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. 2017 Nov 22;551(7681):E6-E9.
doi: 10.1038/nature24634.

Re-evaluating evolution in the HIV reservoir

Daniel I S Rosenbloom  1 , Alison L Hill  2 , Sarah B Laskey  3 , Robert F Siliciano  3   4
Affiliations

Re-evaluating evolution in the HIV reservoir

Daniel I S Rosenbloom et al. Nature. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

Competing Financial Interests: Declared none.

Figures

Figure 1
Figure 1. For the first six months of ART, the persistent latent reservoir makes up a minority of sampled sequences
Yellow dots show longitudinal measurements of inducible, replication-competent HIV-1 in resting CD4+ T cells from one patient. Infection frequency was measured by qVOA and is reported as infectious units per million cells (IUPM). Intact, unintegrated HIV-1 DNA in recently infected cells can be detected in this assay because cellular activation stimulates completion of the viral life cycle,,. The solid-coloured regions show estimated sizes of the underlying populations that combine to yield the observed triphasic decay of IUPM. A latent reservoir (green, proportion shown at three and six months) is established before treatment and persists despite ART. This reservoir decays at a very slow rate, that can be approximated as constant over the one-year period represented here. Initially, there is a large, rapidly decaying viral population (red) that is likely to include unintegrated viral genomes. A smaller population of infected cells decays at a moderate rate (blue). Consequently, at therapy initiation, less than 0.01% of resting CD4+ T cells with replication-competent virus belong to the stable reservoir, while 98% belong to the large, fast-decaying population. Only after a year of therapy would the stable reservoir exceed 95%. All patients in the study showed similar decay, in which the proportion of infected cells belonging to the latent reservoir did not stabilize within the first six months of therapy. Note that cells with infectious provirus are generally outnumbered by orders of magnitude by cells containing defective provirus. The percentages given here therefore overestimate the proportion of all sampled HIV-1 DNA that represents the persistent latent reservoir of replication-competent virus.
Figure 2
Figure 2. Simulated decay of labile infected cell population creates misleading appearance of viral replication and evolution in first six months of treatment
A simulated sample of 50 sequences of length 587 base pairs (bp) is shown at each time point (see Methods); these values were chosen for consistency with the number and length of haplotypes presented in the phylogenetic analysis of ref. . a, Genetic divergence is measured, as in ref. , as the average fraction of sites differing from the most common genotype found at treatment initiation (red symbols). Although simulated treatment halts all viral replication, decay of labile infected cells over the first year of treatment causes the sampled viral population to diverge genetically from this common genotype. If divergence is instead measured from the infection origin (light blue symbols), the true pattern is unmasked: evolution proceeds before treatment, but then reverses during early treatment as an increasing number of ancestral reservoir sequences are sampled. Bars show s.e. b, A time-structured tree, constructed as in Fig. 1 of ref. from sequences sampled at and after initiation of ART, creates the misleading appearance of clocklike evolution. Posterior clade probabilities >60% shown. c, A maximum-likelihood tree, constructed and rooted as in Extended Data Fig. 2 of ref. , recapitulates this pattern. A clock-like evolutionary signal is detected (0.07% substitutions per site per month, R2 = 0.54, P < 10−25). d, When sequences sampled before initiation of ART are also included in the maximum-likelihood tree and the root is placed at the true origin of infection, no clock-like signal is detected. Posterior clade probabilities >60% shown. In c and d, leaf sizes and labels indicate multiplicity of each genotype in the sample; leaves without numbers occur only once; and segments show the proportion sampled at each time, using the colour scheme below a.
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