High prevalence of HIV-1 transmitted drug-resistance mutations from proviral DNA massively parallel sequencing data of therapy-naïve chronically infected Brazilian blood donors.

Rodrigo Pessôa,Sabri S Sanabani,Dimitrios Paraskevis

doi:10.1371/journal.pone.0185559

Abstract

BackgroundAn improved understanding of the prevalence of low-abundance transmitted drug-resistance mutations (TDRM) in therapy-naïve HIV-1–infected patients may help determine which patients are the best candidates for therapy. In this study, we aimed to obtain a comprehensive picture of the evolving HIV-1 TDRM across the massive parallel sequences (MPS) of the viral entire proviral genome in a well-characterized Brazilian blood donor naïve to antiretroviral drugs.Materials and methodsThe MPS data from 128 samples used in the analysis were sourced from Brazilian blood donors and were previously classified by less-sensitive (LS) or “detuned” enzyme immunoassay as non-recent or longstanding HIV-1 infections. The Stanford HIV Resistance Database (HIVDBv 6.2) and IAS-USA mutation lists were used to interpret the pattern of drug resistance. The minority variants with TDRM were identified using a threshold of ≥ 1.0% and ≤ 20% of the reads sequenced. The rate of TDRM in the MPS data of the proviral genome were compared with the corresponding published consensus sequences of their plasma viruses.ResultsNo TDRM were detected in the integrase or envelope regions. The overall prevalence of TDRM in the protease (PR) and reverse transcriptase (RT) regions of the HIV-1 pol gene was 44.5% (57/128), including any mutations to the nucleoside analogue reverse transcriptase inhibitors (NRTI) and non-nucleoside analogue reverse transcriptase inhibitors (NNRTI). Of the 57 subjects, 43 (75.4%) harbored a minority variant containing at least one clinically relevant TDRM. Among the 43 subjects, 33 (76.7%) had detectable minority resistant variants to NRTIs, 6 (13.9%) to NNRTIs, and 16 (37.2%) to PR inhibitors. The comparison of viral sequences in both sources, plasma and cells, would have detected 48 DNA provirus disclosed TDRM by MPS previously missed by plasma bulk analysis.ConclusionOur findings revealed a high prevalence of TDRM found in this group, as the use of MPS drastically increased the detection of these mutations. Sequencing proviral DNA provided additional information about TDRM, which may impact treatment decisions. The overall results emphasize the importance of continuous monitoring.

Highlights

Our findings revealed a high prevalence of Transmitted drug-resistance mutations (TDRM) found in this group, as the use of massive parallel sequences (MPS) drastically increased the detection of these mutations
The 2013 report from the Joint United Nations Programme on HIV/AIDS (UNAIDS) acknowledged that almost 10 million of the approximately 35 million people living with the human immunodeficiency virus type 1 (HIV-1) were receiving antiretroviral (ARV) therapy [1]
29 ARVs in six drug classes have been approved for the treatment of HIV-1 infection, including protease inhibitors (PI), nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTI), integrase inhibitors (INI), fusion inhibitors (FI), and entry inhibitors (EI)

Summary

Introduction

The 2013 report from the Joint United Nations Programme on HIV/AIDS (UNAIDS) acknowledged that almost 10 million of the approximately 35 million people living with the human immunodeficiency virus type 1 (HIV-1) were receiving antiretroviral (ARV) therapy [1]. 29 ARVs in six drug classes have been approved for the treatment of HIV-1 infection, including protease inhibitors (PI), nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTI), integrase inhibitors (INI), fusion inhibitors (FI), and entry inhibitors (EI). Transmitted drug-resistance mutations (TDRM) are defined as a pre-existing resistance in individuals who have not received ARV [2]. A handful of studies have described the prevalence of TDRM in treatment-naïve patients, which varies for different geographic regions [4,5,6]. An improved understanding of the prevalence of low-abundance transmitted drug-resistance mutations (TDRM) in therapy-naïve HIV-1–infected patients may help determine which patients are the best candidates for therapy. We aimed to obtain a comprehensive picture of the evolving HIV-1 TDRM across the massive parallel sequences (MPS) of the viral entire proviral genome in a well-characterized Brazilian blood donor naïve to antiretroviral drugs.

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Methods

Results

Conclusion