Background: HIV-1 Vpr plays a pivotal role in viral pathogenesis and is preferentially targeted by the host immune system. Vpr displays multiple, highly conserved activities, which include cytoplasmic-nuclear shuffling, induction of cell cycle G2 arrest and cell death.

Method: Through 3 independent screenings for multicopy suppressors of these Vpr activities in fission yeast, two small heat shock proteins (spHsp16 and spHsp20) were identified which specifically suppress Vpr activities. Similar suppressive effects were also observed with two other small heat shock proteins, including budding yeast scHsp42 and human hHSP27 in fission yeast and human cells, respectively. These small heat shock proteins suppress Vpr activities in a way that mimics the cellular heat shock responses, but in a MAPK-independent manner. Using spHsp16 as an example, we further show that there is a direct protein-protein interaction between Vpr and spHsp16. Vpr gene expression elicits a moderate increase of spHsp16, indicating spHsp16 responses to Vpr. In contrast, Vpr down-regulates spHsp16 when cells are grown under conditions that normally stimulate spHsp16 production.

Conclusion: Together, these data suggest a dynamic and antagonistic interaction between HIV-1 Vpr and cellular stress responses involving small heat shock proteins. Since hHSP27 is specifically elevated upon HIV infection, these findings suggest a role for small heat shock proteins in cellular anti-HIV responses.