Abstract
During infection, the human immunodeficiency virus type 1 (HIV-1) manipulates host cell mechanisms to its advantage, thereby controlling its replication or latency, and evading immune responses. Sumoylation is an essential post-translational modification that controls vital cellular activities including proliferation, stemness, or anti-viral immunity. SUMO peptides oppose pathogen replication and mediate interferon-dependent anti-viral activities. In turn, several viruses and bacteria attack sumoylation to disarm host immune responses. Here, we show that HIV-1 impairs cellular sumoylation and targets the host SUMO E1-activating enzyme. HIV-1 expression in cultured HEK293 cells or in CD4+ Jurkat T lymphocytes diminishes sumoylation by both SUMO paralogs, SUMO1 and SUMO2/3. HIV-1 causes a sharp and specific decline in UBA2 protein levels, a subunit of the heterodimeric SUMO E1 enzyme, which likely serves to reduce the efficiency of global protein sumoylation. Furthermore, HIV-1-infected individuals display a significant reduction in total leukocyte sumoylation that is uncoupled from HIV-induced cytopenia. Because sumoylation is vital for immune function, T-cell expansion and activity, loss of sumoylation during HIV disease may contribute to immune system deterioration in patients.
Highlights
The human immunodeficiency virus type 1 (HIV-1) replicates primarily in CD4+ T-helper lymphocytes of the immune system, and to a limited extent in dendritic cells and macrophages [1]
We demonstrate that HIV-1 expression and replication in cultured HEK293 or HeLa cells, or in CD4+ Jurkat T lymphocytes can cause a dramatic reduction in host cell sumoylation by targeting the UBA2 subunit of the small ubiquitin-like modifier (SUMO) E1–activating enzyme
This virus is capable of reverse transcription, integration, replication, and expression of all viral genes encoding the structural, accessory, and regulatory HIV-1 proteins in transfected cells, but incapable of forming viral particles due to the impairment of envelope protein production by an EGFP cassette that is inserted within the env gene
Summary
The human immunodeficiency virus type 1 (HIV-1) replicates primarily in CD4+ T-helper lymphocytes of the immune system, and to a limited extent in dendritic cells and macrophages [1]. Along the course of untreated HIV-1 infection, as the viral load progressively increases, the immune function collapses due to the depletion of circulating CD4+ T-cells [1, 2, 3]. HIV-1 interfaces with multiple cellular pathways and proteins, hijacking some to its advantage for efficient replication or for latency control, and targeting others to disarm host immune responses [5, 6, 7, 8]. HIV-1 integrase is a key drug target that plays a central role in the incorporation of viral DNA into the host genome. This critical enzyme undergoes multiple PTMs including phosphorylation, acetylation, ubiquitination, and sumoylation [20]. The biochemical consequences of these modifications are diverse, some modulating the affinity of integrase to DNA, whereas others regulate the enzyme’s stability
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