1887

Journal of General Virology header logo

Volume 103, Issue 10

Development of a novel Macaque-Tropic HIV-1 adapted to cynomolgus macaques No Access

Abstract

Macaque-tropic HIV-1 (HIV-1mt) variants have been developed to establish preferable primate models that are advantageous in understanding HIV-1 infection pathogenesis and in assessing the preclinical efficacy of novel prevention/treatment strategies. We previously reported that a CXCR4-tropic HIV-1mt, MN4Rh-3, efficiently replicates in peripheral blood mononuclear cells (PBMCs) of cynomolgus macaques homozygous for TRIMCyp (CMs). However, the CMs challenged with MN4Rh-3 displayed low viral loads during the acute infection phase and subsequently exhibited short-term viremia. These virological phenotypes differed from those observed in most HIV-1-infected people. Therefore, further development of the HIV-1mt variant was needed. In this study, we first reconstructed the MN4Rh-3 clone to produce a CCR5-tropic HIV-1mt, AS38. In addition, serial passages allowed us to produce a highly adapted AS38-derived virus that exhibits high viral loads (up to approximately 10 copies ml) during the acute infection phase and prolonged periods of persistent viremia (lasting approximately 16 weeks postinfection) upon infection of CMs. Whole-genome sequencing of the viral genomes demonstrated that the emergence of a unique 15-nt deletion within the gene was associated with adaptation. The deletion resulted in a significant increase in Vpr protein expression but did not affect Vif-mediated antagonism of antiretroviral APOBEC3s, suggesting that Vpr is important for HIV-1mt adaptation to CMs. In summary, we developed a novel CCR5-tropic HIV-1mt that can induce high peak viral loads and long-term viremia and exhibits increased Vpr expression in CMs.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): AIDS , APOBEC3 , cynomolgus macaque , HIV-1 , vif and vpr
© 2022 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001790
2022-10-07
2024-04-24
Loading full text...

Full text loading...

References

  1. Evans DT, Silvestri G. Nonhuman primate models in AIDS research. Curr Opin HIV AIDS 2013; 8:255–261 [View Article]
     [Google Scholar]
  2. Apetrei C, Pandrea I, Mellors JW. Nonhuman primate models for HIV cure research. PLoS Pathog 2012; 8:e1002892 [View Article]
     [Google Scholar]
  3. Misra A, Thippeshappa R, Kimata JT. Macaques as model hosts for studies of HIV-1 infection. Front Microbiol 2013; 4:176 [View Article]
     [Google Scholar]
  4. Taylor RA, Xiao S, Carias AM, McRaven MD, Thakkar DN et al. PET/CT targeted tissue sampling reveals virus specific dIgA can alter the distribution and localization of HIV after rectal exposure. PLoS Pathog 2021; 17:e1009632 [View Article]
     [Google Scholar]
  5. Shibata R, Kawamura M, Sakai H, Hayami M, Ishimoto A et al. Generation of a chimeric human and simian immunodeficiency virus infectious to monkey peripheral blood mononuclear cells. J Virol 1991; 65:3514–3520 [View Article]
     [Google Scholar]
  6. Naidu YM, Kestler HW, Li Y, Butler CV, Silva DP et al. Characterization of infectious molecular clones of simian immunodeficiency virus (SIVmac) and human immunodeficiency virus type 2: persistent infection of rhesus monkeys with molecularly cloned SIVmac. J Virol 1988; 62:4691–4696 [View Article]
     [Google Scholar]
  7. Hatziioannou T, Evans DT. Animal models for HIV/AIDS research. Nat Rev Microbiol 2012; 10:852–867 [View Article]
     [Google Scholar]
  8. Agy MB, Frumkin LR, Corey L, Coombs RW, Wolinsky SM et al. Infection of Macaca nemestrina by human immunodeficiency virus type-1. Science 1992; 257:103–106 [View Article]
     [Google Scholar]
  9. Münk C, Brandt SM, Lucero G, Landau NR. A dominant block to HIV-1 replication at reverse transcription in simian cells. Proc Natl Acad Sci 2002; 99:13843–13848 [View Article]
     [Google Scholar]
  10. Cowan S, Hatziioannou T, Cunningham T, Muesing MA, Gottlinger HG et al. Cellular inhibitors with fv1-like activity restrict human and simian immunodeficiency virus tropism. Proc Natl Acad Sci 2002; 99:11914–11919 [View Article]
     [Google Scholar]
  11. Hatziioannou T, Princiotta M, Piatak M, Yuan F, Zhang F et al. Generation of simian-tropic HIV-1 by restriction factor evasion. Science 2006; 314:95 [View Article]
     [Google Scholar]
  12. Hatziioannou T, Ambrose Z, Chung NPY, Piatak M, Yuan F et al. A macaque model of HIV-1 infection. Proc Natl Acad Sci 2009; 106:4425–4429 [View Article]
     [Google Scholar]
  13. Kamada K, Igarashi T, Martin MA, Khamsri B, Hatcho K et al. Generation of HIV-1 derivatives that productively infect macaque monkey lymphoid cells. Proc Natl Acad Sci 2006; 103:16959–16964 [View Article]
     [Google Scholar]
  14. Nomaguchi M, Yokoyama M, Kono K, Nakayama EE, Shioda T et al. Gag-CA Q110D mutation elicits TRIM5-independent enhancement of HIV-1mt replication in macaque cells. Microbes Infect 2013; 15:56–65 [View Article]
     [Google Scholar]
  15. Saito A, Nomaguchi M, Kono K, Iwatani Y, Yokoyama M et al. TRIM5 genotypes in cynomolgus monkeys primarily influence inter-individual diversity in susceptibility to monkey-tropic human immunodeficiency virus type 1. J Gen Virol 2013; 94:1318–1324 [View Article]
     [Google Scholar]
  16. Hatziioannou T, Del Prete GQ, Keele BF, Estes JD, McNatt MW et al. HIV-1-induced AIDS in monkeys. Science 2014; 344:1401–1405 [View Article]
     [Google Scholar]
  17. Thippeshappa R, Polacino P, Chandrasekar SS, Truong K, Misra A et al. In vivo serial passaging of human-simian immunodeficiency virus clones identifies characteristics for persistent viral replication. Front Microbiol 2021; 12:779460 [View Article]
     [Google Scholar]
  18. Saito A, Akari H. Macaque-tropic human immunodeficiency virus type 1: breaking out of the host restriction factors. Front Microbiol 2013; 4:187 [View Article]
     [Google Scholar]
  19. Saito A, Kono K, Nomaguchi M, Yasutomi Y, Adachi A et al. Geographical, genetic and functional diversity of antiretroviral host factor TRIMCyp in cynomolgus macaque (Macaca fascicularis). J Gen Virol 2012; 93:594–602 [View Article]
     [Google Scholar]
  20. Schuitemaker H, Koot M, Kootstra NA, Dercksen MW, de Goede RE et al. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol 1992; 66:1354–1360 [View Article]
     [Google Scholar]
  21. Grivel JC, Shattock RJ, Margolis LB. Selective transmission of R5 HIV-1 variants: where is the gatekeeper?. J Transl Med 2011; 9 Suppl 1:S6 [View Article] [PubMed]
     [Google Scholar]
  22. Schuitemaker H, van’t Wout AB, Lusso P. Clinical significance of HIV-1 coreceptor usage. J Transl Med 2011; 9: [View Article]
     [Google Scholar]
  23. Wei X, Decker JM, Liu H, Zhang Z, Arani RB et al. Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 2002; 46:1896–1905 [View Article]
     [Google Scholar]
  24. Soda Y, Shimizu N, Jinno A, Liu HY, Kanbe K et al. Establishment of a new system for determination of coreceptor usages of HIV based on the human glioma NP-2 cell line. Biochem Biophys Res Commun 1999; 258:313–321 [View Article] [PubMed]
     [Google Scholar]
  25. Saito A, Nomaguchi M, Iijima S, Kuroishi A, Yoshida T et al. Improved capacity of a monkey-tropic HIV-1 derivative to replicate in cynomolgus monkeys with minimal modifications. Microbes Infect 2011; 13:58–64 [View Article] [PubMed]
     [Google Scholar]
  26. Kitamura S, Ode H, Nakashima M, Imahashi M, Naganawa Y et al. The APOBEC3C crystal structure and the interface for HIV-1 Vif binding. Nat Struct Mol Biol 2012; 19:1005–1010 [View Article]
     [Google Scholar]
  27. Nakashima M, Tsuzuki S, Awazu H, Hamano A, Okada A et al. Mapping region of human Restriction factor APOBEC3H Critical for Interaction with HIV-1 Vif. J Mol Biol 2017; 429:1262–1276 [View Article]
     [Google Scholar]
  28. Green TD, Newton BR, Rota PA, Xu Y, Robinson HL et al. C3d enhancement of neutralizing antibodies to measles hemagglutinin. Vaccine 2001; 20:242–248 [View Article]
     [Google Scholar]
  29. Matsuda K, Inaba K, Fukazawa Y, Matsuyama M, Ibuki K et al. In vivo analysis of a new R5 tropic SHIV generated from the highly pathogenic SHIV-KS661, a derivative of SHIV-89.6. Virology 2010; 399:134–143 [View Article]
     [Google Scholar]
  30. Ishida Y, Yoneda M, Otsuki H, Watanabe Y, Kato F et al. Generation of a neutralization-resistant CCR5 tropic simian/human immunodeficiency virus (SHIV-MK38) molecular clone, a derivative of SHIV-89.6. J Gen Virol 2016; 97:1249–1260 [View Article]
     [Google Scholar]
  31. De Clercq E, Yamamoto N, Pauwels R, Balzarini J, Witvrouw M et al. Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100. Antimicrob Agents Chemother 1994; 38:668–674 [View Article]
     [Google Scholar]
  32. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 2005; 49:4721–4732 [View Article]
     [Google Scholar]
  33. Ode H, Matsuda M, Matsuoka K, Hachiya A, Hattori J et al. Quasispecies analyses of the HIV-1 near-full-length genome with illumina MiSeq. Front Microbiol 2015; 6:1258 [View Article]
     [Google Scholar]
  34. Hoshino S, Sun B, Konishi M, Shimura M, Segawa T et al. Vpr in plasma of HIV type 1-positive patients is correlated with the HIV type 1 RNA titers. AIDS Res Hum Retroviruses 2007; 23:391–397 [View Article]
     [Google Scholar]
  35. Pfeifer N, Lengauer T. Improving HIV coreceptor usage prediction in the clinic using hints from next-generation sequencing data. Bioinformatics 2012; 28:i589–i595 [View Article]
     [Google Scholar]
  36. Emery A, Swanstrom R. HIV-1: to splice or not to splice, that is the question. Viruses 2021; 13:181 [View Article] [PubMed]
     [Google Scholar]
  37. Park IW, Steen R, Li Y. Characterization of multiple mRNA species of simian immunodeficiency virus from macaques in a CD4+ lymphoid cell line. J Virol 1991; 65:2987–2992 [View Article] [PubMed]
     [Google Scholar]
