New Insights Into the Nature of the HIV-2 Reservoir
Ferreira, Fernanda de Araujo
MetadataShow full item record
CitationFerreira, Fernanda de Araujo. 2020. New Insights Into the Nature of the HIV-2 Reservoir. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractAcquired immunodeficiency syndrome (AIDS) can be caused by two lentiviruses: HIV-1, which is responsible for the global AIDS pandemic, and HIV-2, which is endemic in west Africa. In Chapter 1, we show how the two viruses share a similar genetic structure and replication cycle, but are markedly different in their clinical outcomes.
In those infected with HIV-1 and HIV-2, the latent reservoir is a major roadblock in the search for a cure. While the nature of the HIV-1 reservoir has and continues to be investigated, the HIV-2 reservoir has only been recently probed. In Chapter 2, we expand on previous work and characterize the proviral landscape of 9 HIV-2-infected study participants. We find that, like HIV-1, the HIV-2 integrated provirus is mostly defective, with large deletions being the most common defect.
One potential HIV-1 cure strategy proposed is “shock and kill,” which involves the use of latency reversal agents (LRAs) to reactivate the HIV provirus and eliminating HIV-infected cells via virus-mediated cytotoxicity or immune clearance. In Chapter 3, we explore the possibilities of “shock and kill” for individuals latently-infected with HIV-2. We performed ex vivo reactivation experiments on PBMCs isolated from HIV-2 study participants and find that, when we control for DNA input, HIV-1 and HIV-2 PBMCs produce comparable amounts of cell-associated RNA. However, HIV-1 PBMCs produce higher levels of supernatant RNA compared to HIV-2 PBMCs for the majority of the LRA conditions.
In Chapter 4, we discuss the need for a consensus proviral landscape characterization pipeline. By exploring the proviruses of 13 HIV-1-infected study participants, we find that the majority of proviruses harbor two or more types of defects, which is not reflected in current pipelines. This discrepancy leads to differences in both individual and cumulative proviral landscapes.
Taken together, our studies highlight that the nature of the proviral landscape is determined more by host factors than viral factors, and that the differences in virions production post-reactivation of HIV-1- and HIV-2-infected PBMCs is not due to differences in DNA or RNA abundance, but rather to a previously undescribed post-transcriptional block.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365108
- FAS Theses and Dissertations