HIV infection in the post-combination antiretroviral therapy era : a human model of immune aging

The deterioration of the immune system is a fundamental characteristic of aging and is accompanied by alterations in immune aging markers including shorter telomere length (TL), decreased mitochondrial DNA (mtDNA) content, and larger differentiated T cell populations. These same markers characterize an accelerated immune aging phenotype in people living with HIV (PLWH). Although HIV is successfully treated with combination antiretroviral therapy (cART), treatment is lifelong and does not fully eliminate the accelerated aging phenotype. Therefore, cART-controlled HIV infection can represent a human model of immune aging compared to the general population. The extent to which longitudinal changes in leukocyte TL (LTL) and blood mtDNA content inter-relate and are together influenced by HIV is unknown. Also unknown is whether slow progressors, a rare population who naturally control HIV without cART, are protected against HIV-mediated accelerated immune aging. The goal of my research was to investigate aging markers in PLWH, considering HIV infection as a human model of immune aging. First, I developed a monochrome multiplex quantitative PCR assay to measure mtDNA content quickly and accurately with low starting material. I measured blood mtDNA content, LTL, and their rates of change among 312 PLWH and 300 HIV-negative controls. I showed that faster rates of LTL attrition and blood mtDNA decline were associated with loss of HIV viral control. Faster LTL attrition was also associated with slower blood mtDNA content decline, regardless of HIV status. I then measured more granular markers of immune aging including lymphocyte subset TL and T cell differentiation in 57 slow progressors with sex- and age-matched cART-controlled PLWH and HIV-negative controls. My analyses revealed that slow progressors had shorter immune subset TL and more differentiated CD8 T cells compared to both cART-controlled PLWH and HIV-negative controls, indicating that they experience even faster immune aging despite naturally controlling the disease. My research confirms that uncontrolled chronic/latent viral infections such as HIV accelerate immune aging but demonstrates that naturally controlling HIV may also age immune cells. This suggests that preventing and controlling chronic/latent viral infections with therapy could extend lifespan and may represent an evolution to the paradigm of aging research.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat