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iPSCs Provide HIV “Killer” Cells

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by Stuart P. Atkinson

From the lab of Dan Kaufman at the Department of Medicine and Stem Cell Institute, University of Minnesota comes a report on the potential use of patient specific human induced pluripotent stem cells (hiPSCs) in the battle against HIV-1 infection. Kaufman’s lab have previously shown that embryonic stem cell (ESC) derived Natural Killer (NK) cells, a key component of the innate immune system, can potentially kill tumour cells in vivo and dramatically reduce tumour size in vitro (Woll et al and Woll et al). Several studies have also shown that NK cells can provide protection against HIV-1 replication in which sufferers show decreased NK cell function. In their most recent study published in the Journal of Virology, Kaufman’s lab now demonstrate that NK cells derived from human ESC (hESC) and also hiPSCs have potent anti-HIV-1 activity (Ni et al).

Using a well-defined protocol, both hESC and hiPSC were induced to undergo haematopoietic differentiation to generate NK cells. hESC-NK and hiPSC-NK cells displayed a similar capacity to kill tumour cells as NK cells from peripheral blood (PB-NK cells). To test the effects of these cells on HIV-1 they utilised a reporter T cell line (CEM-GFP) infected with HIV-1 NL4-3 with the expression of GFP driven by the HIV long terminal repeat (LTR). When iPSC-NK or hESC-NK cells were co-cultured with CEM-GFP cells, HIV-1 activity (as measured by a decrease in GFP expression) was inhibited by 80-90% in both cell types, similar to that observed after co-culture of PB-NK cells with CEM-GFP cells. This approach was then extended to HIV-1 infected primary CD4+ T cells, and results again demonstrated that both hESC- and iPSC-derived NK cells acted at the same efficiency as PB-NK cells with regards to cytotoxicity measured by CD107a expression, a well-established measure of NK cell cytotoxic activity. Another mode of attack by NK cells is to cause cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) through CD16, in which both hESC-NK and iPSC-NK cells functioned better than PB-NK cells. An additional strategy of NK cells to attack HIV-1 is via the production of b-chemokines. Levels of CCL4, used as a representative of NK b-chemokine production, were up-regulated in hESC-NKs and iPSC-NKs, as was IFN-g production, which works through a non-cytolytic mechanism, although not to the level observed in PB-NK cells.

This study demonstrates two important points; firstly, the potential for a patient specific treatment for HIV-1 infection and secondly, the authors note that while different hiPSC lines do show differing levels of haematopoietic differentiation, once the cells are differentiated to haematopoietic progenitors, they have similar potential for NK cell development. This is perhaps at odds with other studies which suggest that hiPSC-derived cells may not function as well as hESC-derived cells. Nonetheless, this study brings hope for the future for a patient-specific stem cell based treatment for HIV infection.

 

References

Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity.
Woll PS, Grzywacz B, Tian X, Marcus RK, Knorr DA, Verneris MR, Kaufman DS.
Blood. 2009 Jun 11;113(24):6094-101.

Human embryonic stem cell-derived NK cells acquire functional receptors and cytolytic activity.
Woll PS, Martin CH, Miller JS, Kaufman DS.
J Immunol. 2005 Oct 15;175(8):5095-103.

Human pluripotent stem cells produce natural killer cells that mediate anti-HIV-1 activity utilizing diverse cellular mechanisms.
Ni Z, Knorr DA, Clouser CL, Hexum MK, Southern P, Mansky LM, Park IH, Kaufman DS.
J Virol. 2010 Oct 20.