Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1996 Jan;70(1):445–458. doi: 10.1128/jvi.70.1.445-458.1996

Quantitative analysis of serum neutralization of human immunodeficiency virus type 1 from subtypes A, B, C, D, E, F, and I: lack of direct correlation between neutralization serotypes and genetic subtypes and evidence for prevalent serum-dependent infectivity enhancement.

L G Kostrikis 1, Y Cao 1, H Ngai 1, J P Moore 1, D D Ho 1
PMCID: PMC189833  PMID: 8523557

Abstract

Human immunodeficiency virus type 1 (HIV-1) M group strains have been assigned to date to nine distinct genetic subtypes, designated A through I, according to phylogenetic analyses of nucleotide sequences of their env or gag genes. Whether there is any relationship between phylogenetic subtypes and the neutralization serotypes is not clear, yet defining the nature of any such relationship by mathematical means would be of major importance for the development of globally effective HIV-1 vaccines. We have therefore developed a quantitative method to analyze serum neutralization of HIV-1 isolates and to identify HIV-1 neutralization serotypes. This method involves calculations of the neutralization index, N(i), a newly defined parameter derived from plots generated from in vitro neutralization assays, calculations of pairwise serum-virus vector distances, and cluster analyses. We have applied this approach to analyze three independent neutralization matrices involving primary HIV-1 strains and sera from genetic subtypes A, B, C, D, E, F, and I. Detailed serum and HIV-1 isolate cluster analyses have shown that in general, the identified neutralization serotypes do not directly correlate with HIV-1 genetic subtypes. These results suggest that neutralization serotypes do not during natural HIV-1 infection are not governed by antibodies directed against simple epitopes within gp120 monomers. A significant proportion (28%) of 1,213 combinations of sera and HIV-1 isolates caused serum-dependent infectivity enhancement [negative N(i) values] rather than neutralization. We also noted that negative N(i) values tended to correlate better with certain HIV-1 isolates rather than with HIV-1-positive sera. Syncytium-inducing variants of HIV-1 were slightly more likely than non-syncytium-inducing variants to undergo serum-dependent infectivity enhancement, although the latter variants could clearly be susceptible to enhancement.

Full Text

The Full Text of this article is available as a PDF (309.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abimiku A. G., Stern T. L., Zwandor A., Markham P. D., Calef C., Kyari S., Saxinger W. C., Gallo R. C., Robert-Guroff M., Reitz M. S. Subgroup G HIV type 1 isolates from Nigeria. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1581–1583. doi: 10.1089/aid.1994.10.1581. [DOI] [PubMed] [Google Scholar]
  2. Allan J. S., Strauss J., Buck D. W. Enhancement of SIV infection with soluble receptor molecules. Science. 1990 Mar 2;247(4946):1084–1088. doi: 10.1126/science.2309120. [DOI] [PubMed] [Google Scholar]
  3. Baskar P. V., Ray S. C., Rao R., Quinn T. C., Hildreth J. E., Bollinger R. C. Presence in India of HIV type 1 similar to North American strains. AIDS Res Hum Retroviruses. 1994 Aug;10(8):1039–1041. doi: 10.1089/aid.1994.10.1039. [DOI] [PubMed] [Google Scholar]
  4. Bobkov A., Cheingsong-Popov R., Garaev M., Rzhaninova A., Kaleebu P., Beddows S., Bachmann M. H., Mullins J. I., Louwagie J., Janssens W. Identification of an env G subtype and heterogeneity of HIV-1 strains in the Russian Federation and Belarus. AIDS. 1994 Dec;8(12):1649–1655. doi: 10.1097/00002030-199412000-00002. [DOI] [PubMed] [Google Scholar]
  5. Bruce C., Clegg C., Featherstone A., Smith J., Biryahawaho B., Downing R., Oram J. Presence of multiple genetic subtypes of human immunodeficiency virus type 1 proviruses in Uganda. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1543–1550. doi: 10.1089/aid.1994.10.1543. [DOI] [PubMed] [Google Scholar]
