293    

Background:  CTLA4 encodes cytotoxic T-lymphocyte (CTL)-associated antigen 4 (CTLA-4), which down-regulates CTL responses. We examined the relationships between common CTLA4 variants and several outcome measures during HIV-1 infection in both adult and adolescent populations.

Methods:  We studied 777 HIV-1-infected persons:  570 Caucasian seroconverters from 3 cohorts (Multi-Center Aids Cohort Study [MACS], American Cancer Society [ACS], and DC Gay Cohort [DCG]) of men who have sex with men (MSM) and 207 infected male and female adolescents from a Reaching for Excellence in Adolescent Care and Health (REACH) cohort of mixed ethnicity. Single nucleotide polymorphisms (SNP) in the CTLA4 promoter (-1147C/T, -658C/T, -318C/T), coding sequence (49A/G) or 3’ untranslated region (UTR) (CT60C/T) were detected by polymerase chain reaction (PCR)- based techniques. Repeated measures and survival analyses were used to test allelic and haplotypic associations with HIV-1 viral load (VL) and time to progression to AIDS, respectively.

Results:  When stratified by ethnicity, the distribution of the CTLA4 genotypes in the study populations conformed to known frequencies in other highly comparable groups. We found no uniformly strong relationship of any allele or genotype with the outcome of HIV-1 infection. Individuals carrying -318T had elevated mean HIV-1 VL in the MACS cohort (p = 0.034) and the REACH (P = 0.075), but reduced mean VL in the DCG (P = 0.056) and ACS (P = 0.17). Different time-dependent associations of CTLA4 -318T with VL were observed at various evaluation intervals in all 4 cohorts (P = 0.005-0.08). By multivariable Cox regression models adjusted for markers in known contributory (CCR5 and HLA class I) genes in each of the 3 MSM cohorts, CTLA -318T carriage was associated with a rapid rate of progression to AIDS in the MACS (hazard ratio 1.69 [95% confidence interval (CI) 1.15-2.49]); with a slower progression rate in the ACS (0.56 [0.28-1.11]); and with an approximately average rate in DCG (1.1 [0.55-2.19]).

Conclusions:  CTLA4 genotypes showed heterogeneous associations with clinical and virological outcomes following HIV-1 infection.  The effects appeared to vary with time and among the cohorts. Future studies of variants in the neighboring, biologically related genes CD28 and ICOS on human chromosome 2q33 may help explain the observed heterogeneity.

Keywords: CTLA4 ; viral load; disease progression