Risk of HIV Infection and Lethality Are Decreased in CCR5del32 Heterozygotes: Focus Nosocomial Infection Study and Meta-analysis

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Abstract

CCR5del32 Homozygous deletion in the chemokine receptor R5 gene provides almost complete protection to individuals against HIV infection. However, data relating to the protective effect for CCR5del32 heterozygous individuals have been contradictory. The frequency of the CCR5del32 allele in population control cohorts was compared with that of a group of children (27 Kalmyks and 50 Russians) infected by G-subtype HIV-1 in a nosocomial outbreak. The frequency of the CCR5del32 allele was shown to be lower among the infected children in comparison with that of the control group; however, the difference was small and statistically insignificant. Similar results were obtained in a number of earlier studies. The insignificance of the small differences could be a result of one of two reasons. (i) The fact that there is no protective effect of the heterozygous state, and that the phenomenon depends only on the fluctuation of allele frequencies. In this case, there would be no differences even if the infected cohort is enlarged. (ii)The protective effect of the heterozygous state is real; however, the size of the studied cohort is insufficient to demonstrate it. In order to discern between these two reasons, a meta-analysis of data from 25 published articles (a total of 5,963 HIV-infected individuals and 5,048 individuals in the control group, including the authors’ own data) was undertaken. A conclusion was drawn from the meta-analysis that the CCR5del32 allele protects individuals against the HIV infection even in a heterozygous state (OR=1.22, 95%CI=1.10-1.36). The risk of HIV infection for CCR5 wt/del32 heterozygotes was lower by at least 13% as compared to that for wild type CCR5 wt/wt homozygotes. Prior to this study, no data of the type or any conclusions had been published for Caucasians. The mortality rate in the 15 years following the infection was found to be approximately 40% lower for CCR5del32 heterozygotes in comparison with that for the wild type homozygotes in the studied group. The size of the studied group was insufficient to claim difference validity (OR=2.0; p= 0.705), even though the effect quantitatively matched the published data. The features of the meta-analysis influencing the threshold level and the statistical validity of the effects are being discussed. The level of the CCR5del32 protective effect on the chances to be infected with HIV and on the outcome of the HIV infection was assessed for various ethnic groups.

About the authors

S. A. Borinskaya

Vavilov Institute of General Genetics, Russian Academy of Sciences

Email: yankovsky@vigg.ru
Russian Federation

Zh. M. Kozhekbaeva

Vavilov Institute of General Genetics, Russian Academy of Sciences

Email: yankovsky@vigg.ru
Russian Federation

A. V. Zalesov

Vavilov Institute of General Genetics, Russian Academy of Sciences; Moscow Institute of Physics and Technology

Email: yankovsky@vigg.ru
Russian Federation

E. V. Olseeva

Ministry of Health and Social Development of the Republic of Kalmykia

Email: yankovsky@vigg.ru
Russian Federation

A. R. Maksimov

Blood Centre of the Republic of Kalmykia

Email: yankovsky@vigg.ru
Russian Federation

S. I. Kutsev

Rostov State Medical University

Email: yankovsky@vigg.ru
Russian Federation

M. M. Garaev

Ivanovsky Research Institute of Virology, Russian Academy of Medical Sciences

Email: yankovsky@vigg.ru
Russian Federation

A. V. Rubanovich

Vavilov Institute of General Genetics, Russian Academy of Sciences

Email: yankovsky@vigg.ru
Russian Federation

N. K. Yankovsky

Vavilov Institute of General Genetics, Russian Academy of Sciences; Moscow Institute of Physics and Technology; Lomonosov Moscow State University

