Substantial induction of non-apoptotic CD4 T-cell death during the early phase of HIV-1 infection in a humanized mouse model

Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

“…Even if the CD4 + T-cell counts do not decrease in the peripheral blood, cell death is certainly induced in the tissues. We recently reported using CB-HSC-NOJ mice that, whereas a significant decrease in memory CD4 + T cells was observed 4 weeks after R5 HIV-1 challenge and that in naïve CD4 + T cells was observed 3 weeks after X4 HIV-1 challenge in the peripheral blood, cell death was induced as early as 3 days post-challenge with both R5 and X4 HIV-1 in the spleen [ 111 ]. Such an early induction of tissue CD4 + T-cell death by HIV-1 infection has also been observed in other humanized mice, such as FL-HSC-NOG [ 112 ], FL-HSC-NRG [ 113 ], and FL-HSC-DKO [ 113 , 114 ] mice.…”

“…Therefore, our research group investigated whether such non-apoptotic cell death is induced in CD4 + T cells in vivo during the early stage of HIV-1 infection. We recently showed in CB-HSC-NOJ mice that non-apoptotic CD4 + T-cell death including caspace-1 + pyroptosis and phosphorylated mixed-lineage kinase domain-like protein (pMLKL) + necroptosis was induced in the spleen at 3 days post-HIV-1 challenge when HIV-1 productive infection was less visible [ 111 ]. In addition, caspase-3/7 + apoptosis was not enhanced by either R5 or X4 HIV-1, but rather repressed in naïve CD4 + T cells when compared with that for mock infection [ 111 ].…”

“…We recently showed in CB-HSC-NOJ mice that non-apoptotic CD4 + T-cell death including caspace-1 + pyroptosis and phosphorylated mixed-lineage kinase domain-like protein (pMLKL) + necroptosis was induced in the spleen at 3 days post-HIV-1 challenge when HIV-1 productive infection was less visible [ 111 ]. In addition, caspase-3/7 + apoptosis was not enhanced by either R5 or X4 HIV-1, but rather repressed in naïve CD4 + T cells when compared with that for mock infection [ 111 ]. Although we did not observe a significant repression of apoptosis within the CD45RA - memory CD4 + T cell population [ 111 ], the induction of apoptosis by Treg cells, most of which do not express CD45RA in humanized mice [ 47 , 112 ] and were thus included in the memory population, might have offset this repression.…”

“…In addition, caspase-3/7 + apoptosis was not enhanced by either R5 or X4 HIV-1, but rather repressed in naïve CD4 + T cells when compared with that for mock infection [ 111 ]. Although we did not observe a significant repression of apoptosis within the CD45RA - memory CD4 + T cell population [ 111 ], the induction of apoptosis by Treg cells, most of which do not express CD45RA in humanized mice [ 47 , 112 ] and were thus included in the memory population, might have offset this repression.…”

“…However, for a long time, it remained unclear whether necroptosis was induced in CD4 + T cells following HIV-1 infection in vivo until we showed it in CB-HSC-NOJ mice. We showed that pMLKL + necroptosis could be induced by X4 HIV-1 but not R5 HIV-1, suggesting that naïve rather than memory CD4 + T cells are sensitive to necroptosis [ 111 ].…”