, Howard E.

doi:10.1016/j.ebiom.2020.102667

Cited by 13 publications

(5 citation statements)

References 132 publications

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“…Although 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][40][41]. Therefore, more sophisticated distribution systems ensuring the delivery of therapeutics to all tissues harboring HIV sanctuary need to be pursued [42,43].…”

Section: Key Pointsmentioning

confidence: 99%

Recent advances on anti-HIV chimeric antigen receptor-T-cell treatment to provide sustained HIV remission

Su,

Mueller,

Goldstein

2024

Current Opinion in HIV and AIDS

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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 of 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 and posttreatment controllers 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 elite controllers. CAR-T cells can exhibit superior antiviral activity as compared with 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.

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Section: Key Pointsmentioning

confidence: 99%

Recent advances on anti-HIV chimeric antigen receptor-T-cell treatment to provide sustained HIV remission

Su,

Mueller,

Goldstein

2024

Current Opinion in HIV and AIDS

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“…Survival of CD4 + T cells harboring producer proviruses not only relies on downregulation of apoptosis and IFN programs, but also resistance to killing. 50 HIV-specific CD8 + T cells, which recognize viral peptides presented in complex with HLA Class-I (HLA-A, -B, and -C), are thought to be one of the most important mediators of viral control. 51 This appears to be the case even in the setting of ART, as CD8-depletion in the nonhuman primate model leads to loss of viral suppression 52 .…”

Section: Non-suppressible Viremia Does Not Increase Hiv-specific Cd8 ...mentioning

confidence: 99%

Viral and Host Mediators of Non-Suppressible HIV-1 Viremia

Mohammadi

Etemad

Zhang

et al. 2023

Preprint

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Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combination antiretroviral therapy (ART) and in the absence of significant drug resistance. Here, we show that plasma NSV sequences are comprised primarily of large clones without evidence of viral evolution over time. We defined proviruses that contribute to plasma viremia as producer, and those that did not as non-producer. Compared to ART-suppressed individuals, NSV participants had a significantly larger producer reservoir. Producer proviruses were enriched in chromosome 19 and in proximity to the activating H3K36me3 epigenetic mark. CD4+ cells from NSV participants demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, NSV participants showed no elevation in HIV-specific CD8+ cell responses and producer proviruses were enriched for HLA escape mutations. We identified critical host and viral mediators of NSV that represent potential targets to disrupt HIV persistence and promote viral silencing.

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“…This strategy is known as shock-and-kill ( Figure 2 ) [ 83 , 84 , 85 ]. As of today, more than 300 molecules have been evaluated in vitro to reactivate latent HIV-1, including epigenetic, chromatin, signaling, and transcription modulators [ 86 , 87 ]. The chromatin-modifying agents, HDAC inhibitors (e.g., Vorinostat, Romidepsin and Panobinostat), are the most characterized class of LRAs explored in shock-and-kill approaches [ 86 ].…”

Section: Latency Reversal Agentsmentioning

confidence: 99%

Block-And-Lock: New Horizons for a Cure for HIV-1

Moranguinho

Valente

2020

Viruses

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HIV-1/AIDS remains a global public health problem. The world health organization (WHO) reported at the end of 2019 that 38 million people were living with HIV-1 worldwide, of which only 67% were accessing antiretroviral therapy (ART). Despite great success in the clinical management of HIV-1 infection, ART does not eliminate the virus from the host genome. Instead, HIV-1 remains latent as a viral reservoir in any tissue containing resting memory CD4+ T cells. The elimination of these residual proviruses that can reseed full-blown infection upon treatment interruption remains the major barrier towards curing HIV-1. Novel approaches have recently been developed to excise or disrupt the virus from the host cells (e.g., gene editing with the CRISPR-Cas system) to permanently shut off transcription of the virus (block-and-lock and RNA interference strategies), or to reactivate the virus from cell reservoirs so that it can be eliminated by the immune system or cytopathic effects (shock-and-kill strategy). Here, we will review each of these approaches, with the major focus placed on the block-and-lock strategy.

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Pathways towards human immunodeficiency virus elimination

Cited by 13 publications

References 132 publications

Recent advances on anti-HIV chimeric antigen receptor-T-cell treatment to provide sustained HIV remission

Recent advances on anti-HIV chimeric antigen receptor-T-cell treatment to provide sustained HIV remission

Viral and Host Mediators of Non-Suppressible HIV-1 Viremia

Block-And-Lock: New Horizons for a Cure for HIV-1

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