1887

Abstract

Infection of macaques with live attenuated simian immunodeficiency virus (SIV) usually results in long-lasting efficient protection against infection with pathogenic immunodeficiency viruses. However, attenuation by deletion of regulatory genes such as is not complete, leading to a high viral load and fatal disease in some animals. To characterize immunological parameters and polymorphic host factors, we studied 17 rhesus macaques infected with attenuated SIVmac239ΔNU. Eight animals were able to control viral replication, whereas the remaining animals (non-controllers) displayed variable set-point viral loads. Peak viral load at 2 weeks post-infection (p.i.) correlated significantly with set-point viral load (<0.0001). CD4 T-cell frequencies differed significantly soon after infection between controllers and non-controllers. Abnormal B-cell activation previously ascribed to Nef function could already be observed in non-controllers 8 weeks after infection despite the absence of Nef. Two non-controllers developed an AIDS-like disease within 102 weeks p.i. Virus from these animals transmitted to naïve animals replicated at low levels and the recipients did not develop immunodeficiency. This suggested that host factors determined differential viral load and subsequent disease course. Known Mhc class I alleles associated with disease progression in SIV WT infection only marginally influenced the viral load in Δ-infected animals. Protection from SIVmac251 was associated with homozygosity for MHC class II in conjunction with a polymorphism and showed a trend with initial viral replication. We speculated that host factors whose effects were usually masked by Nef were responsible for the different disease courses in individual animals upon infection with -deleted viruses.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.066563-0
2014-10-01
2021-10-22
Loading full text...

Full text loading...

/deliver/fulltext/jgv/95/10/2273.html?itemId=/content/journal/jgv/10.1099/vir.0.066563-0&mimeType=html&fmt=ahah

References

  1. Alexander L., Illyinskii P. O., Lang S. M., Means R. E., Lifson J., Mansfield K., Desrosiers R. C. 2003; Determinants of increased replicative capacity of serially passaged simian immunodeficiency virus with nef deleted in rhesus monkeys. J Virol 77:6823–6835 [View Article][PubMed]
    [Google Scholar]
  2. Alpert M. D., Harvey J. D., Lauer W. A., Reeves R. K., Piatak M. Jr, Carville A., Mansfield K. G., Lifson J. D., Li W.other authors 2012; ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challenge. PLoS Pathog 8:e1002890 [View Article][PubMed]
    [Google Scholar]
  3. Baba T. W., Liska V., Khimani A. H., Ray N. B., Dailey P. J., Penninck D., Bronson R., Greene M. F., McClure H. M.other authors 1999; Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques. Nat Med 5:194–203 [View Article][PubMed]
    [Google Scholar]
  4. Berry N., Ham C., Mee E. T., Rose N. J., Mattiuzzo G., Jenkins A., Page M., Elsley W., Robinson M.other authors 2011; Early potent protection against heterologous SIVsmE660 challenge following live attenuated SIV vaccination in Mauritian cynomolgus macaques. PLoS ONE 6:e23092 [View Article][PubMed]
    [Google Scholar]
  5. Blatt S. P., McCarthy W. F., Bucko-Krasnicka B., Melcher G. P., Boswell R. N., Dolan J., Freeman T. M., Rusnak J. M., Hensley R. E.other authors 1995; Multivariate models for predicting progression to AIDS and survival in human immunodeficiency virus-infected persons. J Infect Dis 171:837–844 [View Article][PubMed]
    [Google Scholar]
  6. Carl S., Daniels R., Iafrate A. J., Easterbrook P., Greenough T. C., Skowronski J., Kirchhoff F. 2000; Partial “repair” of defective NEF genes in a long-term nonprogressor with human immunodeficiency virus type 1 infection. J Infect Dis 181:132–140 [View Article][PubMed]
    [Google Scholar]
