A small molecule compound IMB-LA inhibits HIV-1 infection by preventing viral Vpu from antagonizing the host restriction factor BST-2

Mi, Zeyun; Ding, Jiwei; Zhang, Quan; Zhao, Jin; Ma, Ling; Yu, Haisheng; Liu, Zhenlong; Shan, Guangzhi; Li, Xiaoyü; Zhou, Jinming; Wei, Tao; Zhang, Liguo; Guo, Fei; Liang, Chen

doi:10.1038/srep18499

Cited by 16 publications

(13 citation statements)

References 54 publications

(84 reference statements)

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“…New treatments designed to disrupt the function of Nef and Vpu will likely aid host immunity combat HIV-1 infection by restoring normal PM physiology. In fact, Nef and Vpu antagonists are currently in development [ 176 , 177 ]. Given the ability of Nef and Vpu to overcome intrinsic restriction factors and innate immunity, these drugs may have benefits as part of prophylactic regimens designed to prevent infection.…”

Section: Discussionmentioning

confidence: 99%

Remodeling of the Host Cell Plasma Membrane by HIV-1 Nef and Vpu: A Strategy to Ensure Viral Fitness and Persistence

Sugden

Bego

Pham

et al. 2016

Viruses

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The plasma membrane protects the cell from its surroundings and regulates cellular communication, homing, and metabolism. Not surprisingly, the composition of this membrane is highly controlled through the vesicular trafficking of proteins to and from the cell surface. As intracellular pathogens, most viruses exploit the host plasma membrane to promote viral replication while avoiding immune detection. This is particularly true for the enveloped human immunodeficiency virus (HIV), which assembles and obtains its lipid shell directly at the plasma membrane. HIV-1 encodes two proteins, negative factor (Nef) and viral protein U (Vpu), which function primarily by altering the quantity and localization of cell surface molecules to increase virus fitness despite host antiviral immune responses. These proteins are expressed at different stages in the HIV-1 life cycle and employ a variety of mechanisms to target both unique and redundant surface proteins, including the viral receptor CD4, host restriction factors, immunoreceptors, homing molecules, tetraspanins and membrane transporters. In this review, we discuss recent progress in the study of the Nef and Vpu targeting of host membrane proteins with an emphasis on how remodeling of the cell membrane allows HIV-1 to avoid host antiviral immune responses leading to the establishment of systemic and persistent infection.

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Section: Discussionmentioning

confidence: 99%

Remodeling of the Host Cell Plasma Membrane by HIV-1 Nef and Vpu: A Strategy to Ensure Viral Fitness and Persistence

Sugden

Bego

Pham

et al. 2016

Viruses

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“…Moreover, the Vpu proteins expressed by several of these viruses were unable to oppose tetherin, suggesting that this function may be acquired by Nef under circumstances where it is lost by Vpu. One implication of these observations is that efforts to develop antiretroviral drugs that interfere with the ability of Vpu to counteract tetherin may lead to the selection of Nef variants that gain this function (57,58). Thus, understanding the conditions that lead to tetherin antagonism by Nef will be important for the development of therapies to increase the susceptibility of HIV-1 to this restriction factor.…”

Section: Discussionmentioning

confidence: 99%

Tetherin Antagonism by HIV-1 Group M Nef Proteins

Arias

Colomer-Lluch

Bredow

et al. 2016

J Virol

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Although Nef is the viral gene product used by most simian immunodeficiency viruses to overcome restriction by tetherin, this activity was acquired by the Vpu protein of HIV-1 group M due to the absence of sequences in human tetherin that confer susceptibility to Nef. Thus, it is widely accepted that HIV-1 group M uses Vpu instead of Nef to counteract tetherin. Challenging this paradigm, we identified Nef alleles of HIV-1 group M isolates with significant activity against human tetherin. These Nef proteins promoted virus release and tetherin downmodulation from the cell surface and, in the context of vpu-deleted HIV-1 recombinants, enhanced virus replication and resistance to antibody-dependent cell-mediated cytotoxicity (ADCC). Further analysis revealed that the Vpu proteins from several of these viruses lack antitetherin activity, suggesting that under certain circumstances, HIV-1 group M Nef may acquire the ability to counteract tetherin to compensate for the loss of this function by Vpu. These observations illustrate the remarkable plasticity of HIV-1 in overcoming restriction by tetherin and challenge the prevailing view that all HIV-1 group M isolates use Vpu to counteract tetherin. IMPORTANCEMost viruses of HIV-1 group M, the main group of HIV-1 responsible for the global AIDS pandemic, use their Vpu proteins to overcome restriction by tetherin (BST-2 or CD317), which is a transmembrane protein that inhibits virus release from infected cells. Here we show that the Nef proteins of certain HIV-1 group M isolates can acquire the ability to counteract tetherin. These results challenge the current paradigm that HIV-1 group M exclusively uses Vpu to counteract tetherin and underscore the importance of tetherin antagonism for efficient viral replication.

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“…Zhang et al 227 developed a cell-based high-throughput enzyme-linked immunosorbent assay for the quantification of cell-surface BST-2 levels, 227 and a lead compound IMB-LA (95; Figure 19) was identified to inhibit Vpu-mediated BST-2 degradation and recover the expression of BST-2 at the cell surface. 228 This compound inhibited both the HIV infection and release in a BST-2 dependent fashion. The mechanism studies showed that compound 95 did not inhibit the interaction between BST-2 and Vpu, but it blocked the sorting of BST-2 into JI AND LI | 23 lysosomes for degradation.…”

Section: Bone Marrow Stromal Cell Antigenmentioning

confidence: 97%

Medicinal chemistry strategies toward host targeting antiviral agents

2020

Medicinal Research Reviews

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Direct-acting antiviral agents (DAAs) represent a class of drugs targeting viral proteins and have been demonstrated to be very successful in combating viral infections in clinic. However, DAAs suffer from several inherent limitations, including narrow-spectrum antiviral profiles and liability to drug resistance, and hence there are still unmet needs in the treatment of viral infections. In comparison, host targeting antivirals (HTAs) target host factors for antiviral treatment. Since host proteins are probably broadly required for various viral infections, HTAs are not only perceived, but also demonstrated to exhibit broad-spectrum antiviral activities. In addition, host proteins are not under the genetic control of viral genome, and hence HTAs possess much higher genetic barrier to drug resistance as compared with DAAs. In recent years, much progress has been made to the development of HTAs with the approval of chemokine receptor type 5 antagonist maraviroc for human immunodeficiency virus treatment and more in the pipeline for other viral infections. In this review, we summarize various host proteins as antiviral targets from a medicinal chemistry prospective. Challenges and issues associated with HTAs are also discussed. K E Y W O R D S broad-spectrum antivirals, direct-acting antiviral agents, drug resistance, host targeting antiviral agents

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A small molecule compound IMB-LA inhibits HIV-1 infection by preventing viral Vpu from antagonizing the host restriction factor BST-2

Cited by 16 publications

References 54 publications

Remodeling of the Host Cell Plasma Membrane by HIV-1 Nef and Vpu: A Strategy to Ensure Viral Fitness and Persistence

Remodeling of the Host Cell Plasma Membrane by HIV-1 Nef and Vpu: A Strategy to Ensure Viral Fitness and Persistence

Tetherin Antagonism by HIV-1 Group M Nef Proteins

Medicinal chemistry strategies toward host targeting antiviral agents

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