HLA, HCP5 and ZNRD1 in HIV Table 3. Likelihood of possessing specific alleles in subjects with different rates of HIV disease progression. Allele HLA-B*57 HLA-B*5701 HCP5-G HLA-C59-C N 90 145 184 585 168 90 145 184 585 168 98 157 198 612 184 98 157 198 612 184 Group{ 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 OR (95% CI), P Unadjusted 1.00 3.18 (0.37–27.66), 0.295 5.11 (0.64–40.59), 0.123 8.87 (1.21–64.93), 0.032 12.71 (1.68–96.16), 0.014 1.00 1.00 2.52 (0.28–22.95), 0.411 4.05 (0.50–32.85), 0.191 4.14 (0.55–30.89), 0.166 5.63 (0.71–44.73), 0.102 3.19 (0.37–27.72), 0.293 4.62 (0.58–36.99), 0.149 4.48 (0.60–33.33), 0.143 4.99 (0.62–39.96), 0.130 1.00 1.32 (0.80–2.19), 0.281 1.30 (0.80–2.12), 0.285 1.36 (0.89–2.09), 0.159 2.16 (1.31–3.55), 0.003 Adjusted{ 1.00 3.10 (0.36–27.04), 0.306 4.76 (0.60–37.89), 0.140 7.62 (1.02–56.69), 0.047 10.80 (1.42–82.05), 0.021 1.00 2.41 (0.26–22.03), 0.437 4.03 (0.49–32.92), 0.194 4.42 (0.58–33.81), 0.153 5.59 (0.70–44.87), 0.105 1.00 1.00 3.05 (0.35–26.68), 0.314 4.63 (0.57–37.35), 0.150 4.84 (0.63–36.94), 0.128 5.10 (0.63–41.25), 0.127 1.28 (0.76–2.14), 0.351 1.27 (0.77–2.09), 0.341 1.47 (0.93–2.32), 0.096 2.16 (1.29–3.60), 0.003 Results of multinomial logistic regression analyses and data are derived from all subjects in the HIV+ WHMC cohort. {Group 1 (progression to AIDS in less than two years) is the reference group, groups 1–5 are as defined in Figure 3D. {Adjusted for seroconversion, race, and the moderate and high CCL3L1-CCR5 genetic risk groups (GRG), which in previous studies were identified as independent determinants of AIDS development [39]. N, number of subjects. doi:10.1371/journal.pone.0003636.t003 Effects of B*57-, HLA-C- and HCP5-containing genotypes The aforementioned findings indicated that the ‘protective’ phenotype attributable to B*57 (e.g. Figure 2A) is a composite, i.e., an overall phenotype that is evident before accounting for the independent phenotypic effects of the SNPs in HLA-C and HCP5- G. Based on the LD patterns between the HLA-B*57, HCP5-G and HLA-C59-C alleles (Figure 1B and Figure 1C, top) and associations described above for each of these alleles, we surmised that a more accurate assessment of the phenotypic effects attributable to B*57 alleles might be attained by evaluation of the genotype-phenotype relationships for B*57-containing geno- types that are defined based on whether or not they also contained the HCP5-G and/or HLA-C59-C alleles. Conversely, such an approach we surmised would also provide insights into the extent to which the protective effects attributed to the HLA-C59-C allele is due to its presence in B*57-containing genotypes. To investigate this, we categorized subjects into six genotypic groups which permitted an analysis of the phenotypic effects associated with HCP5 and HLA-C alleles in genotypes that contained or lacked a B*57 allele (Figure 4A). These six genotypic groups together explained ,3.1% of 2 variability in steady-state viral load (as analyzed by R ) and conferred differential rates of disease progression (Figure 4B). Examination of the survival curves for these six genotypic groups revealed the following genotype-phenotype relationships. Subjects lacking a B*57 allele were assigned to genotypic groups 4 to 6 (Figure 4A). Predictably, as group 4 lacked a B*57 allele as well as the protective HLA-C59 allele, subjects within this group displayed the fastest rate of disease progression among the six genotypic groups (Figure 4B). It was noteworthy that in those subjects who lacked B*57, but were heterozygous (group 5) or homozygous (group 6) for the HLA-C59-C allele had comparable rates of disease progression (Figure 4B). This contrasted with the observation that when LD patterns with the B*57 allele had not been accounted for, homozygosity for the HLA-C59-C allele was associated with a greater protective effect against disease progression than heterozygosity for this allele (Figure 3B). The latter finding indicated that the maximal protective effects of HLA- C59-C allele on HIV disease course might be evident when this allele is present in HLA-B*57-containing genotypes, and the data presented below affirm this possibility. Subjects with a B*57 allele were assigned to genotypic groups 1 to 3, but despite containing a B*57 allele, these genotypic groups were associated with contrasting disease-influencing effects (Figure 4B). Compared to subjects assigned to genotypic groups 1 or 3, those in group 2 had a faster rate of disease progression (Figure 4B). The distribution of the HCP5-G allele in group 2 revealed that individuals assigned to this group could be stratified into two broad categories, with subgroups 2A and 2B possessing or lacking a HCP5-G allele, respectively (Figure 4A). Remarkably, none of the 10 subjects categorized to group 2B progressed to AIDS (Figure 4C), and they all had a genotype that contained a HLA-B*57 and a HLA-C59-C allele but lacked a HCP5-G allele (Figure 4A). By contrast, the HCP5-G-carrying subjects catego- PLoS ONE | www.plosone.org 11 November 2008 | Volume 3 | Issue 11 | e3636