  7. Chakrabarti L. A., Metzner K. J., Ivanovic T., Cheng H., Louis-Virelizier J., Connor R. I., Cheng-Mayer C. 2003; A truncated form of Nef selected during pathogenic reversion of simian immunodeficiency virus SIVmac239Δnef increases viral replication. J Virol 77:1245–1256 [View Article][PubMed]
    [Google Scholar]
  8. Connor R. I., Montefiori D. C., Binley J. M., Moore J. P., Bonhoeffer S., Gettie A., Fenamore E. A., Sheridan K. E., Ho D. D.other authors 1998; Temporal analyses of virus replication, immune responses, and efficacy in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J Virol 72:7501–7509[PubMed]
    [Google Scholar]
  9. Daniel M. D., Kirchhoff F., Czajak S. C., Sehgal P. K., Desrosiers R. C. 1992; Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 258:1938–1941 [View Article][PubMed]
    [Google Scholar]
  10. De Milito A. 2004; B lymphocyte dysfunctions in HIV infection. Curr HIV Res 2:11–21 [View Article][PubMed]
    [Google Scholar]
  11. de Souza M. S., Ratto-Kim S., Chuenarom W., Schuetz A., Chantakulkij S., Nuntapinit B., Valencia-Micolta A., Thelian D., Nitayaphan S.other authors 2012; The Thai phase III trial (RV144) vaccine regimen induces T cell responses that preferentially target epitopes within the V2 region of HIV-1 envelope. J Immunol 188:5166–5176 [View Article][PubMed]
    [Google Scholar]
  12. Dolan M. J., Clerici M., Blatt S. P., Hendrix C. W., Melcher G. P., Boswell R. N., Freeman T. M., Ward W., Hensley R., Shearer G. M. 1995; In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ T cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus. J Infect Dis 172:79–87 [View Article][PubMed]
    [Google Scholar]
  13. Fellay J., Ge D., Shianna K. V., Colombo S., Ledergerber B., Cirulli E. T., Urban T. J., Zhang K., Gumbs C. E.other authors 2009; Common genetic variation and the control of HIV-1 in humans. PLoS Genet 5:e1000791 [View Article][PubMed]
    [Google Scholar]
  14. Freissmuth D., Hiltgartner A., Stahl-Hennig C., Fuchs D., Tenner-Racz K., Racz P., Uberla K., Strasak A., Dierich M. P.other authors 2010; Analysis of humoral immune responses in rhesus macaques vaccinated with attenuated SIVmac239Δnef and challenged with pathogenic SIVmac251. J Med Primatol 39:97–111 [View Article][PubMed]
    [Google Scholar]
  15. Fukazawa Y., Park H., Cameron M. J., Lefebvre F., Lum R., Coombes N., Mahyari E., Hagen S. I., Bae J. Y.other authors 2012; Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines. Nat Med 18:1673–1681 [View Article][PubMed]
    [Google Scholar]
  16. Giraldo-Vela J. P., Rudersdorf R., Chung C., Qi Y., Wallace L. T., Bimber B., Borchardt G. J., Fisk D. L., Glidden C. E.other authors 2008; The major histocompatibility complex class II alleles Mamu-DRB1*1003 and -DRB1*0306 are enriched in a cohort of simian immunodeficiency virus-infected rhesus macaque elite controllers. J Virol 82:859–870 [View Article][PubMed]
    [Google Scholar]
  17. Gorry P. R., Churchill M., Learmont J., Cherry C., Dyer W. B., Wesselingh S. L., Sullivan J. S. 2007; Replication-dependent pathogenicity of attenuated nef-deleted HIV-1 in vivo. J Acquir Immune Defic Syndr 46:390–394 [View Article][PubMed]
    [Google Scholar]
  18. Gundlach B. R., Linhart H., Dittmer U., Sopper S., Reiprich S., Fuchs D., Fleckenstein B., Hunsmann G., Stahl-Hennig C., Uberla K. 1997; Construction, replication, and immunogenic properties of a simian immunodeficiency virus expressing interleukin-2. J Virol 71:2225–2232[PubMed]
    [Google Scholar]
  19. Gundlach B. R., Lewis M. G., Sopper S., Schnell T., Sodroski J., Stahl-Hennig C., Uberla K. 2000; Evidence for recombination of live, attenuated immunodeficiency virus vaccine with challenge virus to a more virulent strain. J Virol 74:3537–3542 [View Article][PubMed]
    [Google Scholar]
  20. Haynes B. F., Gilbert P. B., McElrath M. J., Zolla-Pazner S., Tomaras G. D., Alam S. M., Evans D. T., Montefiori D. C., Karnasuta C.other authors 2012; Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med 366:1275–1286 [View Article][PubMed]
    [Google Scholar]