  6. Cao Y. Z., Friedman-Kien A. E., Mirabile M., Li X. L., Alam M., Dieterich D., Ho D. D. HIV-1 neutralizing antibodies in urine from seropositive individuals. J Acquir Immune Defic Syndr. 1990;3(3):195–199. [PubMed] [Google Scholar]
  7. Cao Y., Qin L., Zhang L., Safrit J., Ho D. D. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med. 1995 Jan 26;332(4):201–208. doi: 10.1056/NEJM199501263320401. [DOI] [PubMed] [Google Scholar]
  8. De Wolf F., Hogervorst E., Goudsmit J., Fenyö E. M., Rübsamen-Waigmann H., Holmes H., Galvao-Castro B., Karita E., Wasi C., Sempala S. D. Syncytium-inducing and non-syncytium-inducing capacity of human immunodeficiency virus type 1 subtypes other than B: phenotypic and genotypic characteristics. WHO Network for HIV Isolation and Characterization. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1387–1400. doi: 10.1089/aid.1994.10.1387. [DOI] [PubMed] [Google Scholar]
  9. Dietrich U., Grez M., von Briesen H., Panhans B., Geissendörfer M., Kühnel H., Maniar J., Mahambre G., Becker W. B., Becker M. L. HIV-1 strains from India are highly divergent from prototypic African and US/European strains, but are linked to a South African isolate. AIDS. 1993 Jan;7(1):23–27. doi: 10.1097/00002030-199301000-00003. [DOI] [PubMed] [Google Scholar]
  10. Dumitrescu O., Kalish M. L., Kliks S. C., Bandea C. I., Levy J. A. Characterization of human immunodeficiency virus type 1 isolates from children in Romania: identification of a new envelope subtype. J Infect Dis. 1994 Feb;169(2):281–288. doi: 10.1093/infdis/169.2.281. [DOI] [PubMed] [Google Scholar]
  11. Earl P. L., Broder C. C., Long D., Lee S. A., Peterson J., Chakrabarti S., Doms R. W., Moss B. Native oligomeric human immunodeficiency virus type 1 envelope glycoprotein elicits diverse monoclonal antibody reactivities. J Virol. 1994 May;68(5):3015–3026. doi: 10.1128/jvi.68.5.3015-3026.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gao F., Yue L., Craig S., Thornton C. L., Robertson D. L., McCutchan F. E., Bradac J. A., Sharp P. M., Hahn B. H. Genetic variation of HIV type 1 in four World Health Organization-sponsored vaccine evaluation sites: generation of functional envelope (glycoprotein 160) clones representative of sequence subtypes A, B, C, and E. WHO Network for HIV Isolation and Characterization. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1359–1368. doi: 10.1089/aid.1994.10.1359. [DOI] [PubMed] [Google Scholar]
  13. Gelderblom H. R., Hausmann E. H., Ozel M., Pauli G., Koch M. A. Fine structure of human immunodeficiency virus (HIV) and immunolocalization of structural proteins. Virology. 1987 Jan;156(1):171–176. doi: 10.1016/0042-6822(87)90449-1. [DOI] [PubMed] [Google Scholar]
  14. Gelderblom H. R., Ozel M., Pauli G. Morphogenesis and morphology of HIV. Structure-function relations. Arch Virol. 1989;106(1-2):1–13. doi: 10.1007/BF01311033. [DOI] [PubMed] [Google Scholar]
  15. Grez M., Dietrich U., Balfe P., von Briesen H., Maniar J. K., Mahambre G., Delwart E. L., Mullins J. I., Rübsamen-Waigmann H. Genetic analysis of human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2) mixed infections in India reveals a recent spread of HIV-1 and HIV-2 from a single ancestor for each of these viruses. J Virol. 1994 Apr;68(4):2161–2168. doi: 10.1128/jvi.68.4.2161-2168.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ho D. D., McKeating J. A., Li X. L., Moudgil T., Daar E. S., Sun N. C., Robinson J. E. Conformational epitope on gp120 important in CD4 binding and human immunodeficiency virus type 1 neutralization identified by a human monoclonal antibody. J Virol. 1991 Jan;65(1):489–493. doi: 10.1128/jvi.65.1.489-493.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ho D. D., Sarngadharan M. G., Hirsch M. S., Schooley R. T., Rota T. R., Kennedy R. C., Chanh T. C., Sato V. L. Human immunodeficiency virus neutralizing antibodies recognize several conserved domains on the envelope glycoproteins. J Virol. 