Heritability of the HIV-1 reservoir size and decay under long-term suppressive ART

Chenjie Wan ,Chenjie Wan ,Luigia Elzi ,Huldrych F Günthard ,Christian R Kahlert ,Dominique L Braun ,Huldrych F Günthard ,Barbara Hasse ,Volker Röth ,Katja Neumann ,Niko Beerenwinkel ,Matthieu Perreau ,Laura N Walti ,Irène Hösli ,Paolo Paioni ,Marcel Stöckle ,Thomas Klimkait ,Matthias Cavassini ,Susana Posada-Céspedes ,François Blanquart ,Michael Huber ,Jürg Böni ,Helen Kovari ,Venelin Mitov ,Patrick Schmid ,Matthias Egger ,Teja Turk ,Pietro Vernazza ,Gilles Wandeler ,Roger D Kouyos ,Dunja Nicca ,Alexia Anagnostopoulos ,Heiner C Bucher ,Laurent Kaiser ,Rainer Weber ,Andri Rauch ,Jacques Fellay ,Angela Ciuffi ,David Haerry ,Catia Marzolini ,Christoph A Fux ,Jasmina Bogojeska ,Hansjakob Furrer ,Enos Bernasconi ,Alexandra U Scherrer ,Alexandra Trkola ,Manuel Battegay ,Jan Fehr ,Karin J Metzner ,Philip Tarr ,Alexandra Calmy ,Olivia Keiser ,G Pantaleo ,Christoph Rudin ,Hans H Hirsch ,Bruno Ledergerber ,Matthias Hoffmann ,Nadine Bachmann ,Begoña Martínez De Tejada ,Gladys Martinetti ,Katharina Kusejko ,Nicolas Müller ,Sabine Yerly ,Günter Dollenmaier ,R Renae Speck

doi:10.1038/s41467-020-19198-7

Abstract

The HIV-1 reservoir is the major hurdle to curing HIV-1. However, the impact of the viral genome on the HIV-1 reservoir, i.e. its heritability, remains unknown. We investigate the heritability of the HIV-1 reservoir size and its long-term decay by analyzing the distribution of those traits on viral phylogenies from both partial-pol and viral near full-length genome sequences. We use a unique nationwide cohort of 610 well-characterized HIV-1 subtype-B infected individuals on suppressive ART for a median of 5.4 years. We find that a moderate but significant fraction of the HIV-1 reservoir size 1.5 years after the initiation of ART is explained by genetic factors. At the same time, we find more tentative evidence for the heritability of the long-term HIV-1 reservoir decay. Our findings indicate that viral genetic factors contribute to the HIV-1 reservoir size and hence the infecting HIV-1 strain may affect individual patients’ hurdle towards a cure.

Highlights

The HIV-1 reservoir is the major hurdle to curing HIV-1
From 1057 individuals enrolled in the Swiss HIV Cohort Study (SHCS) with successfully quantified total HIV-1 DNA at least ~1.5, ~3.5, and ~5.4 years after the initiation of antiretroviral therapy (ART), we identified 475 individuals with available generation sequences (NGS) of viral near fulllength genome and 869 individuals with available Sanger sequences of partial pol region obtained for genotypic resistance testing (GRT) (Fig. 1)
In line with the reported heritability estimates, we found that all heritability estimators (i.e., Brownian motion (BM), Ornstein Uhlenbeck (OU), or mixed-effect model) provided a better fit compared to the null model, for HIV-1 reservoir size using both sequence types, and for HIV-1 reservoir decay using near full-length genome sequences

Summary

Introduction

The HIV-1 reservoir is the major hurdle to curing HIV-1. the impact of the viral genome on the HIV-1 reservoir, i.e. its heritability, remains unknown. Our findings indicate that viral genetic factors contribute to the HIV-1 reservoir size and the infecting HIV-1 strain may affect individual patients’ hurdle towards a cure. The HIV-1 reservoir refers to the proviral HIV-1 DNA that persists mainly in infected resting memory CD4+ T cells throughout the body[4], including the brain, lymph nodes, blood, and digestive tract It is established already early during primary infection and persists even in patients under long-term ART with no detectable viremia[2,5,6,7]. Pre-treatment viral load correlates positively with reservoir size[3,11] Immunological factors such as homeostatic proliferation[12], clonal expansion[13,14,15], and initial antiviral immune responses[16,17] and epidemiological factors such as transmission group and ethnicity[3] play a role. Common approaches include phylogenetic mixed models with an underlying Brownian motion process (PMM)[31,32,33,34] and phylogenetic mixed models with an underlying Ornstein Uhlenbeck process (POUMM)[28,30,35,36,37]

Methods

Results

Conclusion