HIV-1 infectability of CD4+ lymphocytes with relation to beta-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 (delta32) deletion in the gene encoding for CCR5. In screening diverse populations, HIV-1 infected individuals heterozygous for the delta32 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 delta32 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.
Paxton
W A
WA
Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Netherlands. w.a.paxton@amc.uva.nl
Kang
S
S
Liu
R
R
Landau
N R
NR
Gingeras
T R
TR
Wu
L
L
Mackay
C R
CR
Koup
R A
RA
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D019742:Chemokines, CC / Q000378:metabolism*; D005838:Genotype; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D010641:Phenotype; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*
D019742:Chemokines, CC; D019713:Receptors, CCR5