TY - JOUR
T1 - A Matter of Life or Death
T2 - Productively Infected and Bystander CD4 T Cells in Early HIV Infection
AU - Cao, Dechao
AU - Khanal, Sushant
AU - Wang, Ling
AU - Li, Zhengke
AU - Zhao, Juan
AU - Nguyen, Lam Nhat
AU - Nguyen, Lam Ngoc Thao
AU - Dang, Xindi
AU - Schank, Madison
AU - Thakuri, Bal Krishna Chand
AU - Zhang, Jinyu
AU - Lu, Zeyuan
AU - Wu, Xiao Y.
AU - Morrison, Zheng D.
AU - El Gazzar, Mohamed
AU - Ning, Shunbin
AU - Moorman, Jonathan P.
AU - Yao, Zhi Q.
N1 - Publisher Copyright:
© Copyright © 2021 Cao, Khanal, Wang, Li, Zhao, Nguyen, Nguyen, Dang, Schank, Thakuri, Zhang, Lu, Wu, Morrison, El Gazzar, Ning, Moorman and Yao.
PY - 2021/2/12
Y1 - 2021/2/12
N2 - CD4 T cell death or survival following initial HIV infection is crucial for the development of viral reservoirs and latent infection, making its evaluation critical in devising strategies for HIV cure. Here we infected primary CD4 T cells with a wild-type HIV-1 and investigated the death and survival mechanisms in productively infected and bystander cells during early HIV infection. We found that HIV-infected cells exhibited increased programmed cell death, such as apoptosis, pyroptosis, and ferroptosis, than uninfected cells. However, productively infected (p24+) cells and bystander (p24-) cells displayed different patterns of cell death due to differential expression of pro-/anti-apoptotic proteins and signaling molecules. Cell death was triggered by an aberrant DNA damage response (DDR), as evidenced by increases in γH2AX levels, which inversely correlated with telomere length and telomerase levels during HIV infection. Mechanistically, HIV-infected cells exhibited a gradual shortening of telomeres following infection. Notably, p24+ cells had longer telomeres compared to p24- cells, and telomere length positively correlated with the telomerase, pAKT, and pATM expressions in HIV-infected CD4 T cells. Importantly, blockade of viral entry attenuated the HIV-induced inhibition of telomerase, pAKT, and pATM as well as the associated telomere erosion and cell death. Moreover, ATM inhibition promoted survival of HIV-infected CD4 T cells, especially p24+ cells, and rescued telomerase and AKT activities by inhibiting cell activation, HIV infection, and DDR. These results indicate that productively infected and bystander CD4 T cells employ different mechanisms for their survival and death, suggesting a possible pro-survival, pro-reservoir mechanism during early HIV infection.
AB - CD4 T cell death or survival following initial HIV infection is crucial for the development of viral reservoirs and latent infection, making its evaluation critical in devising strategies for HIV cure. Here we infected primary CD4 T cells with a wild-type HIV-1 and investigated the death and survival mechanisms in productively infected and bystander cells during early HIV infection. We found that HIV-infected cells exhibited increased programmed cell death, such as apoptosis, pyroptosis, and ferroptosis, than uninfected cells. However, productively infected (p24+) cells and bystander (p24-) cells displayed different patterns of cell death due to differential expression of pro-/anti-apoptotic proteins and signaling molecules. Cell death was triggered by an aberrant DNA damage response (DDR), as evidenced by increases in γH2AX levels, which inversely correlated with telomere length and telomerase levels during HIV infection. Mechanistically, HIV-infected cells exhibited a gradual shortening of telomeres following infection. Notably, p24+ cells had longer telomeres compared to p24- cells, and telomere length positively correlated with the telomerase, pAKT, and pATM expressions in HIV-infected CD4 T cells. Importantly, blockade of viral entry attenuated the HIV-induced inhibition of telomerase, pAKT, and pATM as well as the associated telomere erosion and cell death. Moreover, ATM inhibition promoted survival of HIV-infected CD4 T cells, especially p24+ cells, and rescued telomerase and AKT activities by inhibiting cell activation, HIV infection, and DDR. These results indicate that productively infected and bystander CD4 T cells employ different mechanisms for their survival and death, suggesting a possible pro-survival, pro-reservoir mechanism during early HIV infection.
KW - AKT
KW - ATM
KW - HIV
KW - T cell death
KW - survival
KW - telomerase
KW - telomere
UR - http://www.scopus.com/inward/record.url?scp=85101884092&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101884092&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.626431
DO - 10.3389/fimmu.2020.626431
M3 - Article
C2 - 33643305
AN - SCOPUS:85101884092
SN - 1664-3224
VL - 11
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 626431
ER -