Abstract
The host genetic landscape surrounding integrated HIV-1 has an impact on the fate of the provirus. Studies analysing HIV-1 integration sites in macrophages are scarce. We studied HIV-1 integration site patterns in monocyte-derived macrophages (MDMs) and activated CD4+ T cells derived from seven antiretroviral therapy (ART)-treated HIV-1-infected individuals whose cells were infected ex vivo with autologous HIV-1 isolated during the acute phase of infection. A total of 1,484 unique HIV-1 integration sites were analysed. Their distribution in the human genome and genetic features, and the effects of HIV-1 integrase polymorphisms on the nucleotide selection specificity at these sites were indistinguishable between the two cell types, and among HIV-1 isolates. However, the repertoires of HIV-1-hosting gene clusters overlapped to a higher extent in MDMs than in CD4+ T cells. The frequencies of HIV-1 integration events in genes encoding HIV-1-interacting proteins were also different between the two cell types. Lastly, HIV-1-hosting genes linked to clonal expansion of latently HIV-1-infected CD4+ T cells were over-represented in gene hotspots identified in CD4+ T cells but not in those identified in MDMs. Taken together, the repertoire of genes targeted by HIV-1 in MDMs is distinct from and more restricted than that of CD4+ T cells.
Highlights
The host genetic landscape surrounding integrated human immunodeficiency virus-1 (HIV-1) has an impact on the fate of the provirus
All HIV-1-infected individuals are enrolled in the Zurich Primary HIV Infection (ZPHI) study[20] and six of seven HIV-1-infected individuals started early antiretroviral therapy (ART) during the acute phase of infection
We compared HIV-1 integration sites patterns between macrophages and CD4+ T cells derived from seven ART-treated HIV-1-infected individuals whose cells were infected ex vivo with autologous, as well as heterologous, primary HIV-1 isolates generated during the acute phase of infection
Summary
The host genetic landscape surrounding integrated HIV-1 has an impact on the fate of the provirus. It is conceivable that the different cellular physiology of macrophages in contrast to that of CD4+ T cells may contribute to the observed difference in productivity of the HIV-1 provirus in these two cell types, a multitude of studies, both in vivo and in vitro, have shown that the host genetic landscape surrounding the provirus does have an impact on the subsequent fate of the provirus. The study of Barr et al.[18] examined HIV-1 integration site patterns in MDMs and compared them with those in CD4+ T cells obtained from other studies. They observed that HIV-1 integration events are found more often in long intergenic regions and, correspondingly, less often in gene-dense regions in MDMs compared to CD4+ T cells. A systematic comparison of HIV-1 integration site patterns between MDMs and CD4+ T cells derived from the same experimental settings has never been done
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