Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape

Publication date: 12 April 2017
Source:Cell Host & Microbe, Volume 21, Issue 4
Author(s): Ross A. Pollack, R. Brad Jones, Mihaela Pertea, Katherine M. Bruner, Alyssa R. Martin, Allison S. Thomas, Adam A. Capoferri, Subul A. Beg, Szu-Han Huang, Sara Karandish, Haiping Hao, Eitan Halper-Stromberg, Patrick C. Yong, Colin Kovacs, Erika Benko, Robert F. Siliciano, Ya-Chi Ho
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.

Graphical abstract

Teaser

Defective HIV-1 proviruses (HIV-1def) are considered clinically irrelevant. Pollack and Jones et al. find that HIV-1def can be transcribed, spliced, and translated. Cells containing HIV-1def can be recognized by cytotoxic T lymphocytes (CTLs). Thus, CTLs shape the proviral landscape, and the scope of CTL targets is larger than previously thought.


http://ift.tt/2px34Vz