Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators

Abstract

The presence of T cell reservoirs in which human immunodeficiency virus (HIV) establishes latency by integrating into the host genome represents a major obstacle to an HIV cure and has prompted the development of strategies aimed at the eradication of HIV from latently infected cells. The “shock-and-kill” strategy is one of the most pursued approaches to the elimination of viral reservoirs. Although several latency-reversing agents (LRAs) have shown promising reactivation activity, they have failed to eliminate the cellular reservoir. In this study, we evaluated a novel immune system-mediated approach to clearing the HIV reservoir, based on a combination of innate immune stimulation and epigenetic reprogramming. The combination of the STING agonist cGAMP (cyclic GMP-AMP) and the FDA-approved histone deacetylase inhibitor resminostat resulted in a significant increase in HIV proviral reactivation and specific apoptosis in HIV-infected cells in vitro. Reductions in the proportion of HIV-harboring cells and the total amount of HIV DNA were also observed in CD4+ central memory T (TCM) cells, a primary cell model of latency, where resminostat alone or together with cGAMP induced high levels of selective cell death. Finally, high levels of cell-associated HIV RNA were detected ex vivo in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from individuals on suppressive antiretroviral therapy (ART). Although synergism was not detected in PBMCs with the combination, viral RNA expression was significantly increased in CD4+ T cells. Collectively, these results represent a promising step toward HIV eradication by demonstrating the potential of innate immune activation and epigenetic modulation for reducing the viral reservoir and inducing specific death of HIV-infected cells. IMPORTANCE One of the challenges associated with HIV-1 infection is that despite antiretroviral therapies that reduce HIV-1 loads to undetectable levels, proviral DNA remains dormant in a subpopulation of T lymphocytes. Numerous strategies to clear residual virus by reactivating latent virus and eliminating the reservoir of HIV-1 (so-called “shock-and-kill” strategies) have been proposed. In the present study, we use a combination of small molecules that activate the cGAS-STING antiviral innate immune response (the di-cyclic nucleotide cGAMP) and epigenetic modulators (histone deacetylase inhibitors) that induce reactivation and HIV-infected T cell killing in cell lines, primary T lymphocytes, and patient samples. These studies represent a novel strategy for HIV eradication by reducing the viral reservoir and inducing specific death of HIV-infected cells.

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

“…A defective STING pathway may render human T cells vulnerable to other pathogens, due to low production of IFN, including other retroviruses (e.g., human T-lymphotropic virus type 1), or viruses (e.g., VZV and HHV 6) that replicate through a DNA ( 18 ). Conversely, other downstream signaling of STING than IFN, like NFκB, are less affected in human T cells, as shown in HIV-1 lymphocytes ( 38 ). This is also observed in SAVI syndromes (induced by gain of function of STING), where over-activation of STING by viruses can lead to T cell hyper-responsiveness with IL-6 secretion (as well as T cell exhaustion, and autophagy-induced lymphopenia).…”

Effect of combination antiretroviral therapy on human immunodeficiency virus 1 specific antibody responses in subtype-C infected children

“…Moreover, any treatment interruption or drug-resistant mutations acquired by the virus can lead to rapid viral rebound. Several LRAs have been employed in an attempt to reactivate latent viruses and clear the viral reservoirs [3,43]. In a recent report, both for in vitro and in ex vivo patient samples, a combination of activators of HIV-1 specific innate immune response and epigenetic modulators has been shown to be effective in latency reversal and targeted killing of HIV-infected T cells [43].…”

“…Several LRAs have been employed in an attempt to reactivate latent viruses and clear the viral reservoirs [3,43]. In a recent report, both for in vitro and in ex vivo patient samples, a combination of activators of HIV-1 specific innate immune response and epigenetic modulators has been shown to be effective in latency reversal and targeted killing of HIV-infected T cells [43]. Furthermore, an ex vivo study demonstrated the elimination of recrudesced HIV-1 latently infected cells treated with a combination of nnAb along with nAbs of diverse epitope specificities, implicating that administration of a combination of mAbs with distinct epitope specificities should be considered in strategies to clear latent HIV-1 infection in vivo [44].…”

Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion

“…The type-I IFNs are the principal first line of defense against viral infections, and failure to mount an effective IFN response leads to widespread systemic infection in the host ( Huang et al, 2019 ). With respect to the human immunodeficiency virus (HIV), innate immunity is of paramount importance to control HIV-1 infection as it is the principal way not only to prevent widespread establishment of latent reservoirs, but also to deplete them ( Soper et al, 2017 ; Palermo et al, 2019 ). The success of other strategies to eliminate latent reservoirs for a functional cure could be enhanced if the innate immunity against HIV-1 is strengthened ( Altfeld and Gale, 2015 ).…”