Evidence for Limited Genetic Compartmentalization of HIV-1 between Lung and Blood

Laura Heath,John E Mittler,Angélique B Van 'T Wout,Hong Zhao,Homer L Twigg,James I Mullins,Alan Fox,David R Park,Kurt Diem,Jeffrey T Schouten,Jan Mcclure,Lawrence Corey,Otto O Yang

doi:10.1371/journal.pone.0006949

Abstract

BackgroundHIV-1 is frequently detected in the lungs of infected individuals and is likely important in the development of pulmonary opportunistic infections. The unique environment of the lung, rich in alveolar macrophages and with specialized local immune responses, may contribute to differential evolution or selection of HIV-1.Methodology and FindingsWe characterized HIV-1 in the lung in relation to contemporaneous viral populations in the blood. The C2-V5 region of HIV-1 env was sequenced from paired lung (induced sputum or bronchoalveolar lavage) and blood (plasma RNA and proviral DNA from sorted or unsorted PBMC) from 18 subjects. Compartmentalization between tissue pairs was assessed using 5 established tree or distance-based methods, including permutation tests to determine statistical significance. We found statistical evidence of compartmentalization between lung and blood in 10/18 subjects, although lung and blood sequences were intermingled on phylogenetic trees in all subjects. The subject showing the greatest compartmentalization contained many nearly identical sequences in BAL sample, suggesting clonal expansion may contribute to reduced viral diversity in the lung in some cases. However, HIV-1 sequences in lung were not more homogeneous overall, nor were we able to find a lung-specific genotype associated with macrophage tropism in V3. In all four subjects in whom predicted X4 genotypes were found in blood, predicted X4 genotypes were also found in lung.ConclusionsOur results support a picture of continuous migration of HIV-1 between circulating blood and lung tissue, with perhaps a very limited degree of localized evolution or clonal replication.

Highlights

HIV-1 infection is associated with a variety of infectious and non-infectious pulmonary complications, and pulmonary infections appear to accelerate the progression of HIV-related disease [1,2,3,4,5,6]
Pulmonary lymphocytes appear to be the major reservoir for HIV-1 DNA in the lung [7,8,9], the lung is distinguished from other organs in having a high percentage of resident macrophages [10] as potential targets of infection and as sites where HIV replication may occur
Study Populations Paired lung and blood samples were obtained from three sources: Induced sputum (IS) and bronchoalveolar lavage (BAL) from HIV-infected subjects collected at the University of Washington (UW-BAL), and BAL samples collected from four serially sampled HIV-infected subjects initiating HAART at Indiana University (IU-BAL) with informed consent using human subjects protocols approved by both institutions

Summary

Introduction

HIV-1 infection is associated with a variety of infectious and non-infectious pulmonary complications, and pulmonary infections appear to accelerate the progression of HIV-related disease [1,2,3,4,5,6]. Previous studies examining HIV-1 in the lung and blood suggest that lung viruses contain amino acid signatures associated with macrophage tropism [11], have higher percentages of monocytotropic viruses [12], are more likely to be CCR5-tropic [13], and are more homogenous than virus found in blood [11,14]. These studies all indicate some degree of genetic compartmentalization between lung and blood as well, though the methods used to define compartmentalization varied. The unique environment of the lung, rich in alveolar macrophages and with specialized local immune responses, may contribute to differential evolution or selection of HIV-1

Methods

Results

Conclusion