Cohort- and time-specific associations of CTLA4 genotypes with HIV-1 disease progression.
BACKGROUND
CTLA4 in the chromosome 2q33 region encodes cytotoxic T-lymphocyte (CTL) associated antigen 4, which downregulates CTL responses. We examined the relationships between common CTLA4 variants and several outcomes of HIV-1 infection in adults and adolescents.


METHODS
We studied 765 HIV-1-infected persons: 558 Caucasian seroconverters from three cohorts (MACS, ACS, and DCG) and 207 infected adolescents (mostly female) from another cohort (REACH) of mixed ethnicity. Single nucleotide polymorphisms in CTLA4 promoter (-1147C/T, -658C/T, -318C/T), coding sequence (49A/G) and the 3' untranslated region (CT60A/G) were resolved by 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 AIDS, respectively.


RESULTS
Individuals carrying -318T or the (-1147) T-(-318) T haplotype had elevated HIV-1 VL in MACS and REACH but reduced VL in DCG and ACS participants. Time-dependent associations of CTLA4-318T with VL were observed in MACS and REACH (P = 0.03-0.09). In Cox regression models adjusted for age and established contributory markers in CCR5 and HLA class I genes, CTLA4-318T was associated with rapid progression to AIDS in MACS (relative hazard 1.69; 95% confidence interval, 1.15-2.49; P < 0.01) as opposed to a non-significant slower disease progression in ACS and no appreciable association in DCG.


CONCLUSIONS
Association of CTLA4 genotypes with clinical and virological outcomes following HIV-1 infection appeared to vary with time and among the cohorts. Further analyses in conjunction with other biologically and positionally related genes, such as CD28 and ICOS, may help explain the disparate findings.
Shao
Wenshuo
W
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022, USA.
Lazaryan
Aleksandr
A
Dorak
M Tevfik
MT
Penman-Aguilar
Ana
A
Wilson
Craig M
CM
Margolick
Joseph B
JB
Goedert
James J
JJ
Prins
Maria
M
Tang
Jianming
J
Kaslow
Richard A
RA
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics* / Q000276:immunology; D018791:CD4 Lymphocyte Count; D060908:CTLA-4 Antigen; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019562:Viral Load
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007166:Immunosuppressive Agents