BCA2 (Breast Cancer-Associated gene 2, also known as RNF115, ZNF364 or Rabring7) is a RING-finger E3 ubiquitin ligase with anti-HIV activity. In particular, BCA2 promotes the lysosomal degradation of Gag, thereby inhibiting virion assembly (Nityanandam and Serra-Moreno, 2014). We now have evidence that BCA2 provides a regulatory negative feedback on NF-?B (Colomer-Lluch and Serra-Moreno, 2017), a pro- inflammatory cascade elicited upon infection. Remarkably, HIV-1 takes advantage of this innate cascade to ensure gene expression and genome replication by enhancing viral transcription. However, the inactivation of NF-?B is a major determinant towards the establishment of a latent infection. Currently, the latent reservoir, a group of long-lived cells carrying latent HIV-1 proviruses, represents the most critical barrier to functionally cure HIV/AIDS. Since BCA2 blocks NF-?B, we predict that this activity enforces proviral latency. We will test this hypothesis by (1) elucidating the molecular mechanism by which BCA2 modulates NF-?B, and its effects on the transcriptional capacity of HIV-1, and (2) assessing the implication of BCA2 in the establishment and maintenance of proviral latency. These studies will increase our fundamental understanding of the mechanisms involved in the establishment of proviral latency, with the ultimate goal of exploiting them to permanently disable the latent reservoir.

Public Health Relevance

These studies will advance our mechanistic understanding of how cellular factors influence proviral latency, with the ultimate goal of using this information to develop lock approaches to neutralize the latent reservoir: a major obstacle to functionally cure HIV/AIDS. Our candidate protein, BCA2, is particularly attractive because it not only hinders HIV-1 transcription, but also halts virion assembly and propagation. Therefore, this research is highly relevant to the HIV/AIDS cure agenda.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI138589-01A1
Application #
9694313
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Mcdonald, David Joseph
Project Start
2018-11-23
Project End
2020-10-31
Budget Start
2018-11-23
Budget End
2019-10-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Texas Tech University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041367053
City
Lubbock
State
TX
Country
United States
Zip Code
79409