Dominant effects of CCR2-CCR5 haplotypes in HIV-1 disease progression.
ABSTRACT Three haplotypes for the CCR2-CCR5 region previously have been shown to affect AIDS progression; however, it is not known if the protective and accelerating effects of the haplotypes are relatively constant throughout infection or exert their effects early or late in HIV type 1 infection. The authors report the relative contributions to AIDS progression of CCR2 64I, CCR5 Delta32, and the CCR5 promoter haplotype +.P1.+ in the GRIV cohort, which included patients representing the extremes of the distribution for AIDS progression: rapid progressors (RP) who developed CD4 T-cell counts of <300/ mm within 3 years after the last HIV-1-seronegative test and slow progressors (SP) who were HIV-1 infected for > or =8 years with CD4 T-cell counts of >500/mm. Comparing the RP with a seroconverter control group including intermediate progressors to AIDS, we observed the early protective effect of CCR5 Delta32 (odds ratio = 0.25; P = 0.007) was similar in strength to the early susceptible effect of CCR5 +.P1.+ (odds ratio = 2.1, P = 0.01). Comparison of the intermediate control group to the SP showed weaker and less significant odd ratios, suggesting that the effect of these factors tended to be stronger on early progression; the tendency towards a disproportionately early effect was significant for CCR5 Delta32 (P = 0.04) but not for CCR5 +.P1.+ (P = 0.12). Follow-up of SP demonstrated that these polymorphisms have little effect after 8 years, because the subset of SP who had progression after study entry had the same genotype distribution as the global population of SP, suggesting that factors other than CCR5 or CCR2 genetic variants must be responsible for the long-term maintenance of nonprogression.
- SourceAvailable from: Margaret May[Show abstract] [Hide abstract]
ABSTRACT: Humans differ substantially with respect to susceptibility to human immunodeficiency virus type 1 (HIV-1). We evaluated variants of nine host genes participating in the viral life cycle for their role in modulating HIV-1 infection. Alleles were assessed ex vivo for their impact on viral replication in purified CD4 T cells from healthy blood donors (n = 128). Thereafter, candidate alleles were assessed in vivo in a cohort of HIV-1-infected individuals (n = 851) not receiving potent antiretroviral therapy. As a benchmark test, we tested 12 previously reported host genetic variants influencing HIV-1 infection as well as single nucleotide polymorphisms in the nine candidate genes. This led to the proposition of three alleles of PML, TSG101, and PPIA as potentially associated with differences in progression of HIV-1 disease. In a model considering the combined effects of new and previously reported gene variants, we estimated that their effect might be responsible for lengthening or shortening by up to 2.8 years the period from 500 CD4 T cells/mul to <200 CD4 T cells/mul.Journal of Virology 10/2005; 79(20):12674-80. DOI:10.1128/JVI.79.20.12674-12680.2005 · 4.65 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: It became clear over the recent years that most, if not all, G protein-coupled receptors (GPCR) are able to form dimers or higher order oligomers. Chemokine receptors make no exception to this new rule and both homo- and heterodimerization were demonstrated for CC and CXC receptors. Functional analyses demonstrated negative binding cooperativity between the two subunits of a dimer. The consequence is that only one chemokine can bind with high affinity onto a receptor dimer. In the context of receptor activation, this implies that the motions of helical domains triggered by the binding of agonists induce correlated changes in the other protomer. The impact of the chemokine dimerization process in terms of co-receptor function and drug development is discussed.Cytokine & Growth Factor Reviews 01/2006; 16(6):611-23. DOI:10.1016/j.cytogfr.2005.05.005 · 6.54 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The frequencies of four CCR5 promoter polymorphisms, and of the Delta32 deletion, have been evaluated in Brazilian HIV-1 positive (HIV+) and HIV-1 negative (HIV-) children, both born from HIV-1 positive mothers and healthy controls (HC), with the aim of investigating whether CCR5 polymorphisms could be associated to vertical transmission of HIV-1. One hundred and six HIV-1 positive children and 70 HIV-1 negative children were enrolled from impoverished areas of Recife (Brazil). We recruited also as healthy controls 104 uninfected children from the same ethnic background, matched for age and known to be not at risk for HIV-1 infection. CCR5 polymorphisms were detected by PCR amplification and direct sequencing. Although no significative divergence was found for CCR5 Delta32, CCR5-59356-C/T and CCR5-59653 C/T polymorphisms, the frequency of CCR5-59353-T/C and CCR5-59402-A/G genotypes differed among HIV+, HIV- and HC children. The presence of the CCR5-59353-TT genotype indicated a trend for increased risk of vertical transmission of HIV-1 infection in Brazilian children, while the presence of the CCR5-59402-AA genotype is suggestive for a protective effect against HIV-1 vertical transmission.Journal of Reproductive Immunology 03/2006; 69(1):77-84. DOI:10.1016/j.jri.2005.09.001 · 2.37 Impact Factor