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Evasion of cGAS and TRIM5 defines pandemic HIV.

<div class='caption-title'>a–c, Replication of HIV-1(M) (a), HIV-2 (b) or HIV-1(O) (c) isolates in human MDM in the presence of interferon α/β receptor (IFNα/β-R) or control antibody (CAb). Two-way ANOVA vs CAb, ROD10 P = 0.0001, pSTbx P = 0.0001, ps7312s P = 0,0001, RBF206 P = 0.033. d, Single-round infection of MDM with equal genome copies of VSV-G-pseudotyped HIV-1(M), HIV-2 and HIV-1(O)-GFP measured 48 h post infection. e, Secreted IL-8 and CXCL10 from infections in d measured by ELISA 48 h post infection. f, GAPDH-normalized mRNA levels in infections from d expressed as fold induction over untreated MDM 24 h post infection or after HT-DNA transfection (1 ug ml−1) or LPS stimulation (100 ng ml−1). g, Infection of THP-1 cells with equal genome copies of VSV-G-pseudotyped HIV-1(M), HIV-2 and HIV-1(O)-GFP measured 48 h post infection. h, GAPDH-normalized mRNA levels from infections in g expressed as fold induction over untreated THP-1 cells 24 h post infection. Mean ± s.d., n = 3 donors (a–e) or independent experiments (f–h). Two-tailed unpaired t-test vs untreated MDM (d–f), paired t-test vs untreated THP-1 cells (g,h). *P < 0.05, **P < 0.01, ***P < 0.001. NS, not significant.</div>
<div class='caption-title'>a, Example of GAPDH-normalized cGAS mRNA levels in MDM representing 3 independent donors transfected with cGAS-targeting siRNA (sicGAS), TRIM5-targeting siRNA (siTRIM5) or non-targeting control (siCtrl). b–e, GAPDH-normalized mRNA levels (left and middle), or secreted cytokine levels (right) (ELISA) (CXCL10, IL-8), expressed as fold induction over uninfected (mock) samples 24 h post infection (mRNA) or 48 h post infection (cytokine) from cells in a. f, GAPDH-normalized mRNA levels, expressed as fold induction over uninfected samples, in non-targeting CRISPR-treated cells (NT-KO) transfected with control siRNA (siCtrl) (NT-KO siCtrl), NT-KO siTRIM5, cGAS KO siCtrl or cGAS KO siTRIM5 THP-1 cells 24 h post infection or after HT-DNA (1 ug ml−1) transfection. Mean ± s.d., n = 3 independent experiments and donors. Two-tailed unpaired t-test vs untreated MDM (b–e), paired t-test vs THP-1 Ctrl vector (f). *P < 0.05, **P < 0.01.</div>
<div class='caption-title'>a, GAPDH-normalized mRNA levels expressed as fold induction over uninfected THP-1 cells 24 h post viral-like particles (VLP) treatment. b, HIV-1(M), HIV-2 and HIV-1(O) infection levels normalized to levels of infection without previous exposure to VLP. Mean ± s.d., n = 3 independent experiments. Two-tailed paired t-test vs untreated THP-1 (a). *P < 0.05, **P < 0.01. VSV-G-pseudotyped VLP were made without genome.</div>
Zuliani-Alvarez L, Govasli ML, Rasaiyaah J, Monit C, Perry SO, Sumner RP, McAlpine-Scott S, Dickson C, Rifat Faysal KM, Hilditch L, Miles RJ, Bibollet-Ruche F, Hahn BH, Boecking T, Pinotsis N, James LC, Jacques DA, Towers GJ
OpenAccess logo Nat Microbiol 7 1762-1776 (2022)
Related entries: 7qdf, 7t12, 7t13, 7t14, 8d3b

Cited: 20 times
EuropePMC logo PMID: 36289397

Abstract

Of the 13 known independent zoonoses of simian immunodeficiency viruses to humans, only one, leading to human immunodeficiency virus (HIV) type 1(M) has become pandemic, causing over 80 million human infections. To understand the specific features associated with pandemic human-to-human HIV spread, we compared replication of HIV-1(M) with non-pandemic HIV-(O) and HIV-2 strains in myeloid cell models. We found that non-pandemic HIV lineages replicate less well than HIV-1(M) owing to activation of cGAS and TRIM5-mediated antiviral responses. We applied phylogenetic and X-ray crystallography structural analyses to identify differences between pandemic and non-pandemic HIV capsids. We found that genetic reversal of two specific amino acid adaptations in HIV-1(M) enables activation of TRIM5, cGAS and innate immune responses. We propose a model in which the parental lineage of pandemic HIV-1(M) evolved a capsid that prevents cGAS and TRIM5 triggering, thereby allowing silent replication in myeloid cells. We hypothesize that this capsid adaptation promotes human-to-human spread through avoidance of innate immune response activation.

Articles - 7t15 mentioned but not cited (1)

  1. Evasion of cGAS and TRIM5 defines pandemic HIV. Zuliani-Alvarez L, Govasli ML, Rasaiyaah J, Monit C, Perry SO, Sumner RP, McAlpine-Scott S, Dickson C, Rifat Faysal KM, Hilditch L, Miles RJ, Bibollet-Ruche F, Hahn BH, Boecking T, Pinotsis N, James LC, Jacques DA, Towers GJ. Nat Microbiol 7 1762-1776 (2022)


Reviews citing this publication (7)

  1. Function and regulation of cGAS-STING signaling in infectious diseases. Du Y, Hu Z, Luo Y, Wang HY, Yu X, Wang RF. Front Immunol 14 1130423 (2023)
  2. On the Evolutionary Trajectory of SARS-CoV-2: Host Immunity as a Driver of Adaptation in RNA Viruses. Warger J, Gaudieri S. Viruses 15 70 (2022)
  3. The ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication. Lin C, Kuffour EO, Li T, Gertzen CGW, Kaiser J, Luedde T, König R, Gohlke H, Münk C. Viruses 16 485 (2024)
  4. The role of the cGAS-STING signaling pathway in viral infections, inflammatory and autoimmune diseases. Wang MM, Zhao Y, Liu J, Fan RR, Tang YQ, Guo ZY, Li T. Acta Pharmacol Sin 45 1997-2010 (2024)
  5. Capsid-dependent lentiviral restrictions. Twentyman J, Emerman M, Ohainle M. J Virol 98 e0030824 (2024)
  6. TRIM5α: A Protean Architect of Viral Recognition and Innate Immunity. Spada SJ, Grigg ME, Bouamr F, Best SM, Zhang P. Viruses 16 997 (2024)
  7. The capsid revolution. Taylor IA, Fassati A. J Mol Cell Biol 15 mjad076 (2024)

Articles citing this publication (12)



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