Elsevier

Current Opinion in Pharmacology

Volume 48, October 2019, Pages 24-32
Current Opinion in Pharmacology

Phylogenies in ART: HIV reservoirs, HIV latency and drug resistance

https://doi.org/10.1016/j.coph.2019.03.003Get rights and content

Highlights

  • •

    During ART, HIV persists latently in several cell types and tissues.

  • •

    Proliferation of latently infected cells is likely responsible for residual viremia.

  • •

    DRMs do not appear during ART in patients with suppressed viral loads.

  • •

    Transmission and replication fitness are highly variable across DRMs.

  • •

    Because of epistasis, the viral genetic background strongly influences DRM fitness.

Combination antiretroviral therapy (ART) has significantly reduced the morbidity and mortality resulting from HIV infection. ART is, however, unable to eradicate HIV, which persists latently in several cell types and tissues. Phylogenetic analyses suggested that the proliferation of cells infected before ART initiation is mainly responsible for residual viremia, although controversy still exists. Conversely, it is widely accepted that drug resistance mutations (DRMs) do not appear during ART in patients with suppressed viral loads. Studies based on sequence clustering have in fact indicated that, at least in developed countries, HIV-infected ART-naive patients are the major source of drug-resistant viruses. Analysis of longitudinally sampled sequences have also shown that DRMs have variable fitness costs, which are strongly influenced by the viral genetic background.

Introduction

Modern antiretroviral therapy (ART) for HIV infection makes use of drugs that target viral enzymes. These include nucleoside and non-nucleoside inhibitors of the reverse transcriptase (NRTIs and NNRTIs), as well as protease and integrase strand-transfer inhibitors (PIs and INSTIs). Although ART can effectively block viral replication and reduce plasmatic viremia to undetectable levels, it is still impossible to cure HIV. In fact, the virus is able to persist in cellular reservoirs (long-lived cells hosting replication competent HIV) and viral load rapidly rebounds after ART interruption. This is mainly a consequence of HIV latency — that is, the integration of a replication-competent intact virus (provirus) into the host genome, in the absence of virus production [1, 2, 3].

In this review, we provide a brief overview of current knowledge about HIV reservoirs, and we describe how, in the era of high-throughput sequencing, valuable insights can be gained by the analysis of viral phylogenies and the application of molecular evolution approaches.

Section snippets

The viral reservoir and sanctuaries

A key challenge for virological studies in ART-treated patients is how to identify the cellular reservoirs of HIV, and, specifically, how to measure their extent and replication capacity.

HIV reservoirs are established early during acute infection, few days after transmission [4,5]; notably, ART initiation, even in the very initial steps of acute HIV infection, does not prevent the establishment of latently infected cells. Henrich et al. recently described two cases of extremely early initiation

Does HIV evolve during ART?

Whereas it is undisputed that the long-lived viral reservoir is the major barrier to cure HIV, the mechanisms underlying HIV persistence are a matter of debate [21]. One line of thought maintains that the proliferation of cells infected before ART initiation is mainly responsible for residual viremia [8,22••,23,24,25•,26,27]. The alternative hypothesis envisages ongoing and low-level viral replication in sanctuary sites as a consequence of reduced antiretroviral drug concentrations [15•,28, 29,

Fate and fitness of drug-resistance mutations

Sequence clustering has been widely applied to study HIV outbreaks and transmission chains. Several studies exploited sequence data generated for surveillance purposes in the USA and Europe to analyze drug resistant virus transmission [43••,44, 45, 46]. In particular, Drescher et al. [44] defined clusters as monophyletic groups of sequences with high bootstrap support (a measure of confidence in phylogenic inference) (Figure 2a), whereas Wertheim et al. [43••] applied a method based on pairwise

Conclusions

The application of high-throughput techniques to the field of clinical virology has generated an unprecedented availability of sequence data. Using molecular evolution techniques, such data can be mined to reveal viral dynamics, evolutionary trajectories (or lack thereof), and selective forces. The study of HIV antiviral resistance has greatly benefited from these advances. Although the mechanisms responsible for the maintenance of the viral reservoirs have not been fully elucidated, a wealth

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors are grateful to Dr Giorgio Bozzi for reading of the manuscript and for valuable suggestion. This work was supported by the Associazione Nazionale per la Lotta contro l’Aids-Sezione Lombarda, unrestricted grant to A.G. and by the Italian Ministry of Health, grant n. RC 2019 to M.S.

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