Author for correspondence.
Email: yankovsky@vigg.ru
Russian Federation

References

  1. Bridge J., Lazarus J.V., Atun R. // AIDS. 2010. V. 24. Suppl 3. P. S86-S94.
  2. Pokrovskiĭ V.V., Eramova I.Iu., Deulina M.O., Lipetikov VV., Iashkulov K.B., Sliusareva L.A., Chemizova N.M., Savchenko S.P. // Zh Mikrobiol Epidemiol Immunobiol. 1990. № 4. P 17-23.
  3. Pokrovskiĭ VV. Epidemiologiya i profilaktika VICh-infektsii i SPIDa (Epidemiology and prophylactics of HIV infection and AIDS). M: Meditsina. 1996. 275 p.
  4. Restrepo C., Rallon N.I., Carrillo J., Soriano V., Blanco J., Benito J.M. // AIDS Rev. 2011. V. 13. № 1. P. 30-40.
  5. Martinson J.J., Chapman N.H., Rees D.C., Liu Y.T., Clegg J.B. // Nat. Genet. 1997. V. 16. № 1. P. 100-103.
  6. Novembre J., Galvani A.P., Slatkin M. // PLoS Biol. 2005. V. 3. № 11. P. e339.
  7. Balanovsky O., Pocheshkhova E., Pshenichnov A., Solovieva D., Kuznetsova M., Voronko O., Churnosov M., Tegako O., Atramentova L., Lavryashina M., et al. // J. Physiol. Anthropol. Appl. Human Sci. 2005. V. 24. № 4. P. 375-382.
  8. Huang Y., Paxton W.A., Wolinsky S.M., Neumann A.U., Zhang L., He T., Kang S., Ceradini D., Jin Z., et al. // Nat. Med. 1996. V. 2. P. 1240-1243.
  9. Liu R., Paxton W.A., Choe S., Ceradini D., Martin S.R. // Cell. 1996. V. 86. P. 367-377.
  10. Samson M., Libert F., Doranz B.J., Rucker J., Liesnard C., Farber C.M., Saragosti S., Lapoumeroulie C., Cognaux J., Forceille C. // Nature. 1996. V. 382. P. 722-725.
  11. Dean M., Carrington M., Winkler C., Huttley G.A., Smith M.W., Allikmets R., Goedert J., Buchbinder S.P., Vittinghoff E., Gomperts E., et al. // Science. 1996. V. 273. P. 1856-1862.
  12. Marmor M., Sheppard H.W., Donnell D., Bozeman S., Celum C., Buchbinder S., Koblin B., Seage G.R., HIV Network for Prevention Trials Vaccine Preparedness Protocol Team. // J. Acquir. Immune Defic. Syndr. 2001. V. 27. № 5. P. 472-481.
  13. Agrawal L., Lu X., Qingwen J., VanHorn-Ali Z., Nicolescu I.V., McDermott D.H., Murphy P.M., Alkhatib G. // J. Virol. 2004. V. 78. P. 2277-2287.
  14. Oh D.Y., Jessen H., Kücherer C., Neumann K., Oh N., Poggensee G., Bartmeyer B., Jessen A., Pruss A., Schumann R.R., et al. // PloS One. 2008. V. 3. № 7. P. e2747.
  15. Hendel H., Hénon N., Lebuanec H., Lachgar A., Poncelet H., Caillat-Zucman S., Winkler C.A., Smith M.W., Kenefic L., O'Brien S., et al. // J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 1998. V. 19. P. 381-386.
  16. Misrahi M., Teglas J.P., N'Go N., Burgard M., Mayaux M.J., Rouzioux C., Delfraissy J.F., Blanche S. // JAMA. 1998. V. 279. P. 277-280.
  17. Ioannidis J.P., Contopoulos-Ioannidis D.G., Rosenberg P.S., Goedert J.J., De Rossi A., Espanol T., Frenkel L., Mayaux M.J., Newell M.L., Pahwa S.G., et al. // AIDS. 2003. V. 17. P. 1631-1638.
  18. Mulherin S.A., O'Brien T.R., Ioannidis J.P., Goedert J. J., Buchbinder S.P., Coutinho R.A., Jamieson B.D., Meyer L., Michael N.L., Pantaleo G., et al. // AIDS. 2003. V. 17. P. 377-387.
  19. Barroga C.F., Raskino C., Fangon M.C., Palumbo P.E., Baker C.J., Englund J.A., Spector S.A. // J. Infect Dis. 2000. V. 182. № 2. P. 413-419.
  20. Kazennova E.V., Aarons E., Selimova L.M., Ladnaia N.N., Kravchenko A.V., Zhemchugov V.E., Chaingon-Popov R., Weber J., Pokrovski! V.V., Bobkov A.F. // Vopr Virusol. 1998. V. 43 (1). P. 30-32.
