Causal pathways of the effects of age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on AIDS development.
OBJECTIVE
To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS.


METHODS
Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up.


METHODS
The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways.


RESULTS
Persons of younger age or having the CCR2-64I or SDF-1 3'A mutation have significantly higher CD4 levels. Persons with the CCR5-Delta32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3'A mutation significantly increases the AIDS risk.


CONCLUSIONS
Age and the CCR5-Delta32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3'A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.
Geskus
Ronald B
RB
Municipal Health Service, Amsterdam, The Netherlands and Leiden University Medical Center, The Netherlands. rgeskus@gggd.amsterdam.nl
Meyer
Laurence
L
Hubert
Jean-Baptiste
JB
Schuitemaker
Hanneke
H
Berkhout
Ben
B
Rouzioux
Christine
C
Theodorou
Ioannis D
ID
Delfraissy
Jean-François
JF
Prins
Maria
M
Coutinho
Roel A
RA
D000163:Acquired Immunodeficiency Syndrome / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000821:virology; D000328:Adult; D000367:Age Factors; D000483:Alleles; D018791:CD4 Lymphocyte Count; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics*; D015331:Cohort Studies; D006679:HIV Seropositivity; D015497:HIV-1; D006801:Humans; D008297:Male; D012367:RNA, Viral / Q000097:blood; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics*
C515334:CCR2 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D012367:RNA, Viral; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine