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

Abstract

Following the identification of the C-C chemokines RANTES, MIP-1alpha and MIP-1beta as major human immunodeficiency virus (HIV)-suppressive factors produced by CD8+ T cells, several chemokine receptors were found to serve as membrane co-receptors for primate immunodeficiency lentiretroviruses. 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-1alpha and MIP-1 receptor, is used preferentially by non-MT2-tropic HIV-1 and HIV-2 strains and by simian immunodeficiency virus (SIV), whereas CXCR4, a receptor for the C-X-C chemokine SDF-1, is used by MT2-tropic HIV-1 and HIV-2, but not by SIV. Other receptors with a more restricted cellular distribution, such as CCR2b, CCR3 and STRL33, can also function as co-receptors for selected viral isolates. The third variable region (V3) of the gp120 envelope glycoprotein of HIV-1 has been fingered as a critical determinant of the co-receptor choice. 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-1alpha and MIP-1beta, 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.

• Authors: G Scarlatti, E Tresoldi, A Björndal, R Fredriksson, C Colognesi, H K Deng, M S Malnati, A Plebani, A G Siccardi, D R Littman, E M Fenyö, P Lusso
• Journal: Nature medicine (Nat Med) Vol. 3 Issue 11 Pg. 1259-65 (Nov 1997) ISSN: 1078-8956 [Print] United States
• PMID: 9359702 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CCR3 protein, human
• CXCL12 protein, human
• Chemokine CCL3
• Chemokine CCL4
• Chemokine CCL5
• Chemokine CXCL12
• Chemokines
• Chemokines, CC
• Chemokines, CXC
• Macrophage Inflammatory Proteins
• Receptors, CCR3
• Receptors, CCR5
• Receptors, CXCR4
• Receptors, Chemokine
• Receptors, HIV

Topics

• Adolescent
• Adult
• Aged
• Amino Acid Sequence
• Chemokine CCL3
• Chemokine CCL4
• Chemokine CCL5 (pharmacology)
• Chemokine CXCL12
• Chemokines (pharmacology)
• Chemokines, CC (metabolism)
• Chemokines, CXC
• Child
• HIV Infections (metabolism, transmission)
• HIV-1
• Humans
• Infant
• Infectious Disease Transmission, Vertical
• Longitudinal Studies
• Macrophage Inflammatory Proteins (pharmacology)
• Middle Aged
• Molecular Sequence Data
• Receptors, CCR3
• Receptors, CCR5 (metabolism)
• Receptors, CXCR4 (metabolism)
• Receptors, Chemokine (metabolism)
• Receptors, HIV (metabolism)