  21. Shadrina M.I., Kapylov V.M., Miloserdova O.V., Slominskiĭ P. A., Limborskaia S.A. // Genetika. 2000. V. 36 (5). P. 718-720.
  22. Adojaan M., Mölder T., Männik A., Kivisild T., Villems R., Krispin T., Ustav M. // AIDS Res. Hum. Retroviruses. 2007. V. 23. № 2. P. 193-197.
  23. Bobkov A., Cheingsong-Popov R., Garaev M., Rzhaninova A., Kaleebu P., Beddows S., Bachmann M.H., Mullins J.I., Louwagie J., Janssens W., et al. // AIDS. 1994. V. 8. № 12. P. 1649-1655.
  24. Gafarova I.E., Shideeva Zh.A., Sandzhieva D.B., Garaev M.M. // Vopr Virusol. 2010. V. 55 (1). P. 16-22.
  25. Slominskiĭ P. A., Shadrina M.I., Spitsyn V.A., Mikulich V.A., Khusnutdinova E.K., Limborskaia S.A. // Genetika. 1997. V. 33 (11). P. 1596-1598.
  26. Abramson J.H. // Epidemiol. Perspectives & Innovations. 2004. V. 1. P. 6.
  27. Du Q., Wang F., Hong W., Liu M., Jin L., Shi H., Lei Z., E.E. // Zhonghua Liu Xing Bing Xue Za Zhi. 2000. V. 6. P. 413-416.
  28. Magierowska M., Lepage V., Boubnova L., Carcassi C., de Juan D., Djoulah S., El Chenawi F., Grunnet N., Hallo L., Ivanova R., et al. // Immunogenetics. 1998. V. 48. P. 417-419.
  29. Kozhekbaeva G.M., Borodina T.A., Borinskaia S.A., Gusar V.A., Feshchenko S.P., Akhmetova V.L., Khusainova R.I., Gupalo E.Iu., Spitsyn V.A., Grechanina E.Ia., Khusnutdinova E.K., Iankovskiĭ N.K. // Genetika. 2004. V. 40 (10). P. 1394-1401.
  30. Aseev M.V., Shaui A., Baranov V.S. // Russ J. Genet. 1997. V. 33 (12). P. 1724-1726.
  31. Libert F., Cochaux P., Beckman G., Samson M., Aksenova M., Cao A., Czeizel A., Claustres M., de la Rúa C., Ferrari M., et al. // Hum. Mol. Genet. 1998. V. 7. № 3. P. 399-406.
  32. Voevodin A., Samilchuk E., Dashti S. // J. Med. Virol. 1998. V. 55. P. 147-151.
  33. Limborska S.A., Balanovsky O.P., Balanovskaya E.V., Slominsky P. A., Schadrina M.I., Livshits L.A., Kravchenko S.A., Pampuha V.M., Khusnutdinova E.K., Spitsyn V.A. // Hum. Hered. 2002. V. 53. № 1. P. 49-54.
  34. Yudin N.S., Vinogradov S.V., Potapova T.A., Naykova T.M., Sitnikova V.V., Kulikov I.V., Khasnulin V.I., Konchuk C., Vloschinskii P.E., Ivanov S.V., et al. // Hum. Genet. 1998. V. 102. P. 695-698.
  35. Riabov G.S., Kazennova E.V., Korepanova L.B., Mal'tseva E.A., Zhalnin V.V., Krasnikova L.A., Zverev S.Ia., Pokrovskiĭ V.V., Bobkov A.F., Weber J.N. // Vopr Virusol. 2002. V. 47 (4). P. 13-16.
  36. Ryabov G.S., Kazennova E.V., Bobkova M.R., Bobkov A.F. // Genet. Test. 2004. V. 8. № 1. P. 73-76.
  37. Morawetz R.A., Rizzardi G.P., Glauser D., Rutschmann O., Hirschel B., Perrin L., Opravil M., Flepp M., von Overbeck J., Glauser M.P., et al. // Eur. J. Immunol. 1997. V. 27. № 12. P. 3223-3227.
  38. Lucotte G. // Hum. Immunol. 2001. V. 62. № 9. P. 933-936.
  39. Zimmerman P. A., Buckler-White A., Alkhatib G., Spalding T., Kubofcik J., Combadiere C., Weissman D., Cohen O., Rubbert A., Lam G., et al. // Mol. Med. 1997. V. 3. P. 23-36.
  40. Eugen-Olsen J., Iversen A.K., Garred P., Koppelhus U., Pedersen C., Benfield T.L., Sorensen A.M., Katzenstein T., Dickmeiss E., Gerstoft J., et al. // AIDS. 1997. V. 11. P. 305-310.
