Baseline CD4+ T Cell Counts Correlates with HIV-1 Synonymous Rate in HLA-B*5701 Subjects with Different Risk of Disease Progression

Melissa M Norström,Jennifer Cook,Marco Salemi,Frederick M Hecht,Wendy Hartogensis,Nazle M Veras,Mattia C F Proper,Annika C Karlsoon,Wei Huang,Sergei L Kosakovsky Pond

doi:10.1371/journal.pcbi.1003830

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.

Highlights

The clinical course of HIV-1 infection is characterized by considerable variability in the rate of disease progression among patients with different genetic background [1,2,3]
human leukocyte antigen (HLA)-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression [1,9] and, in subjects with this allele, the CD8+ T cell responses target several epitopes in the gag p24 gene [10,11,12]
The clinical course of HIV-1 infection is characterized by considerable variability in the rate of progression to acquired immunodeficiency syndrome (AIDS) among patients with different genetic background

Summary

Introduction

The clinical course of HIV-1 infection is characterized by considerable variability in the rate of disease progression among patients with different genetic background [1,2,3]. HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression [1,9] and, in subjects with this allele, the CD8+ T cell responses target several epitopes in the gag p24 gene [10,11,12]. This often results in the evolution of viral variants that escape CD8+ T cell responses [13,14], there is evidence that some escape mutations in HLA-B*5701-restricted epitopes in p24 might occur at the expense of viral fitness [15,16,17]

Methods

Results

Discussion

Conclusion