  21. Hofmann-Lehmann R., Vlasak J., Williams A. L., Chenine A. L., McClure H. M., Anderson D. C., O’Neil S., Ruprecht R. M. 2003; Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation. AIDS 17:157–166 [View Article][PubMed]
    [Google Scholar]
  22. Holterman L., Niphuis H., ten Haaft P. J., Goudsmit J., Baskin G., Heeney J. L. 1999; Specific passage of simian immunodeficiency virus from end-stage disease results in accelerated progression to AIDS in rhesus macaques. J Gen Virol 80:3089–3097[PubMed]
    [Google Scholar]
  23. Hrecka K., Swigut T., Schindler M., Kirchhoff F., Skowronski J. 2005; Nef proteins from diverse groups of primate lentiviruses downmodulate CXCR4 to inhibit migration to the chemokine stromal derived factor 1. J Virol 79:10650–10659 [View Article][PubMed]
    [Google Scholar]
  24. Kaul S., Fishbein M. C., Siegel R. J. 1991; Cardiac manifestations of acquired immune deficiency syndrome: a 1991 update. Am Heart J 122:535–544 [View Article][PubMed]
    [Google Scholar]
  25. Khazand M., Peiberg C., Nagy M., Sauermann U. 1999; Mhc-DQ-DRB haplotype analysis in the rhesus macaque: evidence for a number of different haplotypes displaying a low allelic polymorphism. Tissue Antigens 54:615–624 [View Article][PubMed]
    [Google Scholar]
  26. Kneitz C., Kerkau T., Müller J., Coulibaly C., Stahl-Hennig C., Hunsmann G., Hünig T., Schimpl A. 1993; Early phenotypic and functional alterations in lymphocytes from simian immunodeficiency virus infected macaques. Vet Immunol Immunopathol 36:239–255 [View Article][PubMed]
    [Google Scholar]
  27. Koff W. C., Johnson P. R., Watkins D. I., Burton D. R., Lifson J. D., Hasenkrug K. J., McDermott A. B., Schultz A., Zamb T. J.other authors 2006; HIV vaccine design: insights from live attenuated SIV vaccines. Nat Immunol 7:19–23 [View Article][PubMed]
    [Google Scholar]
  28. Landi A., Iannucci V., Nuffel A. V., Meuwissen P., Verhasselt B. 2011; One protein to rule them all: modulation of cell surface receptors and molecules by HIV Nef. Curr HIV Res 9:496–504 [View Article][PubMed]
    [Google Scholar]
  29. Mansfield K., Lang S. M., Gauduin M. C., Sanford H. B., Lifson J. D., Johnson R. P., Desrosiers R. C. 2008; Vaccine protection by live, attenuated simian immunodeficiency virus in the absence of high-titer antibody responses and high-frequency cellular immune responses measurable in the periphery. J Virol 82:4135–4148 [View Article][PubMed]
    [Google Scholar]
  30. Michel N., Ganter K., Venzke S., Bitzegeio J., Fackler O. T., Keppler O. T. 2006; The Nef protein of human immunodeficiency virus is a broad-spectrum modulator of chemokine receptor cell surface levels that acts independently of classical motifs for receptor endocytosis and Gαi signaling. Mol Biol Cell 17:3578–3590 [View Article][PubMed]
    [Google Scholar]
  31. Moir S., Fauci A. S. 2009; B cells in HIV infection and disease. Nat Rev Immunol 9:235–245 [View Article][PubMed]
    [Google Scholar]
  32. Moir S., Fauci A. S. 2010; Nef, macrophages and B cells: a highway for evasion. Immunol Cell Biol 88:1–2 [View Article][PubMed]
    [Google Scholar]
  33. Niino M., Hirotani M., Miyazaki Y., Sasaki H. 2009; Memory and naïve B-cell subsets in patients with multiple sclerosis. Neurosci Lett 464:74–78 [View Article][PubMed]
    [Google Scholar]
  34. Nilsson C., Mäkitalo B., Thorstensson R., Norley S., Binninger-Schinzel D., Cranage M., Rud E., Biberfeld G., Putkonen P. 1998; Live attenuated simian immunodeficiency virus (SIV)mac in macaques can induce protection against mucosal infection with SIVsm. AIDS 12:2261–2270 [View Article][PubMed]
    [Google Scholar]
  35. Oh D. Y., Baumann K., Hamouda O., Eckert J. K., Neumann K., Kücherer C., Bartmeyer B., Poggensee G., Oh N.other authors 2009; A frequent functional toll-like receptor 7 polymorphism is associated with accelerated HIV-1 disease progression. AIDS 23:297–307 [View Article][PubMed]
    [Google Scholar]
