HIV-1 infectability of CD4+ lymphocytes with relation to β-chemokines and the CCR5 coreceptor

CD4(+) lymphocytes exhibit variable permissiveness to the replication of HIV-1. A cohort of sexually-exposed-yet-uninfected individuals were previously shown to have CD4(+) lymphocytes refractory. for M-tropic viral replication. In particular, two individuals from this population whose CD4(+) lymphocytes exhibited complete resistance to M-tropic viral replication were later shown to be homozygous for a 32bp (Delta 32) deletion in the gene encoding for CCR5. In screening diverse populations, HIV-1 infected individuals heterozygous for the Delta 32 allele were statistically favored in their disease course to harbor lower viral loads and exhibit slower rates of CD4(+) cell loss when compared to control CCR5 wild-type individuals. Further comparative analysis between individuals in the exposed but uninfected cohort who demonstrated intermediate levels of in vitro viral replication and CD4(+) lymphocytes isolated from uninfected Delta 32 heterozygous individuals indicate that reduced levels of in vitro M-tropic replication are a CCR5-related phenomenon: CD4(+) lymphocytes from these individuals were more sensitive to the HIV-1 blocking effects of recombinant chemokines, displayed lower CCR5 cell surface expression levels and a proportionate increase in the production of RANTES when compared to CD4(+) lymphocytes from control individuals. These results suggest that the CCR5 phenotype is important in determining the replicative capacity of M-tropic HIV-1 in vitro. The implications of these results with relation to HIV-1 transmission and disease progression are discussed. (C) 1999 Elsevier Science B.V. All rights reserved.