Restriction factors and lentiviral antagonism

Retrovirus, Infection and Latency
Microbiology Cellular plasticity and reproduction

Project leader(s)

Florence MARGOTTIN-GOGUET Permanent researcher Team co-leader

Florence Margottin-Goguet’s group has a long-standing interest in the study of host immune defense proteins, the so-called restriction factors and their antagonism by viral proteins. Viruses hijack the cellular machinery and counteract host cell defenses to propagate into the organism, while the host cell uses different strategies to inactivate the virus and overcome the infection.

Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) are responsible for Acquired Immunodeficiency Syndrome (AIDS). Today, about 38 million people are living with HIV worldwide. HIV-1 and HIV-2 appeared in humans after cross-species transmission from non-human primate viruses (simian Immunodeficiency viruses or SIV). Zoonotic transmission of a virus, at least a lentivirus, is a rare event. While SIVs are present in more than 40 non-human primate species from sub-Saharan Africa, only three of them (chimpanzees, gorillas and sooty mangabeys) have transmitted their viruses to humans. SIVcpz and SIVgor (infecting chimpanzee and gorilla, respectively) gave rise to HIV-1 on the one hand, SIVsmm (infecting sooty mangabey) to HIV-2 on the other hand. SIVsmm has also been transmitted to macaques in captivity (SIVmac). Ecological and environmental factors are of course predominant determinants of cross-species transmission explaining its scarcity, though several lines of evidence suggest that host and viral factors are also key players in this process. In line with this, APOBEC3G, BST-2/tetherin and Trim5alpha restriction factors were shown to provide an intrinsic host-species specific barrier to infection. The team is interested in the discovery of new host restriction factors and in the study of their antagonism by divergent lentiviruses.

The different lentiviral lineages share a similar “Gag-Pol-Env” organization but they differ in their set of accessory proteins. For example, Vpx is found only in two lineages (HIV-2/SIVmac/SIVsmm and SIVrcm/mnd2 infecting red-capped mangabey and mandrill). In contrast, all extant primate lentiviruses encode for Vpr, a paralog of Vpx, including SIVagm (infecting African green monkeys). These viral accessory proteins, which bear no structural or catalytic function, allow the virus to adapt to its host’s environment in order to ensure efficient replication and survival in the infected cell. The study of HIV accessory proteins by our team and others has led to the discovery of restriction factors in the past 20 years. Restriction factors belong to innate immunity and provide a first line of defence against the virus within the host cell. They are usually characterized by their cell-autonomous antiviral activity and their interaction with a viral component (often a viral accessory protein). Altogether, the restriction factor inhibits the virus, which, in turn, inactivates the restriction factor. Because of continual host-virus competition along evolution, restriction factors show signs of positive selection that may be witnessed by comparing protein-coding sequences of genes from different host species. Such signature may reflect the capacity of the host to escape or not viral antagonism or to inhibit or not the virus, in turn restriction factors contribute to cross-species transmission.

General objectives

The molecular battle at stake between the host cell and the virus is at the heart of the ongoing research of our team. Our general objectives are to better understand the role of viral accessory proteins and to identify and characterize host restrictions factors. Understanding how the virus is blocked at different steps could lead to the proposal of new antiviral therapies.

Our main lines of research are:

-The search for host proteins targeted by viral auxiliary proteins from HIV-1/HIV-2/SIV. Recently, we have discovered that HUSH, a complex that is involved in the repression of gene expression, is degraded in the presence of the HIV-2/SIVsmm Vpx protein (Chougui et al, Nature microbio 2018)

-The study of the mechanism of viral antagonism by divergent lentiviral proteins. Vpx induces the degradation of two host factors: SAMHD1 and HUSH. In both cases, degradation relies on the hijacking of the DCAF1 adaptor of a Cullin 4A-based ubiquitin ligase. Nonetheless, our recent results show that differences exist between SAMHD1 and HUSH antagonism by Vpx (Martin*, Matkovic* et al, plos path 2021)

-The study of the mechanism of action of host restriction factors. Our team has contributed to characterize the mechanisms of action of SAMHD1 and HUSH. SAMHD1 is a dNTP hydrolase, which depletes nucleotides; in turn SAMHD1 inhibits the synthesis of viral DNA in non-dividing cells (Lahouassa et al, Nature Immunology 2012). HUSH represses expression of the viral genome integrated into the host genome, both at the epigenetic and post-transcriptional levels (Chougui et al, Nature microbio 2018; Matkovic et al, Nature com 2022).