  36. Putkonen P., Kaaya E. E., Böttiger D., Li S. L., Nilsson C., Biberfeld P., Biberfeld G. 1992; Clinical features and predictive markers of disease progression in cynomolgus monkeys experimentally infected with simian immunodeficiency virus. AIDS 6:257–263 [View Article][PubMed]
    [Google Scholar]
  37. Qiao X., He B., Chiu A., Knowles D. M., Chadburn A., Cerutti A. 2006; Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nat Immunol 7:302–310 [View Article][PubMed]
    [Google Scholar]
  38. Reynolds M. R., Weiler A. M., Weisgrau K. L., Piaskowski S. M., Furlott J. R., Weinfurter J. T., Kaizu M., Soma T., León E. J.other authors 2008; Macaques vaccinated with live-attenuated SIV control replication of heterologous virus. J Exp Med 205:2537–2550 [View Article][PubMed]
    [Google Scholar]
  39. Sauermann U., Siddiqui R., Suh Y. S., Platzer M., Leuchte N., Meyer H., Mätz-Rensing K., Stoiber H., Nürnberg P.other authors 2008; Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques. Genes Immun 9:69–80 [View Article][PubMed]
    [Google Scholar]
  40. Sawai E. T., Hamza M. S., Ye M., Shaw K. E., Luciw P. A. 2000; Pathogenic conversion of live attenuated simian immunodeficiency virus vaccines is associated with expression of truncated Nef. J Virol 74:2038–2045 [View Article][PubMed]
    [Google Scholar]
  41. Sharpe S. A., Cope A., Dowall S., Berry N., Ham C., Heeney J. L., Hopkins D., Easterbrook L., Dennis M.other authors 2004; Macaques infected long-term with attenuated simian immunodeficiency virus (SIVmac) remain resistant to wild-type challenge, despite declining cytotoxic T lymphocyte responses to an immunodominant epitope. J Gen Virol 85:2591–2602 [View Article][PubMed]
    [Google Scholar]
  42. Siddiqui R. A., Sauermann U., Altmüller J., Fritzer E., Nothnagel M., Dalibor N., Fellay J., Kaup F. J., Stahl-Hennig C.other authors 2009; X chromosomal variation is associated with slow progression to AIDS in HIV-1-infected women. Am J Hum Genet 85:228–239 [View Article][PubMed]
    [Google Scholar]
  43. Siddiqui R. A., Krawczak M., Platzer M., Sauermann U. 2011; Association of TLR7 variants with AIDS-like disease and AIDS vaccine efficacy in rhesus macaques. PLoS ONE 6:e25474 [View Article][PubMed]
    [Google Scholar]
  44. Sopper S., Stahl-Hennig C., Demuth M., Johnston I. C., Dörries R., ter Meulen V. 1997; Lymphocyte subsets and expression of differentiation markers in blood and lymphoid organs of rhesus monkeys. Cytometry 29:351–362 [View Article][PubMed]
    [Google Scholar]
  45. Sopper S., Sauer U., Müller J. G., Stahl-Hennig C., ter Meulen V. 2000; Early activation and proliferation of T cells in simian immunodeficiency virus-infected rhesus monkeys. AIDS Res Hum Retroviruses 16:689–697 [View Article][PubMed]
    [Google Scholar]
  46. Stahl-Hennig C., Voss G., Nick S., Petry H., Fuchs D., Wachter H., Coulibaly C., Lüke W., Hunsmann G. 1992; Immunization with Tween-ether-treated SIV adsorbed onto aluminum hydroxide protects monkeys against experimental SIV infection. Virology 186:588–596 [View Article][PubMed]
    [Google Scholar]
  47. Stahl-Hennig C., Dittmer U., Nisslein T., Petry H., Jurkiewicz E., Fuchs D., Wachter H., Mätz-Rensing K., Kuhn E. M.other authors 1996; Rapid development of vaccine protection in macaques by live-attenuated simian immunodeficiency virus. J Gen Virol 77:2969–2981 [View Article][PubMed]
    [Google Scholar]
  48. Stahl-Hennig C., Eisenblatter M., Franz M., Stoiber H., Tenner-Racz K., Suh Y. S., Jasny E., Falkensammer B., Ugucchioni M.other authors 2007; A single vaccination with attenuated SIVmac 239 via the tonsillar route confers partial protection against challenge with SIVmac 251 at a distant mucosal site, the rectum. Front Biosci 12:2107–2123 [View Article][PubMed]
    [Google Scholar]
  49. Stebbings R., Berry N., Stott J., Hull R., Walker B., Lines J., Elsley W., Brown S., Wade-Evans A.other authors 2004; Vaccination with live attenuated simian immunodeficiency virus for 21 days protects against superinfection. Virology 330:249–260 [View Article][PubMed]
