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. 2014 Aug 1;345(6196):570-3.
doi: 10.1126/science.1256304. Epub 2014 Jul 10.

HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection

Thor A Wagner  1 , Sherry McLaughlin  1 , Kavita Garg  2 , Charles Y K Cheung  2 , Brendan B Larsen  3 , Sheila Styrchak  4 , Hannah C Huang  4 , Paul T Edlefsen  5 , James I Mullins  3 , Lisa M Frenkel  6
Affiliations

HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection

Thor A Wagner et al. Science. .

Abstract

Antiretroviral treatment (ART) of HIV infection suppresses viral replication. Yet if ART is stopped, virus reemerges because of the persistence of infected cells. We evaluated the contribution of infected-cell proliferation and sites of proviral integration to HIV persistence. A total of 534 HIV integration sites (IS) and 63 adjacent HIV env sequences were derived from three study participants over 11.3 to 12.7 years of ART. Each participant had identical viral sequences integrated at the same position in multiple cells, demonstrating infected-cell proliferation. Integrations were overrepresented in genes associated with cancer and favored in 12 genes across multiple participants. Over time on ART, a greater proportion of persisting proviruses were in proliferating cells. HIV integration into specific genes may promote proliferation of HIV-infected cells, slowing viral decay during ART.

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Conflict of interest statement

The authors report no conflicts of interest related to this research.

Figures

Fig. 1
Fig. 1. Representation of HIV integration sites sampled through time
(A to C) show the scaled representation of each gene with integration sites mapped for the three participants at three intervals (times in years given along the x axis) after initiation of suppressive ART. Integration sites were detected in all chromosomes of all participants, except for chromosome 18 in participant B1, and chromosome 20 and the Y chromosome in L1, the only male studied. The gray and black regions at the top of each column indicate the proportion of uncharacterized noncoding regions (UNC, black) and genes (gray) that had only one integration site found at any time point. The other colors represent each of the genes (intragenic regions) and uncharacterized noncoding regions that were found to have virus integrated at the same position in multiple cells. (D to F) show the proportion of all HIV-infected cells found to be demonstrably proliferating (blue triangles), defined by ≥2 cells with identical integration sites (from any time point), and the proportion of unique integration sites with evidence of proliferation (red dots). Data are plotted by time (x axis) after initiation of suppressive ART. The P values shown report the significance of the upward trends of these values through time using nonparametric Cochrane-Armitage tests (45).
Fig. 2
Fig. 2. Phylogenetic relationships between HIV-1 env (C2V5 region) genes sampled from participant L1 through time
A neighbor-joining tree was generated using viral gene sequences derived from PBMC DNA from participant L1 by single-genome sequencing, including from this (with integration sites determined) and a previous study (8). Identical sequences are collapsed into horizontal strings of symbols. The year the blood specimen was collected is shown by different colored symbols (see the color key). When an env gene was linked to an integration site, a dotted line was drawn from the symbols to the gene name corresponding to that integration site. The text color of the gene name indicates the year that the specimen was collected with a specific integration site, using the same color key. Participant L1 was perinatally infected with HIV-1, and viral sequences from his mother are shown with open boxes. The horizontal scale indicates a 1% difference between sequences. Asterisks after the year indicate cancer-associated genes time points that integration sites were determined, and § indicates genes with GO terms from the list of hallmarks of cancer (25). Three proviruses (indicated in the figure) were found to be defective as a result of hypermutation (assessed using the tool at www.hiv.lanl.gov/content/sequence/HYPERMUT/hypermut.html), resulting in the introduction of stop codons into the env genes of all three sequences.
Fig. 3
Fig. 3. HIV-1 integration sites in chromosome 6, including the BACH2 locus
(B) (bottom) shows the integration sites mapped in the human chromosome 6 in this (SCRI, Seattle Children’s Research Institute) and other studies of individuals sampled while on suppressive ART, including from Han et al. (26), Imamichi et al. (10), Ikeda et al. (9), and Ho et al. (27). Data taken from the Wang et al. (21) study of virus integrations found 72 hours after infection of Jurkat cells are also shown. The vertical lines represent an integration site over the 172-MB chromosome. Vertical black lines above the horizontal line from each study represent virus integration in the same orientation (5′ to 3′) as the chromosome. Vertical orange lines below the horizontal indicate virus integrations in the opposite orientation. (A) shows an enlargement of the region of chromosome 6 encoding the BACH2 gene. The exons corresponding to a common mRNA transcript are shown on the red line with red arrowheads. The coding sequences (CDS) of the gene are shown with black arrowheads. The position of intron 5 is enclosed in the alignment below in a broken-line box.
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