Inhibition of HTLV-1 Infection by HIV-1 First- and Second-Generation Integrase Strand Transfer Inhibitors

Barski, M.S.; Minnell, Jordan James; Maertens, Goedele N.

doi:10.3389/fmicb.2019.01877

Cited by 27 publications

(59 citation statements)

References 66 publications

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“…Similarly, understanding the integrase (IN) enzyme of HTLV, and how it can be inhibited, will be a critical part of the effort to control HTLV infections. We recently reported that the first- and second-generation HIV INSTIs are effective at inhibiting HTLV-1 strand transfer in vitro and integration in tissue culture 9 . In this report, we have characterised several groups of INSTIs that have been reported to inhibit the replication of HIV 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures

et al. 2021

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Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.

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Section: Introductionmentioning

confidence: 99%

Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures

et al. 2021

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“…Akin to HTLV-1 IN, the enzyme readily utilizes short, double-stranded oligonucleotide mimics of vDNA ends for integration ( Supplementary Fig. 2a, c) 14,18 . Formation of stable intasomes in vitro can be technically challenging, and often requires the presence of host factors and/or hyperactivating mutations 11,12,19 .…”

Section: Resultsmentioning

confidence: 99%

Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ

et al. 2020

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Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor disease, unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the retroviral integrase (IN) enzyme. Here, we use X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of the functional deltaretroviral IN assembled on viral DNA ends and bound to the B56γ subunit of its human host factor, protein phosphatase 2 A. The structure reveals a tetrameric IN assembly bound to two molecules of the phosphatase via a conserved short linear motif. Insight into the deltaretroviral intasome and its interaction with the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.

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“…The model analysis suggested that co-infected individuals with both viruses will have smaller number of healthy CD4 þ T cells in comparison with HIV or HTLV-I monoinfected individuals. It was reported in [62] that no treatments exist for acute or chronic HTLV-I infection. However, antiviral treatments of HIV infection is currently used to suppress viral replication.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Modeling and analysis of a within-host HIV/HTLV-I co-infection

Ełaiw

AlShamrani

2021

Bol. Soc. Mat. Mex.

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Human immunodeficiency virus (HIV) and human T-lymphotropic virus type I (HTLV-I) are two retroviruses that attack the T cells and impair their functions. Both HIV and HTLV-I can be transmitted between individuals through direct contact with certain body fluids from infected individuals. Therefore, a person can be co-infected with both viruses. HIV causes acquired immunodeficiency syndrome (AIDS), while HTLV-I is the causative agent for adult T-cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Several mathematical models have been developed in the literature to describe the within-host dynamics of HIV and HTLV-I mono-infections. However, modeling a within-host dynamics of HIV/HTLV-I co-infection has not been involved. The present paper is concerned with the formulation and investigation of a new HIV/HTLV-I co-infection model under the effect of Cytotoxic T lymphocytes (CTLs) immune response. The model describes the interaction between susceptible T cells, silent HIV-infected cells, active HIV-infected cells, silent HTLV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. The HIV can spread by virus-to-cell transmission. On the other side, HTLV-I has two modes of transmission, (i) horizontal transmission via direct cell-to-cell contact through the virological synapse, and (ii) vertical transmission through the mitotic division of Tax-expressing HTLV-infected cells. The well-posedness of the model is established by showing that the solutions of the model are nonnegative and bounded. We define a set of threshold parameters which govern the existence and stability of all equilibria of the model. We explore the global asymptotic stability of all equilibria by utilizing Lyapunov function and Lyapunov–LaSalle asymptotic stability theorem. We have presented numerical simulations to justify the applicability and effectiveness of the theoretical results. In addition, we evaluate the effect of HTLV-I infection on the HIV dynamics and vice versa.

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Inhibition of HTLV-1 Infection by HIV-1 First- and Second-Generation Integrase Strand Transfer Inhibitors

Cited by 27 publications

References 66 publications

Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures

Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures

Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ

Modeling and analysis of a within-host HIV/HTLV-I co-infection

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