    [Google Scholar]
  50. Stebbings R., Berry N., Waldmann H., Bird P., Hale G., Stott J., North D., Hull R., Hall J.other authors 2005; CD8+ lymphocytes do not mediate protection against acute superinfection 20 days after vaccination with a live attenuated simian immunodeficiency virus. J Virol 79:12264–12272 [View Article][PubMed]
    [Google Scholar]
  51. Stolte-Leeb N., Sauermann U., Norley S., Fagrouch Z., Heeney J., Franz M., Hunsmann G., Stahl-Hennig C. 2006; Sustained conservation of CD4+ T cells in multiprotein triple modality-immunized rhesus macaques after intrarectal challenge with simian immunodeficiency virus. Viral Immunol 19:448–457 [View Article][PubMed]
    [Google Scholar]
  52. Swingler S., Zhou J., Swingler C., Dauphin A., Greenough T., Jolicoeur P., Stevenson M. 2008; Evidence for a pathogenic determinant in HIV-1 Nef involved in B cell dysfunction in HIV/AIDS. Cell Host Microbe 4:63–76 [View Article][PubMed]
    [Google Scholar]
  53. Tan R. C., Harouse J. M., Gettie A., Cheng-Mayer C. 1999; In vivo adaptation of SHIV(SF162): chimeric virus expressing a NSI, CCR5-specific envelope protein. J Med Primatol 28:164–168 [View Article][PubMed]
    [Google Scholar]
  54. Ten Haaft P., Verstrepen B., Uberla K., Rosenwirth B., Heeney J. 1998; A pathogenic threshold of virus load defined in simian immunodeficiency virus- or simian-human immunodeficiency virus-infected macaques. J Virol 72:10281–10285[PubMed]
    [Google Scholar]
  55. Tenner-Racz K., Stahl Hennig C., Uberla K., Stoiber H., Ignatius R., Heeney J., Steinman R. M., Racz P. 2004; Early protection against pathogenic virus infection at a mucosal challenge site after vaccination with attenuated simian immunodeficiency virus. Proc Natl Acad Sci U S A 101:3017–3022 [View Article][PubMed]
    [Google Scholar]
  56. Vigon N., Sauermann U. 2002; Sequence-based typing techniques for rhesus macaque MhcMamu-DQB1 allow the identification of more than 35 alleles. Tissue Antigens 59:88–94 [View Article][PubMed]
    [Google Scholar]
  57. Wade-Evans A. M., Stott J., Hanke T., Stebbings R., Berry N., Lines J., Sangster R., Silvera P., Walker B.other authors 2001; Specific proliferative T cell responses and antibodies elicited by vaccination with simian immunodeficiency virus Nef do not confer protection against virus challenge. AIDS Res Hum Retroviruses 17:1517–1526 [View Article][PubMed]
    [Google Scholar]
  58. Weber J. N., Weiss R. A., Roberts C., Weller I., Tedder R. S., Clapham P. R., Parker D., Duncan J., Carne C.other authors 1987; Human immunodeficiency virus infection in two cohorts of homosexual men: neutralising sera and association of anti-gag antibody with prognosis. Lancet 329:119–122 [View Article][PubMed]
    [Google Scholar]
  59. Whatmore A. M., Cook N., Hall G. A., Sharpe S., Rud E. W., Cranage M. P. 1995; Repair and evolution of nef in vivo modulates simian immunodeficiency virus virulence. J Virol 69:5117–5123[PubMed]
    [Google Scholar]
  60. Whitney J. B., Ruprecht R. M. 2004; Live attenuated HIV vaccines: pitfalls and prospects. Curr Opin Infect Dis 17:17–26 [View Article][PubMed]
    [Google Scholar]
  61. Xu W., Santini P. A., Sullivan J. S., He B., Shan M., Ball S. C., Dyer W. B., Ketas T. J., Chadburn A.other authors 2009; HIV-1 evades virus-specific IgG2 and IgA responses by targeting systemic and intestinal B cells via long-range intercellular conduits. Nat Immunol 10:1008–1017 [View Article][PubMed]
    [Google Scholar]
  62. Zhang F., Wilson S. J., Landford W. C., Virgen B., Gregory D., Johnson M. C., Munch J., Kirchhoff F., Bieniasz P. D., Hatziioannou T. 2009; Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Cell Host Microbe 6:54–67 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.066563-0
Loading
/content/journal/jgv/10.1099/vir.0.066563-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited this month 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