1987 Jun;61(6):2024–2028. doi: 10.1128/jvi.61.6.2024-2028.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Homsy J., Meyer M., Levy J. A. Serum enhancement of human immunodeficiency virus (HIV) infection correlates with disease in HIV-infected individuals. J Virol. 1990 Apr;64(4):1437–1440. doi: 10.1128/jvi.64.4.1437-1440.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Homsy J., Meyer M., Tateno M., Clarkson S., Levy J. A. The Fc and not CD4 receptor mediates antibody enhancement of HIV infection in human cells. Science. 1989 Jun 16;244(4910):1357–1360. doi: 10.1126/science.2786647. [DOI] [PubMed] [Google Scholar]
  20. Jain M. K., John T. J., Keusch G. T. A review of human immunodeficiency virus infection in India. J Acquir Immune Defic Syndr. 1994 Nov;7(11):1185–1194. [PubMed] [Google Scholar]
  21. Janssens W., Heyndrickx L., Fransen K., Motte J., Peeters M., Nkengasong J. N., Ndumbe P. M., Delaporte E., Perret J. L., Atende C. Genetic and phylogenetic analysis of env subtypes G and H in central Africa. AIDS Res Hum Retroviruses. 1994 Jul;10(7):877–879. doi: 10.1089/aid.1994.10.877. [DOI] [PubMed] [Google Scholar]
  22. Janssens W., Heyndrickx L., Fransen K., Temmerman M., Leonaers A., Ivens T., Motte J., Piot P., Van der Groen G. Genetic variability of HIV type 1 in Kenya. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1577–1579. doi: 10.1089/aid.1994.10.1577. [DOI] [PubMed] [Google Scholar]
  23. Janssens W., Heyndrickx L., Van de Peer Y., Bouckaert A., Fransen K., Motte J., Gershy-Damet G. M., Peeters M., Piot P., van der Groen G. Molecular phylogeny of part of the env gene of HIV-1 strains isolated in Côte d'Ivoire. AIDS. 1994 Jan;8(1):21–26. doi: 10.1097/00002030-199401000-00004. [DOI] [PubMed] [Google Scholar]
  24. Kalish M. L., Luo C. C., Weniger B. G., Limpakarnjanarat K., Young N., Ou C. Y., Schochetman G. Early HIV type 1 strains in Thailand were not responsible for the current epidemic. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1573–1575. doi: 10.1089/aid.1994.10.1573. [DOI] [PubMed] [Google Scholar]
  25. Kliks S. C., Shioda T., Haigwood N. L., Levy J. A. V3 variability can influence the ability of an antibody to neutralize or enhance infection by diverse strains of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11518–11522. doi: 10.1073/pnas.90.24.11518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Korber B. T., MacInnes K., Smith R. F., Myers G. Mutational trends in V3 loop protein sequences observed in different genetic lineages of human immunodeficiency virus type 1. J Virol. 1994 Oct;68(10):6730–6744. doi: 10.1128/jvi.68.10.6730-6744.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kostrikis L. G., Bagdades E., Cao Y., Zhang L., Dimitriou D., Ho D. D. Genetic analysis of human immunodeficiency virus type 1 strains from patients in Cyprus: identification of a new subtype designated subtype I. J Virol. 1995 Oct;69(10):6122–6130. doi: 10.1128/jvi.69.10.6122-6130.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kuiken C. L., Zwart G., Baan E., Coutinho R. A., van den Hoek J. A., Goudsmit J. Increasing antigenic and genetic diversity of the V3 variable domain of the human immunodeficiency virus envelope protein in the course of the AIDS epidemic. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9061–9065. doi: 10.1073/pnas.90.19.9061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Louwagie J., McCutchan F. E., Peeters M., Brennan T. P., Sanders-Buell E., Eddy G. A., van der Groen G., Fransen K., Gershy-Damet G. M., Deleys R. Phylogenetic analysis of gag genes from 70 international HIV-1 isolates provides evidence for multiple genotypes. AIDS. 1993 Jun;7(6):769–780. doi: 10.1097/00002030-199306000-00003. [DOI] [PubMed] [Google Scholar]
