Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Cohort- and time-specific associations of CTLA4 genotypes with HIV-1 disease progression Wenshuo Shao a , Aleksandr Lazaryan a , M. Tevfik Dorak a , Ana Penman-Aguilar a , Craig M. Wilson b,c , Joseph B. Margolick d , James J. Goedert e , Maria Prins f , Jianming Tang c and Richard A. Kaslow a,c 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 infec- tion 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 0 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 ¼ 0.03–0.09). In Cox regression models adjusted for age and established con- tributory 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. ß 2006 Lippincott Williams & Wilkins AIDS 2006, 20:1583–1590 Keywords: AIDS, CTLA4, genetics, HIV, virus load Introduction As a T-cell costimulatory molecule, cytotoxic T- lymphocyte-associated antigen 4 (CTLA-4, also known as CD152) downregulates T-cell responses [1–4] pri- marily in the contraction phase of immune response, by outcompeting CD28 for binding to CD80 (B7.1) and CD86 (B7.2) [5]. CTLA-4 apparently enhances From the a Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA, the b Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA, the c Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA, the d Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, Maryland, USA, the e National Cancer Institute, Rockville, Maryland, USA, and the f Health Service, Amsterdam, the Netherlands. Correspondence to R.A. Kaslow, Department of Epidemiology, University of Alabama at Birmingham, 1665 University Boulevard, RPHB Room 220, Birmingham, AL 35294-0022, USA. Tel: +1 205 975 8608; fax: +1 205 934 8665; e-mail: rkaslow@uab.edu Received: 9 July 2005; accepted: 24 April 2006. ISSN 0269-9370 Q 2006 Lippincott Williams & Wilkins 1583