Selected contributions of the team to the HIV field

-Discovery of the mechanism of Vpu-mediated CD4 degradation. First example of ubiquitin ligase hijacking by a HIV protein (second example in the whole world of pathogens).
A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif.
Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R. Mol Cell. 1998 Mar;1(4):565-74. doi: 10.1016/s1097-2765(00)80056-8.

-Discovery of the mechanism of action of HIV-1 Vpr and first demonstration that HIV-2 Vpx uses the same ubiquitin ligase as Vpr (the starting point of the discovery of restriction factors).
HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase.
Le Rouzic E, Belaïdouni N, Estrabaud E, Morel M, Rain JC, Transy C, Margottin-Goguet F.Cell Cycle. 2007 Jan 15;6(2):182-8. doi: 10.4161/cc.6.2.3732.

-Discovery of the mechanism of action of SAMHD1 in myeloid cells and the discovery of nucleotide depletion as an antiviral mechanism.
SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates.
Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, Bloch N, Maudet C, Bertrand M, Gramberg T, Pancino G, Priet S, Canard B, Laguette N, Benkirane M, Transy C, Landau NR, Kim B, Margottin-Goguet F. Nat Immunol. 2012 Feb 12;13(3):223-228. doi: 10.1038/ni.2236.

-Demonstration that SAMHD1 restriction is not involved in the Interferon block to HIV-1 transduction.
Interferon block to HIV-1 transduction in macrophages despite SAMHD1 degradation and high deoxynucleoside triphosphates supply.
Dragin L, Nguyen LA, Lahouassa H, Sourisce A, Kim B, Ramirez BC, Margottin-Goguet F.
Retrovirology. 2013 Mar 11;10:30. doi: 10.1186/1742-4690-10-30.

-Identification of HLTF as a host target of HIV-1 Vpr (one of the first endogenous target of Vpr).
HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages.
Lahouassa H, Blondot ML, Chauveau L, Chougui G, Morel M, Leduc M, Guillonneau F, Ramirez BC, Schwartz O, Margottin-Goguet F. Proc Natl Acad Sci U S A. 2016 May 10;113(19):5311-6. doi: 10.1073/pnas.1600485113.

-Discovery of a new function of Vpx, its capacity to reactivate latent viruses through HUSH degradation (an unexpected role of the viral protein).
HIV-2/SIV viral protein X counteracts HUSH repressor complex.Chougui G, Munir-Matloob S, Matkovic R, Martin MM, Morel M, Lahouassa H, Leduc M, Ramirez BC, Etienne L, Margottin-Goguet F. Nat Microbiol. 2018 Aug;3(8):891-897. doi: 10.1038/s41564-018-0179-6.

-Characterization of differences between the mechanisms of HUSH and SAMHD1 degradation by HIV-2 Vpx.
Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx. Martin MM, Matkovic R, Larrous P, Morel M, Lasserre A, Vauthier V, Margottin-Goguet F. PLoS Pathogens 2021 Oct 26;17(10):e1009609. doi: 10.1371/journal.ppat.1009609.

-Characterization of differences between the regulation of SAMHD1 and HUSH restriction factors.
HUSH-mediated HIV silencing is independent of TASOR phosphorylation on threonine 819. Vauthier V, Lasserre A, Morel M, Versapuech M, Berlioz-Torrent C, Zamborlini A, Margottin-Goguet* F, Matkovic* R. Retrovirology. 2022 Oct 29;19(1):23. doi: 10.1186/s12977-022-00610-7 (* : co-corresponding)

MARGOTTIN-GOGUET Florence, team leader, Research director INSERM
Orcid number: 0000-0002-3124-6690
Researcher ID: F-9272-2013
Web of Science: indicate for "author": "Margottin F or Margottin-Goguet F"
Pubmed link : http://www.ncbi.nlm.nih.gov/pubmed?term=Margottin-goguet F[Author] or Margottin F[Author]