title: Baseline CD4+ T cell counts correlates with HIV-1 synonymous rate in HLA-B*5701 subjects with different risk of disease progression.
abstract: HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although risk of progression may vary among patients carrying this allele. The interplay between HIV-1 evolutionary rate variation and risk of progression to AIDS in HLA-B*5701 subjects was studied using longitudinal viral sequences from high-risk progressors (HRPs) and low-risk progressors (LRPs). Posterior distributions of HIV-1 genealogies assuming a Bayesian relaxed molecular clock were used to estimate the absolute rates of nonsynonymous and synonymous substitutions for different set of branches. Rates of viral evolution, as well as in vitro viral replication capacity assessed using a novel phenotypic assay, were correlated with various clinical parameters. HIV-1 synonymous substitution rates were significantly lower in LRPs than HRPs, especially for sets of internal branches. The viral population infecting LRPs was also characterized by a slower increase in synonymous divergence over time. This pattern did not correlate to differences in viral fitness, as measured by in vitro replication capacity, nor could be explained by differences among subjects in T cell activation or selection pressure. Interestingly, a significant inverse correlation was found between baseline CD4+ T cell counts and mean HIV-1 synonymous rate (which is proportional to the viral replication rate) along branches representing viral lineages successfully propagating through time up to the last sampled time point. The observed lower replication rate in HLA-B*5701 subjects with higher baseline CD4+ T cell counts provides a potential model to explain differences in risk of disease progression among individuals carrying this allele.
authors.affiliation: Division of Clinical Microbiology & Center for HIV Research, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Norström
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine & Emerging Pathogens Institute, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Nazle M
authors.initials: NM
authors.lastname: Veras
authors.affiliation: Monogram Biosciences Inc., South San Francisco, California, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Centre for Health Informatics, Institute of Population Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Mattia C F
authors.initials: MC
authors.lastname: Proper
authors.affiliation: Monogram Biosciences Inc., South San Francisco, California, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cook
authors.affiliation: UCSF Positive Health Program, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Wendy
authors.initials: W
authors.lastname: Hartogensis
authors.affiliation: UCSF Positive Health Program, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsson
authors.affiliation: Division of Clinical Microbiology & Center for HIV Research, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsoon
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine & Emerging Pathogens Institute, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Marco
authors.initials: M
authors.lastname: Salemi
mesh_terms: D001499:Bayes Theorem; D015496:CD4-Positive T-Lymphocytes; D019295:Computational Biology; D018450:Disease Progression; D016655:HIV Core Protein p24 / Q000145:classification / Q000235:genetics; D015658:HIV Infections / Q000453:epidemiology / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D015235:HLA-B Antigens; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D016655:HIV Core Protein p24; D015235:HLA-B Antigens; C484830:HLA-B*57:01 antigen; C514799:p24 protein, Human Immunodeficiency Virus Type 1