Background:  Human endogenous retrotransposable elements (HERE) are actively controlled by host factors. Some of these factors, such as members of the APOBEC3 protein family, also play defensive roles against exogenous retroviruses including HIV-1. Restriction of HIV-1 by APOBEC 3F/3G is prevented by HIV-1-Vif, which induces their degradation. We hypothesized that the ability of HIV-1 to overcome host cellular defenses would permit retrotransposition of HERE in HIV-1-infected cells.   

Methods:  Transcript expression of HERV-K, LINE-1, and AluSX retro-elements was profiled in various cell subsets from human peripheral blood mononuclear cells (PBMC) by qRT-PCR. Primary CD4⁺ T cells from blood and lymphoid tissue were infected in vitro with HIV-1. Cells from infection cultures, and mock infection controls, were monitored for HERE transcription and increases in HERE genome copy numbers, which would indicate retrotransposition events. NCBI and Los Alamos sequences databases were searched for unannotated retro-element insertions into HIV-1 genomes.

Results:  We found that both LTR (HERV-K) and non-LTR (LINE-1 and AluSX) HERE transcripts were present in resting CD4⁺ and CD8⁺ T cells, and  monocytes from healthy individuals, and that immune activation resulted in diminished transcript levels. Despite the presence of these transcripts, increases in genomic copy numbers of corresponding elements were not observed. HIV-1 infection of primary CD4⁺ T cells in vitro resulted in the induction of retrotransposition events, and the progressive accumulation of genomic copies of AluSX, LINE-1, and HERV-K elements. This proliferation was restricted to HIV-1-infected cells. A LINE-1 insertion into a primary isolate proviral HIV-1 clone was discovered in the NCBI database. This sequence contains the following hallmarks of LINE-1 insertional events:  flanking direct repeats, an inversion, and a deletion.

Conclusions:  While HERV-K, LINE-1, and AluSX transcripts are expressed in healthy ex vivo PBMC, a post-transcriptional block prevents retrotransposition. HIV-1 infection in vitro results in the retrotransposition of HERE in infected cells. The discovery of a LINE-1 insertion into a primary isolate HIV-1 sequence demonstrates the co-existence of LINE-1 and HIV-1 retrotransposition activity and provides evidence for a similar in vivo induction. The association of retrotransposition activity with HIV-1 infection suggests new mechanisms for HIV-1-related pathologies.