PROJECT SUMMARY
Antiretroviral therapy (ART) has dramatically increased the quality of life and life span of HIV-infected individuals worldwide. HIV transmission, AIDS-defining illnesses, and opportunistic infections have dramatically declined due to ART. Despite this improvement, defects persist in the immune system such that ART adherent, virally suppressed individuals are at a higher risk for diseases related to immune activation and inflammation. The mechanisms that underlie persistent immune activation and inflammation despite long-term ART and suppression of viremia remain unclear. We postulate that ongoing transcriptional activity or subclinical replication of HIV-1 from within the pool of latently infected cells could drive persistent immune activation and inflammation. We hypothesize that the bigger the latent HIV reservoir, the more the ongoing viral replication contributing to persistent Immune activation and inflammation despite viral suppression. The IPDA allows for near accurate measurements of the HIV reservoir with fewer limitations compared to other reservoir measurement assays. This assay however has only been optimized for HIV subtypes B yet in Uganda, we majorly have HIV subtypes A and D in circulation. Therefore, this study aims to validate the IPDA assay for measuring the size of the HIV latent reservoir for HIV subtypes A and D.
Besides background viral replication, differences in genetic characteristics of the virus have been shown to influence an individual’s response to HIV infection and ART. Higher rates of CD4 T-cell apoptosis and expression of PD-1 were observed among individuals infected with HIV subtype D compared to those with subtype A. HIV subtypes have also been linked with different rates of HIV progression where subtype D was associated with faster progression to death and with a lower CD4 cell count during follow-up compared with subtype A. In addition, persons infected with HIV subtype B were observed to have bigger HIV reservoir sizes compared to individuals infected with other HIV subtypes. With these findings, we postulate that differences between HIV subtypes, ongoing inflammation, and immune activation may influence the reservoir size. Therefore, we propose to characterize the latent reservoir among ART-treated individuals in the Infectious Disease Institute (IDI) HIV treatment cohort and assess the effects of HIV subtype differences on reservoir size. We will also assess whether HIV subtypes independently or additively contribute differently to persistent immune activation among HIV infected individuals in the IDI cohort.
Impact: Our results will give insight on the influence of the reservoir size on the restoration of immune responses in HIV infected individuals on ART and the influence of viral genetic differences on the reservoir size among our study population. The study may further lead to the exploration of new therapeutic strategies in the control of immune activation and inflammation among ART-treated individuals. This study may also highlight the influence of different HIV subtypes, persistent immune activation, and inflammation on the size of the HIV reservoir.
Funders: This work is supported by the European and Developing Countries Clinical Trials Partnership Career Development Fellowships - TMA2020CDF-3162