CXCR4 and CCR5 Genetic Polymorphisms in Long-Term Nonprogressive Human Immunodeficiency Virus Infection: Lack of Association with Mutations other than CCR5-Δ32

ABSTRACT Polymorphisms in the coding sequences of CCR5 and CXCR4 were studied in a group of human immunodeficiency virus (HIV)-infected long-term nonprogressors. Two different point mutations were found in the CXCR4 coding sequence. One of these CXCR4 mutations was silent, and each was unique to two nonprogressors. The well-described 32-bp deletion within the CCR5 coding sequence (CCR5-Δ32) was found in 4 of 13 nonprogressors, and 12 different point mutations were found scattered over the CCR5 coding sequence from 8 nonprogressors. Most of the mutations created either silent or conservative changes in the predicted amino acid sequence: only one of these mutations was found in more than a single nonprogressor. All nonsilent mutations were tested in an HIV envelope-dependent fusion assay, and all functioned comparably to wild-type controls. Polymorphisms in the CXCR4 and CCR5 coding sequences other than CCR5-Δ32 do not appear to play a dominant mechanistic role in nonprogression among HIV-infected individuals.

[1]  J. Phair,et al.  A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation , 1998, Nature Medicine.

[2]  J J Goedert,et al.  Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC) , 1998, Science.

[3]  J. Hoxie,et al.  Promonocytic U937 subclones expressing CD4 and CXCR4 are resistant to infection with and cell-to-cell fusion by T-cell-tropic human immunodeficiency virus type 1 , 1997, Journal of virology.

[4]  A. Fauci,et al.  Host factors in the pathogenesis of HIV disease , 1997, Immunological reviews.

[5]  J. Margolick,et al.  Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors. , 1997, The Journal of clinical investigation.

[6]  J J Goedert,et al.  Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. , 1997, Science.

[7]  M. Metzker,et al.  The extent of genetic variation in the CCR5 gene , 1997, Nature Genetics.

[8]  Nancy Sullivan,et al.  CCR5 Levels and Expression Pattern Correlate with Infectability by Macrophage-tropic HIV-1, In Vitro , 1997, The Journal of experimental medicine.

[9]  C. Katlama,et al.  HIV-1 infection in an individual homozygous for CCR5▵32 , 1997, The Lancet.

[10]  C. Winkler,et al.  HIV-1 infection in a man homozygous for CCR5▵32 , 1997, The Lancet.

[11]  C. Katlama,et al.  HIV-1 infection in an individual homozygous for CCR5 delta 32. Seroco Study Group. , 1997, Lancet.

[12]  C. Mackay,et al.  The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[13]  A. Iversen,et al.  Heterozygosity for a deletion in the CKR‐5 gene leads to prolonged AIDS‐free survival and slower CD4 T‐cell decline in a cohort of HIV‐seropositive individuals , 1997, AIDS.

[14]  B. Bennetts,et al.  HIV-1 infection in an individual homozygous for the CCR5 deletion allele , 1997, Nature Medicine.

[15]  J. Mascola,et al.  The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression , 1997, Nature Medicine.

[16]  D. Weissman,et al.  Inherited Resistance to HIV-1 Conferred by an Inactivating Mutation in CC Chemokine Receptor 5: Studies in Populations with Contrasting Clinical Phenotypes, Defined Racial Background, and Quantified Risk , 1997, Molecular medicine.

[17]  Steven M. Wolinsky,et al.  The role of a mutant CCR5 allele in HIV–1 transmission and disease progression , 1996, Nature Medicine.

[18]  J J Goedert,et al.  Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene , 1996, Science.

[19]  Marc Parmentier,et al.  Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene , 1996, Nature.

[20]  Richard A Koup,et al.  Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply-Exposed Individuals to HIV-1 Infection , 1996, Cell.

[21]  C. Broder,et al.  CC CKR5: A RANTES, MIP-1α, MIP-1ॆ Receptor as a Fusion Cofactor for Macrophage-Tropic HIV-1 , 1996, Science.

[22]  Marc Parmentier,et al.  A Dual-Tropic Primary HIV-1 Isolate That Uses Fusin and the β-Chemokine Receptors CKR-5, CKR-3, and CKR-2b as Fusion Cofactors , 1996, Cell.

[23]  Ying Sun,et al.  The β-Chemokine Receptors CCR3 and CCR5 Facilitate Infection by Primary HIV-1 Isolates , 1996, Cell.

[24]  Virginia Litwin,et al.  HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5 , 1996, Nature.

[25]  Stephen C. Peiper,et al.  Identification of a major co-receptor for primary isolates of HIV-1 , 1996, Nature.

[26]  Paul E. Kennedy,et al.  HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein-Coupled Receptor , 1996, Science.

[27]  G Vassart,et al.  Molecular cloning and functional expression of a new human CC-chemokine receptor gene. , 1996, Biochemistry.

[28]  J. Cohen.  AIDS mood upbeat--for a change , 1995, Science.

[29]  T. Geiser,et al.  Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. , 1994, The Journal of biological chemistry.