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Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV.

ABSTRACT: Interferon-induced transmembrane (IFITM) proteins are potent antiviral factors shown to restrict the infection of many enveloped viruses, including HIV. Here we report cloning and characterization of a panel of nonhuman primate IFITMs. We show that, similar to human IFITM, nonhuman primate IFITM proteins inhibit HIV and other primate lentiviruses. While some nonhuman primate IFITM proteins are more potent than human counterparts to inhibit HIV-1, they are generally not effective against HIV-2 similar to that of human IFITMs. Notably, depending on SIV strains and also IFITM species tested, nonhuman primate IFITM proteins exhibit distinct activities against SIVs; no correlation was found to support the notion that IFITM proteins are most active in non-natural primate hosts. Consistent with our recent findings for human IFITMs, nonhuman primate IFITM proteins interact with HIV-1 Env and strongly act in viral producer cells to impair viral infectivity and block cell-to-cell transmission. Accordingly, knockdown of primate IFITM3 increases HIV-1 replication in nohuman primate cells. Interestingly, analysis of DNA sequences of human and nonhuman primate IFITMs suggest that IFITM proteins have been undergoing purifying selection, rather than positive selection typical for cellular restriction factors. Overall, our study reveals some new and unexpected features of IFITMs in restricting primate lentiviruses, which enhances our understanding of virus-host interaction and AIDS pathogenesis.

SUBMITTER: Wilkins J

PROVIDER: S-EPMC4892622 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV.

Wilkins Jordan J Zheng Yi-Min YM Yu Jingyou J Liang Chen C Liu Shan-Lu SL

PloS one 20160603 6

Interferon-induced transmembrane (IFITM) proteins are potent antiviral factors shown to restrict the infection of many enveloped viruses, including HIV. Here we report cloning and characterization of a panel of nonhuman primate IFITMs. We show that, similar to human IFITM, nonhuman primate IFITM proteins inhibit HIV and other primate lentiviruses. While some nonhuman primate IFITM proteins are more potent than human counterparts to inhibit HIV-1, they are generally not effective against HIV-2 si ...[more]

PMID: 27257969

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Project description:Interferon-induced transmembrane proteins (IFITMs) are a family of interferon-inducible proteins that inhibit a broad range of viruses by interfering with viral-to-cellular membrane fusion. The antiviral activity of IFITMs is highly regulated by several posttranslational modifications and by a number of protein domains that modulate steady-state protein levels, trafficking, and antiviral effectiveness. Taking advantage of the natural diversity existing among IFITMs of different animal species, we have compared 21 IFITMs for their ability to inhibit HIV-1 at two steps, during virus entry into cells (target cell protection) and during the production of novel virion particles (negative imprinting of virion particles' infectivity). We found a high functional heterogeneity among IFITM homologs with respect to both antiviral modalities, with IFITM members that exhibit enhanced viral inhibition, while others have no ability to block HIV-1. These differences could not be ascribed to known regulatory domains and could only be partially explained through differential protein stability, implying the existence of additional mechanisms. Through the use of chimeras between active and inactive IFITMs, we demonstrate that the cross talk between distinct domains of IFITMs is an important contributor of their antiviral potency. Finally, we identified murine IFITMs as natural variants competent for target cell protection, but not for negative imprinting of virion particles' infectivity, suggesting that the two properties may, at least in principle, be uncoupled. Overall, our results shed new light on the complex relationship between IFITMs and viral infection and point to the cross talk between IFITM domains as a novel layer of regulation of their activity. IMPORTANCE IFITMs are broad viral inhibitors capable of interfering with both early and late phases of the replicative cycle of many different viruses. By comparing 21 IFITM proteins issued from different animal species for their ability to inhibit HIV-1, we have identified several that exhibit either enhanced or impaired antiviral behavior. This functional diversity is not driven by differences in known domains and can only be partly explained through differential protein stability. Chimeras between active and inactive IFITMs point to the cross talk between individual IFITM domains as important for optimal antiviral activity. Finally, we show that murine IFITMs are not capable of decreasing the infectivity of newly produced HIV-1 virion particles, although they retain target cell protection abilities, suggesting that these properties may be, in principle, disconnected. Overall, our results shed new light on the complex layers of regulation of IFITM proteins and enrich our current understanding of these broad antiviral factors.

Project description:HIV-infected persons are at increased risk for developing pulmonary diseases including chronic obstructive pulmonary disease (COPD), and the fungal opportunistic pathogen, Pneumocystis jirovecii (Pc) has been implicated in the pathogenesis of HIV-related COPD. We previously developed a non-human primate model of HIV-related COPD using simian-human immunodeficiency virus (SHIV) and Pc co-infection in cynomolgus macaques. In the present study we examined gene expression profiles in lung tissue from SHIV/Pc co-infected monkeys with COPD and compared them to SHIV-infected monkeys infected with normal lung function. Microarray technology was used to develop gene profiles, and differential gene expression was determined by a comparative evaluation of competing normalization methods applied to our expression data set followed by validation using quantitative real-time polymerase chain reaction analysis for select genes. Of over 52,000 transcripts representing more than 20,000 genes analyzed, the SHIV/Pc infected macaques with COPD exhibited 243 differentially expressed (DE) genes compared to SHIV-infected monkeys with normal lung function. DE genes fell into a number of functional categories which may be important in COPD development including: inflammation (pulmonary surfactants A2, B, C, D, upregulated; alternative macrophage activation-associated CC chemokine, upregulated), protease/antiprotease balance (cathepsin H, upregulated; alpha-1-chymotrypsin and secretory leukocyte peptidase inhibitor, downregulated), redox balance (glutathione peroxidase 4 and mitochondrial aldehyde dehydrogenase 2, upregulated) and tissue homeostasis (connective tissue growth factor, downregulated; ornithine decarboxylase antizyme, upregulated). These results identify factors and pathways that may be involved in early development of Pneumocystis and SHIV-associated COPD and reveal several novel, potential therapeutic targets. There are totally 11 samples in the experiment. The sample breakdown is as follows: KN14(group 1) is a true control in that the monkey was not infected with simian-human immunodeficiency virus (SHIV) nor was it colonized with Pneumocystis. KN02, KN03, KN07 and KN08 (group 2) are also controls of a sort. They were infected with SHIV but they did not become colonized with Pneumocystis. The remainder (KN01, KN04, KN06, KN11, KN12, KN13) (group3) were both infected with SHIV and colonized with Pneumocystis. The primary interest is in comparing the two SHIV-infected groups (2 and 3)

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Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV.

Publications

Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV.

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