Abstract
Human immunodeficiency virus type 1 (HIV-1) efficiently replicates in dividing and non-dividing cells. However, HIV-1 infection is blocked at an early post-entry step in quiescent CD4+ T cells in vitro. The molecular basis of this restriction is still poorly understood. Here, we show that in quiescent cells, incoming HIV-1 sub-viral complexes concentrate and stably reside at the centrosome for several weeks. Upon cell activation, viral replication resumes leading to viral gene expression. Thus, HIV-1 can persist in quiescent cells as a stable, centrosome-associated, pre-integration intermediate.
Highlights
Lentiviruses, such as the human immunodeficiency virus type 1 (HIV-1) productively infect non-dividing cells such as neurons or macrophages
The situation is clearly different in vivo, since the microenvironment allows completion of Human immunodeficiency virus type 1 (HIV-1) life cycle in quiescent cells even in the absence of cell activation [18,19,20]
Since HIV-1 reverse transcription is completed in G0 cells and only exhibits a delayed kinetics [6,8], additional blocks should occur during the early stages of the virus life cycle
Summary
Lentiviruses, such as the human immunodeficiency virus type 1 (HIV-1) productively infect non-dividing cells such as neurons or macrophages (reviewed in [1,2]). We found that the reverse-transcribed viral genome localized at the centrosome in resting cells (Fig. 3A) and that the frequency of co-localization vDNA/γ-tubulin was similar to that of CA/ γ-tubulin Since both incoming CA antigens and the viral DNA genome reside at the MTOC of resting primary cells, we concluded that they likely represent RTCs. To assess whether sub-viral complexes concentrated at the centrosome constitute stable pre-integration intermediates, which might be subsequently reactivated for productive infection, quiescent MRC5 cells were first transduced with a VSVg-pseudotyped HIV-1 vector and later stimu-. GFP expression could be detected following reactivation of transduced cells up to day 21 post-transduction, demonstrating that part of viral DNA present at the MTOC reaches the nucleus to integrate into host chromosomes These results demonstrated that the sub-viral complexes, which persist at the centrosome, in cells maintained quiescent for an extended period of time, are stable, functional and inducible upon cell stimulation
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