In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression

G. Scarlatti, E. Tresoldi, A. Bjorndal, R. Fredriksson, C. Colognesi, Kui Deng Hong Kui Deng, M. S. Malnati, A. Plebani, A. G. Siccardi, D. R. Littman, E. M. Fenyo, P. Lusso

Research output: Contribution to journalArticlepeer-review


Following the identification of the C-C chemokines RANTES, MIP-1α and MIP-1β as major human immunodeficiency virus (HIV)-suppressive factors produced by CD8 T cells1, several chemokine receptors were found to serve as membrane co-receptors for primate immunodeficiency lentiretroviruses2-8. The two most widely used co-receptors thus far recognized, CCR5 and CXCR4, are expressed by both activated T lymphocytes and mononuclear phagocytes. CCR5, a specific RANTES, MIP-1α and MIP-1β receptor, is used preferentially by non-MT2-tropic HIV-1 and HIV-2 strains3-7.9.10 and by simian immunodeficiency virus (SIV)11, whereas CXCR4, a receptor for the C-X-C chemokine SDF-1 (ref. 12, 13), is used by MT2-tropic HIV-1 and HIV-2, but not by SIV (ref. 2-7, 9-11, 14). Other receptors with a more restricted cellular distribution, such as CCR2b, CCR3 and STRL33, can also function as co- receptors for selected viral isolates4.6.8. The third variable region (V3) of the gp120 envelope glycoprotein of HIV-1 has been fingered as a critical determinant of the co-receptor choice4,15. Here, we document a consistent pattern of evolution of viral co-receptor usage and sensitivity to chemokine-mediated suppression in a longitudinal follow-up of children with progressive HIV-1 infection. Viral isolates obtained during the asymptomatic stages generally used only CCR5 as a co-receptor and were inhibited by RANTES, MIP-1α and MIP-1β, but not by SDF-1. By contrast, the majority of the isolates derived after the progression of the disease were resistant to C-C chemokines, having acquired the ability to use CXCR4 and, in some cases, CCR3, while gradually losing CCR5 usage. Surprisingly, most of these isolates were also insensitive to SDF-1, even when used in combination with RANTES. An early acquisition of CXCR4 usage predicted a poor prognosis. In children who progressed to AIDS without a shift to CXCR4 usage, all the sequential isolates were CCR5-dependent but showed a reduced sensitivity to C-C chemokines. Discrete changes in the V3 domain of gp120 were associated with the loss of sensitivity to C-C chemokines and the shift in co-receptor usage. These results suggest an adaptive evolution of HIV-1 in vivo, leading to escape from the control of the antiviral C-C chemokines.

Original languageEnglish
Pages (from-to)1259-1265
Number of pages7
JournalNature Medicine
Issue number11
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)


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