  38. Viglianti GA, Sharma PL, Mullins JI. Simian immunodeficiency virus displays complex patterns of RNA splicing. J Virol 1990; 64:4207–4216 [View Article] [PubMed]
     [Google Scholar]
  39. Baeyens A, Naessens E, Van Nuffel A, Weening KE, Reilly A-M et al. HIV-1 Vpr N-terminal tagging affects alternative splicing of the viral genome. Sci Rep 2016; 6:34573 [View Article] [PubMed]
     [Google Scholar]
  40. Woldemeskel BA, Kwaa AK, Blankson JN. Viral reservoirs in elite controllers of HIV-1 infection: Implications for HIV cure strategies. EBioMedicine 2020; 62:103118 [View Article] [PubMed]
     [Google Scholar]
  41. Robb ML, Eller LA, Kibuuka H, Rono K, Maganga L et al. Prospective study of acute HIV-1 infection in adults in East Africa and Thailand. N Engl J Med 2016; 374:2120–2130 [View Article] [PubMed]
     [Google Scholar]
  42. Chappell SA, Edelman GM, Mauro VP. Ribosomal tethering and clustering as mechanisms for translation initiation. Proc Natl Acad Sci 2006; 103:18077–18082 [View Article]
     [Google Scholar]
  43. Sato K, Misawa N, Iwami S, Satou Y, Matsuoka M et al. HIV-1 Vpr accelerates viral replication during acute infection by exploitation of proliferating CD4+ T Cells in vivo. PLoS Pathog 2013; 9:e1003812 [View Article]
     [Google Scholar]
  44. Levy DN, Refaeli Y, MacGregor RR, Weiner DB. Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc Natl Acad Sci 1994; 91:10873–10877 [View Article]
     [Google Scholar]
  45. Lubow J, Collins KL. Vpr Is a VIP: HIV Vpr and infected macrophages promote viral pathogenesis. Viruses 2020; 12:E809 [View Article] [PubMed]
     [Google Scholar]
  46. Emerman M. HIV-1, Vpr and the cell cycle. Curr Biol 1996; 6:1096–1103 [View Article]
     [Google Scholar]
  47. Wong ME, Jaworowski A, Hearps AC. The HIV reservoir in monocytes and macrophages. Front Immunol 2019; 10:1435 [View Article] [PubMed]
     [Google Scholar]
  48. Richard J, Sindhu S, Pham TNQ, Belzile J-P, Cohen EA. HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing. Blood 2010; 115:1354–1363 [View Article] [PubMed]
     [Google Scholar]
  49. Greenwood EJD, Williamson JC, Sienkiewicz A, Naamati A, Matheson NJ et al. Promiscuous targeting of cellular proteins by Vpr drives systems-level proteomic remodeling in HIV-1 infection. Cell Rep 2019; 27:1579–1596 [View Article] [PubMed]
     [Google Scholar]
  50. Zhao L, Wang S, Xu M, He Y, Zhang X et al. Vpr counteracts the restriction of LAPTM5 to promote HIV-1 infection in macrophages. Nat Commun 2021; 12: [View Article]
     [Google Scholar]
  51. Zhang F, Bieniasz PD. HIV-1 Vpr induces cell cycle arrest and enhances viral gene expression by depleting CCDC137. Elife 2020; 9:e55806 [View Article]
     [Google Scholar]
  52. Mashiba M, Collins DR, Terry VH, Collins KL. Vpr overcomes macrophage-specific restriction of HIV-1 Env expression and virion production. Cell Host Microbe 2014; 16:722–735 [View Article]
     [Google Scholar]
  53. Bauby H, Ward CC, Hugh-White R, Swanson CM, Schulz R et al. HIV-1 Vpr induces widespread transcriptomic changes in CD4(+) T Cells early postinfection. mBio 2021; 12:e0136921 [View Article]
     [Google Scholar]
  54. Silver ZA, Watkins DI. The role of MHC class I gene products in SIV infection of macaques. Immunogenetics 2017; 69:511–519 [View Article]
     [Google Scholar]
  55. Passaes C, Millet A, Madelain V, Monceaux V, David A et al. Optimal maturation of the SIV-specific CD8+ T Cell response after primary infection is associated with natural control of SIV: ANRS SIC study. Cell Rep 2020; 32:108174 [View Article]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001790
Loading
Development of a novel Macaque-Tropic HIV-1 adapted to cynomolgus macaques
J. Gen. Virol. 103, 001790 (2022); https://doi.org/10.1099/jgv.0.001790
/content/journal/jgv/10.1099/jgv.0.001790
/content/journal/jgv/10.1099/jgv.0.001790
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error