  30. McCutchan F. E., Hegerich P. A., Brennan T. P., Phanuphak P., Singharaj P., Jugsudee A., Berman P. W., Gray A. M., Fowler A. K., Burke D. S. Genetic variants of HIV-1 in Thailand. AIDS Res Hum Retroviruses. 1992 Nov;8(11):1887–1895. doi: 10.1089/aid.1992.8.1887. [DOI] [PubMed] [Google Scholar]
  31. McCutchan F. E., Ungar B. L., Hegerich P., Roberts C. R., Fowler A. K., Hira S. K., Perine P. L., Burke D. S. Genetic analysis of HIV-1 isolates from Zambia and an expanded phylogenetic tree for HIV-1. J Acquir Immune Defic Syndr. 1992;5(5):441–449. [PubMed] [Google Scholar]
  32. Moore J. P., Cao Y., Leu J., Qin L., Korber B., Ho D. D. Inter- and intraclade neutralization of human immunodeficiency virus type 1: genetic clades do not correspond to neutralization serotypes but partially correspond to gp120 antigenic serotypes. J Virol. 1996 Jan;70(1):427–444. doi: 10.1128/jvi.70.1.427-444.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Moore J. P., Cao Y., Qing L., Sattentau Q. J., Pyati J., Koduri R., Robinson J., Barbas C. F., 3rd, Burton D. R., Ho D. D. Primary isolates of human immunodeficiency virus type 1 are relatively resistant to neutralization by monoclonal antibodies to gp120, and their neutralization is not predicted by studies with monomeric gp120. J Virol. 1995 Jan;69(1):101–109. doi: 10.1128/jvi.69.1.101-109.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Moore J. P. HIV vaccines. Back to primary school. Nature. 1995 Jul 13;376(6536):115–115. doi: 10.1038/376115a0. [DOI] [PubMed] [Google Scholar]
  35. Moore J. P., Ho D. D. Antibodies to discontinuous or conformationally sensitive epitopes on the gp120 glycoprotein of human immunodeficiency virus type 1 are highly prevalent in sera of infected humans. J Virol. 1993 Feb;67(2):863–875. doi: 10.1128/jvi.67.2.863-875.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Moore J. P., McCutchan F. E., Poon S. W., Mascola J., Liu J., Cao Y., Ho D. D. Exploration of antigenic variation in gp120 from clades A through F of human immunodeficiency virus type 1 by using monoclonal antibodies. J Virol. 1994 Dec;68(12):8350–8364. doi: 10.1128/jvi.68.12.8350-8364.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Moore J. P., Yoshiyama H., Ho D. D., Robinson J. E., Sodroski J. Antigenic variation in gp120s from molecular clones of HIV-1 LAI. AIDS Res Hum Retroviruses. 1993 Dec;9(12):1185–1193. doi: 10.1089/aid.1993.9.1185. [DOI] [PubMed] [Google Scholar]
  38. Morgado M. G., Sabino E. C., Shpaer E. G., Bongertz V., Brigido L., Guimaraes M. D., Castilho E. A., Galvão-Castro B., Mullins J. I., Hendry R. M. V3 region polymorphisms in HIV-1 from Brazil: prevalence of subtype B strains divergent from North American/European prototype and detection of subtype F. AIDS Res Hum Retroviruses. 1994 May;10(5):569–576. doi: 10.1089/aid.1994.10.569. [DOI] [PubMed] [Google Scholar]
  39. Murphy E., Korber B., Georges-Courbot M. C., You B., Pinter A., Cook D., Kieny M. P., Georges A., Mathiot C., Barré-Sinoussi F. Diversity of V3 region sequences of human immunodeficiency viruses type 1 from the central African Republic. AIDS Res Hum Retroviruses. 1993 Oct;9(10):997–1006. doi: 10.1089/aid.1993.9.997. [DOI] [PubMed] [Google Scholar]
  40. Myers G. Tenth anniversary perspectives on AIDS. HIV: between past and future. AIDS Res Hum Retroviruses. 1994 Nov;10(11):1317–1324. doi: 10.1089/aid.1994.10.1317. [DOI] [PubMed] [Google Scholar]
  41. Nkengasong J. N., Janssens W., Heyndrickx L., Fransen K., Ndumbe P. M., Motte J., Leonaers A., Ngolle M., Ayuk J., Piot P. Genotypic subtypes of HIV-1 in Cameroon. AIDS. 1994 Oct;8(10):1405–1412. doi: 10.1097/00002030-199410000-00006. [DOI] [PubMed] [Google Scholar]
  42. Ou C. Y., Takebe Y., Weniger B. G., Luo C. C., Kalish M. L., Auwanit W., Yamazaki S., Gayle H. D., Young N. L., Schochetman G. Independent introduction of two major HIV-1 genotypes into distinct high-risk populations in Thailand. Lancet. 1993 May 8;341(8854):1171–1174. doi: 10.1016/0140-6736(93)91001-3. [DOI] [PubMed] [Google Scholar]
