TY - JOUR
T1 - Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape
AU - Pollack, Ross A.
AU - Jones, R. Brad
AU - Pertea, Mihaela
AU - Bruner, Katherine M.
AU - Martin, Alyssa R.
AU - Thomas, Allison S.
AU - Capoferri, Adam A.
AU - Beg, Subul A.
AU - Huang, Szu Han
AU - Karandish, Sara
AU - Hao, Haiping
AU - Halper-Stromberg, Eitan
AU - Yong, Patrick C.
AU - Kovacs, Colin
AU - Benko, Erika
AU - Siliciano, Robert F.
AU - Ho, Ya Chi
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/4/12
Y1 - 2017/4/12
N2 - Despite antiretroviral therapy, HIV-1 persists in memory CD4+ T cells, creating a barrier to cure. The majority of HIV-1 proviruses are defective and considered clinically irrelevant. Using cells from HIV-1-infected individuals and reconstructed patient-derived defective proviruses, we show that defective proviruses can be transcribed into RNAs that are spliced and translated. Proviruses with defective major splice donors (MSDs) can activate novel splice sites to produce HIV-1 transcripts, and cells with these proviruses can be recognized by HIV-1-specific cytotoxic T lymphocytes (CTLs). Further, cells with proviruses containing lethal mutations upstream of CTL epitopes can also be recognized by CTLs, potentially through aberrant translation. Thus, CTLs may change the landscape of HIV-1 proviruses by preferentially targeting cells with specific types of defective proviruses. Additionally, the expression of defective proviruses will need to be considered in the measurement of HIV-1 latency reversal.
AB - Despite antiretroviral therapy, HIV-1 persists in memory CD4+ T cells, creating a barrier to cure. The majority of HIV-1 proviruses are defective and considered clinically irrelevant. Using cells from HIV-1-infected individuals and reconstructed patient-derived defective proviruses, we show that defective proviruses can be transcribed into RNAs that are spliced and translated. Proviruses with defective major splice donors (MSDs) can activate novel splice sites to produce HIV-1 transcripts, and cells with these proviruses can be recognized by HIV-1-specific cytotoxic T lymphocytes (CTLs). Further, cells with proviruses containing lethal mutations upstream of CTL epitopes can also be recognized by CTLs, potentially through aberrant translation. Thus, CTLs may change the landscape of HIV-1 proviruses by preferentially targeting cells with specific types of defective proviruses. Additionally, the expression of defective proviruses will need to be considered in the measurement of HIV-1 latency reversal.
KW - APOBEC-mediated G-to-A hypermutations
KW - HIV-1 cure
KW - HIV-1 latent reservoir
KW - HIV-1 proviral landscape
KW - alternative splicing
KW - cell-associated HIV-1 RNA
KW - cold-target inhibition
KW - cytotoxic T lymphocytes
KW - defective HIV-1 proviruses
KW - defective ribosomal product
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U2 - 10.1016/j.chom.2017.03.008
DO - 10.1016/j.chom.2017.03.008
M3 - Article
C2 - 28407485
AN - SCOPUS:85017333524
SN - 1931-3128
VL - 21
SP - 494-506.e4
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 4
ER -