Distinct Cell Survival and Metabolic Programming Determines Germinal Center Tfh Survival of HIV-1 Infection

If you need an accessible version of this item, please submit a remediation request.
Date
2023-07
Language
American English
Embargo Lift Date
Department
Committee Chair
Degree
Ph.D.
Degree Year
2023
Department
Microbiology & Immunology
Grantor
Indiana University
Journal Title
Journal ISSN
Volume Title
Found At
Abstract

HIV-1 is the causative agent of AIDS in people living with HIV-1 (PLHIV). HIV-1 predominantly targets and kills immune cells that are needed for defense against infections and illnesses. Although therapy can control the spread of HIV-1 in PLHIV and decrease the amount of virus present in the body, some subsets of infected immune cells are able to survive HIV-1 and escape treatment. Any pause in therapy leads to a return to high levels of viral loads due to these surviving infected cells. These subsets of infected immune cells escaping treatment represent a major obstacle to the eradication of HIV-1. One such subset of immune cells, the Germinal Center T follicular helper (GC Tfh) cells, can both survive infection and expand in PLHIV. Using human tonsil tissues, the major site of GC Tfh cells, our lab was able to find two critical factors that influence the GC Tfh cells’ ability to survive and thrive while infected by HIV-1. First, we found that GC Tfh cells have a distinct metabolic profile compared to other types of CD4 T cells found in human tonsils. This was characterized by a preference towards non-glycolytic metabolism even when infected with HIV-1. We found that inhibiting non-glycolytic metabolism resulted in a significant decrease in HIV-1 infected GC Tfh cells. Second, we found that GC Tfh cells sharply upregulate proteins responsible for stopping controlled cell death. We found one of these proteins, BIRC5, was integral to GC Tfh survival of HIV-1 infection. Inhibition of BIRC5 led to overall decreases in surviving infected cells, as well as significant decreases in infected GC Tfh survival. In contrast, inhibition of BIRC5 had no effect on uninfected cells. Our results signify an important advancement in the study of HIV-1 reservoir and will help in developing novel therapeutics to eradicate rather than suppress HIV-1 in PLHIV.

Description
Indiana University-Purdue University Indianapolis (IUPUI)
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
Source
Alternative Title
Type
Dissertation
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Full Text Available at
This item is under embargo {{howLong}}