  41. Balotta C., Bagnarelli P., Violin M., Ridolfo A.L., Zhou D., Berlusconi A., Corvasce S., Corbellino M., Clementi M., Clerici M., et al. // AIDS. 1997. V. 11. № 10. P. 67-71.
  42. Stewart G.J., Ashton L.J., Biti R.A., Ffrench R.A., Bennetts B.H., Newcombe N.R., Benson E.M., Carr A., Cooper D.A., Kaldor J.M. // AIDS. 1997. V. 11. № 15. P.1833-1838.
  43. Pastinen T., Liitsola K., Niini P., Salminen M., Syvänen A.C. // AIDS Res. Hum. Retroviruses. 1998. V. 14. № 8. P. 695-698.
  44. Poljak M., Tomazic J., Seme K., Maticic M., Vidmar L. // Acta Virol. 1998. V. 42. № 1. P. 23-26.
  45. Alvarez V., López-Larrea C., Coto E. // Hum. Genet. 1998. V. 102. № 4. P. 483-486.
  46. Ruiz A., Royo J.L., Rubio A., Borrego S., Leal M., Sánchez B., Nuñez-Roldán A., Antiñolo G. // AIDS Res. Hum. Retroviruses. 2001. V. 17. № 2. P. 191-193.
  47. Barber Y., Rubio C., Fernández E., Rubio M., Fibla J. // J. Infect Dis. 2001. V. 184. № 10. P. 1279-1288.
  48. Barabás E., Kemény B., González R., Várkonyi V., Nagy K., Horváth A. // Int. J. STD AIDS. 2002. V. 13. № 10. P. 691-697.
  49. Philpott S., Burger H., Charbonneau T., Grimson R., Vermund S.H., Visosky A., Nachman S., Kovacs A., Tropper P., Frey H., et al. // J. Acquir. Immune Defic. Syndr. 1999. V. 21. № 3. P. 189-193.
  50. Bogner J.R., Lutz B., Klein H.G., Pollerer C., Troendle U., Goebel F.D. // HIV Med. 2004. V. 5. № 4. P. 64-72.
  51. Liu H., Hwangbo Y., Holte S., Lee J., Wang C., Kaupp N., Zhu H., Celum C., Corey L., McElrath M.J. // J. Infect. Dis. 2004. V. 190. № 6. P. 1055-1058.
  52. Wasik T.J., Smoleń J., Kruszyński P., Bratosiewicz-Wasik J., Beniowski M. // Wiad Lek. 2005. V. 58. № 9-10. P. 500-507.
  53. Trecarichi E.M., Tumbarello M., de Gaetano Donati K., Tamburrini E., Cauda R., Brahe C., Tiziano F.D. // AIDS Res Ther. 2006. V. 25. P. 3-22.
  54. Takácová M., Nogová P., Hábeková M., Staneková D. // AIDS. 2008. V. 11. № 15. P. 1833-1838.
  55. Parczewski M., Leszczyszyn-Pynka M., Kaczmarczyk M., Adler G., Binczak-Kuleta A., Loniewska B., Boron-Kaczmarska A., Ciechanowicz A. // J. Appl. Genet. 2009. V. 50. № 2. P. 159-166.
  56. Egger M., Smith G.D., Schneider M., Minder C. // Br. Med. J. 1997. V. 315. P. 629-634.
  57. Viera A.J. // South Med. J. 2008. V. 101. № 7. P. 730-734.
  58. Salkowitz J.R., Purvis S.F., Meyerson H., Zimmerman P., O'Brien T.R., Aledort L., Eyster M.E., Hilgartner M., Kessler C., Konkle B.A., et al. // Clin. Immunol. 2001. V. 98. № 2. P. 200-211.
  59. Lederman M.M., Alter G., Daskalakis D.C., Rodriguez B., Sieg S.F., Hardy G., Cho M., Anthony D., Harding C., Weinberg A., et al. // J. Infect. Dis. 2010. V. 202. Suppl. 3. P. S333-S338.
  60. Parczewski M., Bander D., Leszczyszyn-Pynka M., Urbanska A., Kaczmarczyk M., Ciechanowicz A., Boron-Kaczmarska A. // PLoS One. 2011. V. 6. № 7. P. e22215 (1-11).
  61. He X.F., Jia Y. J., Su J., Chen Q., Zhu W.C., Yu S.Y. // Nan Fang Yi Ke Da Xue Xue Bao. 2011. V. 31. № 5. P. 791-795.
  62. Piacentini L., Biasin M., Fenizia C., Clerici M. // J. Intern. Med. 2009. V. 265. № 1. P. 110-124.

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Copyright (c) 2012 Borinskaya S.A., Kozhekbaeva Z.M., Zalesov A.V., Olseeva E.V., Maksimov A.R., Kutsev S.I., Garaev M.M., Rubanovich A.V., Yankovsky N.K.

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