  43. Ozel M., Pauli G., Gelderblom H. R. The organization of the envelope projections on the surface of HIV. Arch Virol. 1988;100(3-4):255–266. doi: 10.1007/BF01487688. [DOI] [PubMed] [Google Scholar]
  44. Potts K. E., Kalish M. L., Bandea C. I., Orloff G. M., St Louis M., Brown C., Malanda N., Kavuka M., Schochetman G., Ou C. Y. Genetic diversity of human immunodeficiency virus type 1 strains in Kinshasa, Zaire. AIDS Res Hum Retroviruses. 1993 Jul;9(7):613–618. doi: 10.1089/aid.1993.9.613. [DOI] [PubMed] [Google Scholar]
  45. Robertson D. L., Sharp P. M., McCutchan F. E., Hahn B. H. Recombination in HIV-1. Nature. 1995 Mar 9;374(6518):124–126. doi: 10.1038/374124b0. [DOI] [PubMed] [Google Scholar]
  46. Robinson W. E., Jr, Montefiori D. C., Mitchell W. M. A human immunodeficiency virus type 1 (HIV-1) infection-enhancing factor in seropositive sera. Biochem Biophys Res Commun. 1987 Dec 16;149(2):693–699. doi: 10.1016/0006-291x(87)90423-2. [DOI] [PubMed] [Google Scholar]
  47. Robinson W. E., Jr, Montefiori D. C., Mitchell W. M., Prince A. M., Alter H. J., Dreesman G. R., Eichberg J. W. Antibody-dependent enhancement of human immunodeficiency virus type 1 (HIV-1) infection in vitro by serum from HIV-1-infected and passively immunized chimpanzees. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4710–4714. doi: 10.1073/pnas.86.12.4710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Sabino E. C., Shpaer E. G., Morgado M. G., Korber B. T., Diaz R. S., Bongertz V., Cavalcante S., Galvão-Castro B., Mullins J. I., Mayer A. Identification of human immunodeficiency virus type 1 envelope genes recombinant between subtypes B and F in two epidemiologically linked individuals from Brazil. J Virol. 1994 Oct;68(10):6340–6346. doi: 10.1128/jvi.68.10.6340-6346.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Schutten M., Andeweg A. C., Bosch M. L., Osterhaus A. D. Enhancement of infectivity of a non-syncytium inducing HIV-1 by sCD4 and by human antibodies that neutralize syncytium inducing HIV-1. Scand J Immunol. 1995 Jan;41(1):18–22. doi: 10.1111/j.1365-3083.1995.tb03528.x. [DOI] [PubMed] [Google Scholar]
  50. Smith R. F., Smith T. F. Pattern-induced multi-sequence alignment (PIMA) algorithm employing secondary structure-dependent gap penalties for use in comparative protein modelling. Protein Eng. 1992 Jan;5(1):35–41. doi: 10.1093/protein/5.1.35. [DOI] [PubMed] [Google Scholar]
  51. Stamatatos L., Cheng-Mayer C. Structural modulations of the envelope gp120 glycoprotein of human immunodeficiency virus type 1 upon oligomerization and differential V3 loop epitope exposure of isolates displaying distinct tropism upon virion-soluble receptor binding. J Virol. 1995 Oct;69(10):6191–6198. doi: 10.1128/jvi.69.10.6191-6198.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sullivan N., Sun Y., Li J., Hofmann W., Sodroski J. Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T-cell line-passaged human immunodeficiency virus type 1 isolates. J Virol. 1995 Jul;69(7):4413–4422. doi: 10.1128/jvi.69.7.4413-4422.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Takeda A., Tuazon C. U., Ennis F. A. Antibody-enhanced infection by HIV-1 via Fc receptor-mediated entry. Science. 1988 Oct 28;242(4878):580–583. doi: 10.1126/science.2972065. [DOI] [PubMed] [Google Scholar]
  54. Trkola A., Pomales A. B., Yuan H., Korber B., Maddon P. J., Allaway G. P., Katinger H., Barbas C. F., 3rd, Burton D. R., Ho D. D. Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG. J Virol. 1995 Nov;69(11):6609–6617. doi: 10.1128/jvi.69.11.6609-6617.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Wu S. C., Spouge J. L., Conley S. R., Tsai W. P., Merges M. J., Nara P. L. Human plasma enhances the infectivity of primary human immunodeficiency virus type 1 isolates in peripheral blood mononuclear cells and monocyte-derived macrophages. J Virol. 1995 Oct;69(10):6054–6062. doi: 10.1128/jvi.69.10.6054-6062.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES