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Longitudinal studies on a cohort of Italian long-term non progressors (LTNP) carrying either WT, CCR5/delta ccr5, and/or CCR2-(+)/641 genotypes.


Int Conf AIDS. 1998;12:157 (abstract no. 13353). Unique Identifier :

OBJECTIVES: LTNP have been early identified as individuals characterized by reduced or absent HIV-induced pathogenicity. However, LTNP with high viremia have been reported and are significantly present (> 40%) in our cohort. We further investigated whether genetic (CCR5/delta ccr5 and CCR2-(+)/641 mutations), virological, or immunological determinants would discriminate within our LTNP between those individuals with relatively slower or faster disease evolution. METHODS: LTNP were originally included as follows: 1. > or = 8 years since documented seroconversion; 2. no assumption of antiretrovirals; 3. healthy clinical conditions; 4. CD4 cell counts > or = 500 cells/cmm. Viremia was monitored by Amplicor Monitor (Roche); determination of CCR5/delta ccr5 and CCR2-(+)/641 genotypes was performed as described (Morawetz et al., Eur. J. Immunol., 27: 3223, 1997: Rizzardi et al., Nature Med., 1998, in press). Cytokines and sIL-2R were tested by ELISA (R&D Systems). HIV isolation was performed in the presence or absence of patients' as well as donor's CD8+ T cells removed by immunomagnetic beads (Dynal). RESULTS: 45 and 35 LTNP were characterized for the presence of CCR5/delta ccr5 and CCR2-(+)/641 genotypes, respectively. As recently reported, both mutations were significantly more prevalent (35% and 33% of LTNP, respectively) both independently considered or combined together (61.5% vs 29%, p = 0.00001, with 3 individuals carrying both mutations) in comparison to a control population of progressors (see above refs.). Approximately 40% of CCR5/CCR5 LTNP had a decline in CD4 cells below 500 cells/cmm, whereas only 13% of CCR5/delta ccr5 heterozygous individuals showed this pattern (p = 0.09, Fisher's Exact Test). Suggestively, 11/11 CCR5/delta ccr5 heterozygous individuals had viremia levels below 10,000 copie of HIV RNA/ml, whereas CCR5/CCR5 were characterized by persistent levels of viremia evenly distributed above or below this arbitrary threshold, although these differences were of borderline statistical meaning. No particular trends in viremia or CD4 counts were observed in CCR2-(+)/641 LTNP. The role of HIV isolation, cytokine and soluble cytokine receptor markers, and of CD8-mediated control of viral replication in this population of LTNP are under evaluation. CONCLUSION: Mutations or deletions in CCR5 and CCR2 genes are significantly associated with the state of LTNP. The predictive role of viremia in LTNP needs further evaluation in that a substantial fraction of LTNP cope with relatively high levels of viremia overtime without obvious signs of disease evolution. The potential role played by CCR mutated genotypes in the natural hystory of LTNP respective to classical markers of disease evolution, such as CD4 cell counts and viremia, warrants longer follow-up and multi-cohort studies.

MEETING ABSTRACTS Biological Markers Cohort Studies CD4 Lymphocyte Count CD8-Positive T-Lymphocytes Gene Deletion Genotype Human HIV Seropositivity/*GENETICS Italy Longitudinal Studies Mutation Receptors, Cytokine/*GENETICS Receptors, CCR5/*GENETICS *Survivors


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