The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression.
Cellular entry of human immunodeficiency virus type 1 (HIV-1) requires binding to both CD4 (ref, 1, 2) and to one of the chemokine receptors recently discovered to act as coreceptors. Viruses that infect T-cell lines to form syncytia (syncytium-inducing, SI) are frequently found in late-stage HIV disease and utilize the chemokine receptor CXCR-4; macrophage-tropic viruses are non-syncytium-inducing (NSI), found throughout disease and utilize CCR-5 (ref. 3-11). We postulated that CCR-5 gene defects might reduce infection risk in seronegative subjects and prolong AIDS-free survival in seropositive subjects with NSI but not SI virus. Homozygous (delta ccr5/delta ccr5) and heterozygous (CCR5/delta ccr5) CCR-5 deletions (delta ccr5) were found in 7 (2.7%) and 51 (19.5%), respectively, of 261 seronegative subjects from the San Francisco Men's Health Study. CCR-5/delta ccr5 genotype was identified in 33 of 172 (19.2%) nonprogressors and 25 of 234 (10.7%) progressors from the seropositive arm of this cohort. The delta ccr5 allele conferred a significant protective effect against HIV-1 infection (P = 0.001) and a survival advantage against disease progression (P = 0.02). Although both progressing and nonprogressing CCR5/delta ccr5 subjects were identified, a distinct survival advantage was shown for those with NSI virus (P < 0.0001). Thus, the protective effect of delta ccr5 against disease progression is lost when the infecting virus uses CXCR-4 as a coreceptor.
Michael
N L
NL
Division of Retrovirology, Walter Reed Army Institute of Research, Rockville, Maryland, USA.
Chang
G
G
Louie
L G
LG
Mascola
J R
JR
Dondero
D
D
Birx
D L
DL
Sheppard
H W
HW
D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002460:Cell Line; D015658:HIV Infections / Q000635:transmission / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D009154:Mutation; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000235:genetics*; D015728:Receptors, HIV / Q000235:genetics*
D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV