Host and Viral Genetic Correlates of Clinical Definitions of HIV-1 Disease Progression Concepcio´ n Casado1., Sara Colombo2., Andri Rauch3, Raquel Martı´nez2, Huldrych F. Gu¨ nthard4, Soledad Garcia5, Carmen Rodr´ıguez5, Jorge del Romero5, Amalio Telenti2*, Cecilio Lo´ pez-Galı´ndez1* 1 Centro Nacional de Microbiolog´ıa, Instituto de Salud Carlos III, Madrid, Spain, 2 Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland, 3 University Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland, 4 Division of Infectious Diseases and Hospital Epidemiology, University of Zurich, Zurich, Switzerland, 5 Centro Sanitario Sandoval, IMSALUD Comunidad Auto´ noma de Madrid, Madrid, Spain Abstract Background: Various patterns of HIV-1 disease progression are described in clinical practice and in research. There is a need to assess the specificity of commonly used definitions of long term non-progressor (LTNP) elite controllers (LTNP-EC), viremic controllers (LTNP-VC), and viremic non controllers (LTNP-NC), as well as of chronic progressors (P) and rapid progressors (RP). Methodology and Principal Findings: We re-evaluated the HIV-1 clinical definitions, summarized in Table 1, using the information provided by a selected number of host genetic markers and viral factors. There is a continuous decrease of protective factors and an accumulation of risk factors from LTNP-EC to RP. Statistical differences in frequency of protective HLA-B alleles (p-0.01), HLA-C rs9264942 (p-0.06), and protective CCR5/CCR2 haplotypes (p-0.02) across groups, and the presence of viruses with an ancestral genotype in the ‘‘viral dating’’ (i.e., nucleotide sequences with low viral divergence from the most recent common ancestor) support the differences among principal clinical groups of HIV-1 infected individuals. Conclusions: A combination of host genetic and viral factors supports current clinical definitions that discriminate among patterns of HIV-1 progression. The study also emphasizes the need to apply a standardized and accepted set of clinical definitions for the purpose of disease stratification and research. Citation: Casado C, Colombo S, Rauch A, Mart´ınez R, Gu¨ nthard HF, et al. (2010) Host and Viral Genetic Correlates of Clinical Definitions of HIV-1 Disease Progression. PLoS ONE 5(6): e11079. doi:10.1371/journal.pone.0011079 Editor: Jean-Pierre Vartanian, Institut Pasteur, France Received March 30, 2010; Accepted May 21, 2010; Published June 11, 2010 Copyright: 2010 Casado et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: CLG is supported by grant SAF 2007-61036, by Fundacion para la Investigacion y Prevencion del SIDA en Espana (FIPSE) grant 36558/06, 36641/07, 36779/08, 360766/09 and in part by the Red Tematica Cooperativa de Investigacion en SIDA (Red de grupos 173) of the Fondo de Investigaciones Sanitarias de la Seguridad Social (FISss). AT is supported by the Swiss National Science Foundation. This work has been partially financed within the framework of the Swiss HIV Cohort Study (SHCS) funded by the Swiss National Science Foundation (grant no#33CSC0-108787) and by the SHCS research foundation. The funders had no role in study design, data collection and analysisis, decision, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: amalio.telenti@chuv.ch (AT); clopez@isciii.es (CLG) . These authors contributed equally to this work. Introduction A continuous spectrum of disease progression rates character- izes HIV-1 infection. This observation led to various definitions of clinical progression that are widely used for the designation of patient subsets: from elite controllers to rapid progressors. It is not well established how clinical definitions relate to various determinants of pathogenesis. In particular, a number of host genetic, immune and virological factors have been associated with various patterns of disease progression [1,2]. The contribution of host factors to viral load and to disease progression has now been established at genome level [3,4]. Genetic variants, validated in several genome-wide association studies, explain 13% of the observed variability in HIV-1 viremia [3]. The addition of gender, age and residual population structure to the genetic model increases the figure up to 22% [4]. Estimates could be improved with more complex and diverse predictive models. Among viral factors studied for their association with HIV-1 disease progression, RNA viral load is the best marker [5]. In addition, HIV DNA levels in peripheral blood mononuclear cells (PBMCs) have prognostic value early in infection [6]. Viral phenotypes related to clinical progression include the CXCR4 or CCR5 coreceptor usage; with CXCR4 use associated with more rapid progression to AIDS [7]. Several studies describe a correlation between disease progression and the extent of HIV-1 genetic variation [8,9,10]. From an evolutionary perspective, the analysis of multiple isolates from the Spanish HIV-1 epidemic permitted the inference of the ‘‘viral dating’’ of isolate sequences as an estimation of viral evolution [11]. A subset of long term non- progressors (LTNPs) carries ancestral viruses (i.e. the estimated date of the viral nucleotide sequences is close to the seroconversion time), because of the control of viral replication. In contrast, individuals with continuous viral evolution carry viruses with modern dating (i.e. close to the sampling time), reflecting the ongoing process of viral divergence [12]. PLoS ONE | www.plosone.org 1 June 2010 | Volume 5 | Issue 6 | e11079