Association between CCR5 genotype and the clinical course of HIV-1 infection.
BACKGROUND
Heterozygosity for a 32-nucleotide deletion in the C-C chemokine receptor 5 gene (CCR5 delta 32) is associated with delayed disease progression in persons infected with HIV-1.


OBJECTIVE
To compare the predictive value of CCR5 genotype with that of established markers in the clinical course of HIV-1 infection.


METHODS
Retrospective longitudinal study and nested case-control study. The latter included only long-term survivors, who were individually matched with progressors.


METHODS
Amsterdam, the Netherlands.


METHODS
364 homosexual men with HIV-1 infection.


METHODS
Polymerase chain reaction was used for CCR5 genotyping. Univariate and multivariate Cox proportional hazard analyses were done for disease progression with CCR5 genotype, CD4+ T-lymphocyte counts, T-lymphocyte function, HIV-1 biological phenotype (syncytium-inducing or non-syncytium-inducing HIV-1), and viral RNA load in serum as covariates.


RESULTS
In the case-control study, 48% of long-term survivors were heterozygous for CCR5 delta 32 compared with 9% of progressors (odds ratio, 6.9 [95% CI, 1.9 to 24.8]). In the total study sample, CCR5 delta 32 heterozygotes had significantly delayed disease progression (P < 0.001; relative hazard, 0.4 [CI, 0.3 to 0.6]), a 1.5-fold slower decrease in CD4+ T-lymphocyte count (P = 0.01), and a 2.6-fold lower viral RNA load (P = 0.01) at approximately 2.3 years after seroconversion compared with CCR5 wild-type homozygotes. At the end of the study, both groups showed the same prevalence of syncytium-inducing HIV-1, but CCR5 delta 32 heterozygotes had a delayed conversion rate. The protective effect of CCR5 delta 32 heterozygosity was stronger in the presence of only non-syncytium-inducing HIV-1. The CCR5 genotype predicted disease progression independent of viral RNA load, CD4+ T-lymphocyte counts, T-lymphocyte function, and HIV-1 biological phenotype.


CONCLUSIONS
The addition of CCR5 genotype to currently available laboratory markers may allow better estimation of the clinical course of HIV-1 infection.
de Roda Husman
A M
AM
Central Laboratory of the Red Cross Blood Transfusion Service, University of Amsterdam Academic Medical Center, The Netherlands.
Koot
M
M
Cornelissen
M
M
Keet
I P
IP
Brouwer
M
M
Broersen
S M
SM
Bakker
M
M
Roos
M T
MT
Prins
M
M
de Wolf
F
F
Coutinho
R A
RA
Miedema
F
F
Goudsmit
J
J
Schuitemaker
H
H
D000163:Acquired Immunodeficiency Syndrome / Q000821:virology; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D018450:Disease Progression; D005838:Genotype; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000097:blood / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015993:Life Tables; D008137:Longitudinal Studies; D008297:Male; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D019713:Receptors, CCR5 / Q000235:genetics*; D012189:Retrospective Studies; D019562:Viral Load
D015415:Biomarkers; D015483:HIV Antibodies; D019713:Receptors, CCR5