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

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

doi:10.1016/j.chom.2017.03.008

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

Cell Host Microbe. 2017 Apr 12;21(4):494-506.e4. doi: 10.1016/j.chom.2017.03.008.

Authors

Ross A Pollack¹, R Brad Jones², Mihaela Pertea³, Katherine M Bruner¹, Alyssa R Martin¹, Allison S Thomas², Adam A Capoferri⁴, Subul A Beg⁴, Szu-Han Huang², Sara Karandish², Haiping Hao⁵, Eitan Halper-Stromberg⁶, Patrick C Yong⁷, Colin Kovacs⁸, Erika Benko⁹, Robert F Siliciano⁴, Ya-Chi Ho¹⁰

Affiliations

¹ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Microbiology, Immunology, and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
³ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
⁵ Deep Sequencing & Microarray Core, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ University of Colorado, Aurora, CO 80045, USA.
⁷ Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Maple Leaf Medical Clinic, Toronto, ON M5G 1K2, Canada.
⁹ Maple Leaf Medical Clinic, Toronto, ON M5G 1K2, Canada.
¹⁰ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: yho10@jhmi.edu.

Abstract

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.

Keywords: APOBEC-mediated G-to-A hypermutations; HIV-1 cure; HIV-1 latent reservoir; HIV-1 proviral landscape; alternative splicing; cell-associated HIV-1 RNA; cold-target inhibition; cytotoxic T lymphocytes; defective HIV-1 proviruses; defective ribosomal product.

MeSH terms

Genetic Variation
HIV Infections / pathology*
HIV Infections / virology*
HIV-1 / classification
HIV-1 / genetics
HIV-1 / immunology*
Humans
Proviruses / classification
Proviruses / genetics
Proviruses / immunology*
T-Lymphocytes, Cytotoxic / immunology*

Abstract

MeSH terms

Grants and funding