HIV-1 infectability of CD4(+) lymphocytes with relation to beta-chemokinesand the CCR5 coreceptor

CD4(+) lymphocytes exhibit variable permissiveness to the replication of HI V-1. A cohort of sexually-exposed-yet-uninfected individuals were previousl y shown to have CD4(+) lymphocytes refractory. for M-tropic viral replicati on. In particular, two individuals from this population whose CD4(+) lympho cytes exhibited complete resistance to M-tropic viral replication were late r shown to be homozygous for a 32bp (Delta 32) deletion in the gene encodin g for CCR5. In screening diverse populations, HIV-1 infected individuals he terozygous for the Delta 32 allele were statistically favored in their dise ase course to harbor lower viral loads and exhibit slower rates of CD4(+) c ell loss when compared to control CCR5 wild-type individuals. Further compa rative analysis between individuals in the exposed but uninfected cohort wh o demonstrated intermediate levels of in vitro viral replication and CD4(+) lymphocytes isolated from uninfected Delta 32 heterozygous individuals ind icate that reduced levels of in vitro M-tropic replication are a CCR5-relat ed phenomenon: CD4(+) lymphocytes from these individuals were more sensitiv e to the HIV-1 blocking effects of recombinant chemokines, displayed lower CCR5 cell surface expression levels and a proportionate increase in the pro duction of RANTES when compared to CD4(+) lymphocytes from control individu als. These results suggest that the CCR5 phenotype is important in determin ing the replicative capacity of M-tropic HIV-1 in vitro. The implications o f these results with relation to HIV-1 transmission and disease progression are discussed. (C) 1999 Elsevier Science B.V. All rights reserved.