Increased frequency of CCR-5 delta 32 heterozygotes among long-term non-progressors with HIV-1 infection. The Australian Long-Term Non-Progressor Study Group.
BACKGROUND
The beta-chemokine receptor CCR-5 is used as a coreceptor by macrophage-tropic strains of HIV-1 to gain entry into CD4+ cells.


OBJECTIVE
To determine the effect of a common 32 base-pair deletion mutation in the CCR-5 gene (CCR-5 delta 32) on progression of HIV infection to AIDS, and to assess the level of heterozygosity for this mutation in a well-defined group of long-term non-progressors (LTNP).


METHODS
Sixty-four HIV-1-infected LTNP (CD4+ T lymphocyte count > 500 x 10(6)/l after 8 years) were compared with 95 individuals infected within a similar period (1983-1986) but who had rapidly progressed to AIDS and death, and with a further 120 HIV-positive individuals with CD4+ counts < 500 x 10(6)/l.


METHODS
The presence of the CCR-5 delta 32 mutation was assessed using polymerase chain reaction with primers spanning the 32 base-pair deletion. CD4+ and CD8+ counts, plasma HIV-1 RNA, p24 antigen and beta 2-microglobulin levels in LTNP carrying the CCR-5 delta 32 mutation were compared with LTNP lacking the mutation.


RESULTS
A marked increase in the frequency of CCR-5 delta 32 heterozygosity was found among LTNP (35.9%) compared with rapid progressors (12.6%; P = 0.0005) and patients selected on the basis of a CD4+ T-cell count < 500 x 10(6)/l (12.5%; P = 0.0004). LTNP heterozygous for CCR-5 delta 32 had a significantly higher CD8+ T-cell count than those without the mutation (1218 versus 972 x 10(6)/l; P = 0.044). No significant correlation was observed between heterozygosity and CD4 count, viral load, p24 antigen or beta 2-microglobulin within the LTNP group.


CONCLUSIONS
This study provides the strongest evidence to date for the importance of a single copy of the CCR-5 delta 32 mutation in long-term non-progression of HIV infection, which may involve, in part, CD8+ T lymphocytes.
Stewart
G J
GJ
Department of Immunology, Westmead Hospital, Sydney, Australia.
Ashton
L J
LJ
Biti
R A
RA
Ffrench
R A
RA
Bennetts
B H
BH
Newcombe
N R
NR
Benson
E M
EM
Carr
A
A
Cooper
D A
DA
Kaldor
J M
JM
D018450:Disease Progression; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D019713:Receptors, CCR5 / Q000235:genetics*; D017741:Survivors; D013997:Time Factors
D019713:Receptors, CCR5