Multifarious immunotherapeutic approaches to cure HIV-1 infection

Imami, Nesrina; Herasimtschuk, Anna

doi:10.1080/21645515.2015.1021523

Cited by 5 publications

(5 citation statements)

References 60 publications

(83 reference statements)

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“…Some studies have previously shown that the cytokine cascade found in AHI might contribute to control of viral replication223. However, both the extent and duration of exponential cytokine expansion during acute infection are poorly understood22224.…”

Section: Discussionmentioning

confidence: 99%

Cytokine cascade and networks among MSM HIV seroconverters: implications for early immunotherapy

Huang

Liu

Meyers

et al. 2016

Sci Rep

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The timing, intensity and duration of the cytokine cascade and reorganized interrelations in cytokine networks are not fully understood during acute HIV-1 infection (AHI). Using sequential plasma samples collected over three years post-infection in a cohort of MSM HIV-1 seroconvertors, we determined the early kinetics of cytokine levels during FiebigI-IV stages using Luminex-based multiplex assays. Cytokines were quantified and relationships between cytokines were assessed by Spearman correlation. Compared with HIV-negative MSM, HIV-infected individuals had significantly increased multiple plasma cytokines, including GM-CSF, IFN-α2, IL-12p70, IP-10 and VEGF, during both acute and chronic stages of infection. Furthermore, rapid disease progressors (RDPs) had earlier and more robust cytokine storms, compared with slow disease progressors (SDPs) (49.6 days vs. 74.9 days, respectively; 6.7-fold vs. 3.7-fold change of cytokines, respectively), suggesting the faster and stronger cytokine storm during AHI could promote disease progression. On the other hand, HIV-1 infection induced more interlocked cytokines network, establishing new strong correlations and imposing a higher rigidity. There were, respectively, 146 (44.9%) statistically significant correlations of cytokines in RDPs and 241 (74.2%) in SDPs (p < 0.001). This study suggests that immunomodulatory interventions aimed at controlling cytokine storm in AHI may be beneficial to slow eventual disease progression.

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Section: Discussionmentioning

confidence: 99%

Cytokine cascade and networks among MSM HIV seroconverters: implications for early immunotherapy

Huang

Liu

Meyers

et al. 2016

Sci Rep

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“…More advanced multifaceted immunotherapeutic approaches were able to improve HIV-1-specific T-cell responses, reduce immune activation, and increase CD4 T-lymphocyte counts 10 . The latest developments including better antigen selection, more efficient vaccine delivery systems, combined interventions that stimulate the immune response and prevent new rounds of viral infection, as well as programming of T cell killers, are making functional HIV cure a feasible goal 11 – 13 . We proposed to complement the functional cure by vaccinating against primary drug-resistant mutations in reverse transcriptase, protease, integrase, and gp41, hypothesizing that such immunotherapy may create a “bottleneck” for viral evolution towards the resistant phenotype(s) 8 , 14 – 16 .…”

Section: Introductionmentioning

confidence: 99%

Codon optimization and improved delivery/immunization regimen enhance the immune response against wild-type and drug-resistant HIV-1 reverse transcriptase, preserving its Th2-polarity

Latanova

Petkov

Kilpeläinen

et al. 2018

Sci Rep

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DNA vaccines require a considerable enhancement of immunogenicity. Here, we optimized a prototype DNA vaccine against drug-resistant HIV-1 based on a weak Th2-immunogen, HIV-1 reverse transcriptase (RT). We designed expression-optimized genes encoding inactivated wild-type and drug-resistant RTs (RT-DNAs) and introduced them into mice by intradermal injections followed by electroporation. RT-DNAs were administered as single or double primes with or without cyclic-di-GMP, or as a prime followed by boost with RT-DNA mixed with a luciferase-encoding plasmid (“surrogate challenge”). Repeated primes improved cellular responses and broadened epitope specificity. Addition of cyclic-di-GMP induced a transient increase in IFN-γ production. The strongest anti-RT immune response was achieved in a prime-boost protocol with electroporation by short 100V pulses done using penetrating electrodes. The RT-specific response, dominated by CD4+ T-cells, targeted epitopes at aa 199–220 and aa 528–543. Drug-resistance mutations disrupted the epitope at aa 205–220, while the CTL epitope at aa 202–210 was not affected. Overall, multiparametric optimization of RT strengthened its Th2- performance. A rapid loss of RT/luciferase-expressing cells in the surrogate challenge experiment revealed a lytic potential of anti-RT response. Such lytic CD4+ response would be beneficial for an HIV vaccine due to its comparative insensitivity to immune escape.

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“…Recognition of viral pathogens by the innate immune system through the pattern recognition receptors (PRR), including the Toll-like receptors, the cGAS-STING cytosolic DNA-sensing pathway, and the retinoic acid-inducible gene I (RIG-I) pathway, can induce apoptosis in virus-infected cells (15)(16)(17)(18)(19), suggesting that stimulation of innate immunity could improve the shock-and-kill strategy. Immunotherapy has been shown to improve the recovery of CD4 ϩ T cells and to induce an HIV-specific T cell response (20), and several immune modulators have been tested as LRAs, including T cell activators, the cytokine interleukin-2 (IL-2), and a T cell receptor (TCR) agonist: a murine anti-CD3 monoclonal antibody. Despite the ability to induce reactivation, these agents caused severe toxicities without reducing the latent reservoir (7).…”

mentioning

confidence: 99%

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

Palermo

Acchioni

Carlo

et al. 2019

J Virol

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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.

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Multifarious immunotherapeutic approaches to cure HIV-1 infection

Cited by 5 publications

References 60 publications

Cytokine cascade and networks among MSM HIV seroconverters: implications for early immunotherapy

Cytokine cascade and networks among MSM HIV seroconverters: implications for early immunotherapy

Codon optimization and improved delivery/immunization regimen enhance the immune response against wild-type and drug-resistant HIV-1 reverse transcriptase, preserving its Th2-polarity

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

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