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TLR9, TLR7 HIV Cure Research
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from Jules: a recent cure research study was announced New HIV Eradication Combo Study - (01/13/17) that will study this TLR9 agonist with 2 neutralizing antibodies. Reported at CROi 2016 Gilead'sTLR7 in monkeys induced immune cytokine response, reduced DNA levels, and after stopping ART 2of the 9 monkeys had undetectable plasma HIV http://www.natap.org/2016/CROI/croi_22.htm.....".TLR7 agonist dosing induced transient and variable increases in plasma SIV RNA levels across all treatment groups. After completing all doses of TLR7 agonist and prior to stopping ART, peripheral lymphocytes and lymph node biopsies from the animals had less inducible virus. Two of the TLR7 agonist-treated rhesus macaques maintained undetectable plasma viral load for more than 90 days after stopping ART. " http://www.natap.org/2016/CROI/croi_20.htm - J&J announced recently they are beginning a cure research phase 1/2 study in HIV+ after publishing http://natap.org/2016/HIV/110916_02.htm results of TLR7 + vaccine in monkeys : "In this new study, conducted in non-human primates (NHPs) infected with simian immunodeficiency virus (SIV), a virus similar to HIV, the strategy was to draw the virus out of hiding with the goal of eradicating it from the body. Researchers combined two investigational therapeutic vaccines (an adenovirus serotype 26 vector vaccine (Ad26) and an MVA vector vaccine (MVA)) with a TLR7 agonist (an investigational drug that works on a protein of the immune system) into a treatment regimen to be administered alongside ART. When the treatment regimen was given to NHPs they achieved decreased levels of viral DNA in peripheral blood and lymph nodes, and improved viral suppression and delayed viral rebound when ART was stopped. Janssen, in collaboration with MHRP, recently began in-human studies to evaluate the potential of the HIV therapeutic vaccine in HIV infected patients who initiated ART during acute HIV infection. The Phase I/IIa study is evaluating the safety, immunogenicity of the Ad26/MVA vaccine regimen. The study will also explore the effect on viremic control after interruption of antiretroviral treatment following vaccination. The study will enroll patients who started ART during acute HIV infection and who are currently on stable ART."http://natap.org/2016/HIV/110916_03.htm
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A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4+ T Cells....."These data suggest that this molecule may serve a dual purpose in HIV-1 eradication therapy: enhanced immune function and potential latency reversal.....These findings..... provide a strong preclinical basis for the inclusion of MGN1703 in future HIV-1 eradication trials."
http://jvi.asm.org/content/90/9/4441.full
ABSTRACT
Toll-like receptor (TLR) agonists are potent enhancers of innate antiviral immunity and may also reverse HIV-1 latency. Therefore, TLR agonists have a potential role in the context of a "shock-and-kill" approach to eradicate HIV-1. Our extensive preclinical evaluation suggests that a novel TLR9 agonist, MGN1703, may indeed perform both functions in an HIV-1 eradication trial. Peripheral blood mononuclear cells (PBMCs) from aviremic HIV-1-infected donors on antiretroviral therapy (ART) that were incubated with MGN1703 ex vivo exhibited increased secretion of interferon alpha (IFN-α) (P = 0.005) and CXCL10 (P = 0.0005) in culture supernatants. Within the incubated PBMC pool, there were higher proportions of CD69-positive CD56dim CD16+ NK cells (P = 0.001) as well as higher proportions of CD107a-positive (P = 0.002) and IFN-γ-producing (P = 0.038) NK cells. Incubation with MGN1703 also increased the proportions of CD69-expressing CD4+ and CD8+ T cells. Furthermore, CD4+ T cells within the pool of MGN1703-incubated PBMCs showed enhanced levels of unspliced HIV-1 RNA (P = 0.036). Importantly, MGN1703 increased the capacity of NK cells to inhibit virus spread within a culture of autologous CD4+ T cells assessed by using an HIV-1 p24 enzyme-linked immunosorbent assay (ELISA) (P = 0.03). In conclusion, we show that MGN1703 induced strong antiviral innate immune responses, enhanced HIV-1 transcription, and boosted NK cell-mediated suppression of HIV-1 infection in autologous CD4+ T cells. These findings support clinical testing of MGN1703 in HIV-1 eradication trials.
DISCUSSION
Here we report a comprehensive preclinical evaluation of the novel TLR9 agonist MGN1703 in an HIV-1 eradication context. Using PBMCs from HIV-infected donors, we performed ex vivo assessments of this molecule's capacity to enhance immune effector functions as well as HIV-1 transcription. We found that MGN1703 induces potent antiviral NK cell responses capable of inhibiting virus spread in a culture of autologous CD4+ T cells. In addition, CD4+ T cells isolated from MGN1703-incubated PBMCs showed enhanced HIV-1 transcription. These data suggest that this molecule may serve a dual purpose in HIV-1 eradication therapy: enhanced immune function and potential latency reversal.
MGN1703-mediated activation is consistent during histone deacetylase inhibitor coadministration.Histone deacetylase inhibitor (HDACi) administration has been used to reverse HIV-1 latency and increase the production of latent virus (17–21), whereas MGN1703 may primarily be used as an immune enhancement therapy to augment the killing of virus-expressing cells. However, a recent study suggested that certain HDACis might impair cellular antiviral immune responses, with obvious implications for their inclusion in shock-and-kill strategies (31). Therefore, we evaluated the potential interaction between a potent HDACi, panobinostat, and MGN1703 by analyzing the same parameters as those displayed in Fig. 1 to 3. To do this, we exposed PBMCs to MGN1703 and panobinostat simultaneously. We examined 13 different immune functions and/or activation parameters (e.g., IFN-α production, CXCL-10 production, and CD69 expression on NK and T cells) but did not observe any statistically significant differences between the outcomes of MGN1703 alone and MGN1703 plus panobinostat (Fig. 4; see also Fig. S5 in the supplemental material). These data suggest that MGN1703 enhancement of immune function during a shock-and-kill eradication trial would persist during concurrent HDACi dosing.
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