HIV-1 Progression Definitions Figure 2. Statistical analyses of the distribution of protective and risk alleles across clinical definitions of disease progression. Patients who fulfilled criteria for the definition of long term non-progressor elite controllers (LTNP-EC), LTNP viremic controllers (LTNP-VC), LTNP non controllers (LTNP-NC), chronic progressors (P), and rapid progressors (RP). Analysis included genotyping for HLA-C-35 (rs9264942) (HLA-C), CCR5 D32 (rs333) and CCR2 V64I (rs1799864), CCR5 haplotypes (inferred from CCR5 D32, CCR2 V64I and rs2856758, rs2734648, rs1799987, rs1799988, rs1800023, rs1800024) which define protective (CCR5_H+/H+) or risk haplotypes (CCR5_HHE/HHE or CCR5_P1/P1), ZNRD1 rs9261174, HLA alleles in the HLA-A and HLA2B loci, including protective (HLA2A+, HLA2B+) and risk (HLA2A2, HLA2B2) alleles, as well as HCP5 rs2395029 allele in linkage disequilibrium with HLA2B*5701. The allele frequency of each analyzed marker is presented, with the exception of CCR5 haplotypes, where the proportion of individuals is reported. The specific alleles and haplotypes are shown in Table S1. doi:10.1371/journal.pone.0011079.g002 evolution in ancestral patients was recently estimated; it showed that the percentage of evolved sequences represent, in general, less than 2% of the sequences in the quasispecies [20]. Other viral factors could also lead to ancestral or modern character- istics. Virus co-culture was positive in 6 out of 8 patients with a modern viral genotype (included in the LTNP-VC and -NC); whereas a viral isolate was recovered from only one of 8 patient with ancestral viral genotype (LTNP-EC and -VC) [20]. Proviral loads were significantly higher in LTNPs with modern versus patients with ancestral viral dating. Viral replication capacity as well as viral fitness may also contribute to the clinical presentation. Earlier work has shown that replication capacity of full primary viral isolates predict viral set-points after stopping treatment and also correlates with baseline env diversity [9,27]. Recent work has shown the reduced replication capacity of chimeric viruses with gag-protease from LTNP-EC in com- parison with chronically infected individuals [28]. Moreover envelope glycoproteins from virus from LTNP-EC exhibit a reduced entry capacity [29]. In conclusion, frequently used clinical definitions of patterns of disease progression are supported by the pattern of enrichment of validated host genetic markers and virological factors. This is particularly relevant for the standardization of definitions, in particular for rapid progression –a spectrum of disease that has been incompletely investigated, as well as for the discrimination within viremic controllers LTNPs. Host genetic and viral markers are also of use to the identification of incongruent assignments, i.e., individuals, with host or viral characteristics inconsistent with the clinical profile, who may signal novel pathogenic factors or mechanisms. This was indicated by Emu et al. [30] who underscored the importance of individuals with a LTNP status that lack any of the recognized protective factors. The study also emphasizes the need to apply a standardized and accepted set of clinical definitions for the purpose of disease stratification and research. PLoS ONE | www.plosone.org 5 June 2010 | Volume 5 | Issue 6 | e11079