Contribution of plasmacytoid DCs to immune senescence in HIV infection

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DESCRIPTION: When the HIV epidemic began in the US, this disease mostly affected younger adults. Now, with the advent of effective anti-retroviral therapies, HIV-1 infection is considered o be a chronic disease and individuals with HIV infection are living for decades. Based on surveillance data, the CDC has estimated that by 2015, fully half of the individuals living with HIV in the US will be over the age of 50. Despite this dramatic shift in life expectancy, individuals with HIV infection still have a projected lifespan that is shorter than their uninfecte counterparts and they suffer from a number of HIV-associated non-AIDS co-morbidities including early development of chronic diseases normally associated with more advanced age including cardiovascular disease, dementia, frailty and fractures. Central to many of these deficiencies is chronic immune activation. Moreover, there is evidence for accelerated senescence of the T cell compartment, including loss of naive T cells, clonal exhaustion, shortened telomeres and replicative senescence of T cells. Although studies have examined the T cell compartment in HIV infected individuals in the context of age, very little is known about the status of the innate immune response, which is required for development of adaptive immune responses. In particular, although many studies have address plasmacytoid dendritic cells (pDC) in the context of HIV infection, and a few studies have reported on pDC status in human aging, nothing has been reported about pDC in the context of HIV and aging. Our preliminary data demonstrate an age-dependent deficiency of not only blood pDC numbers, but also function; these numerical and functional deficiencies also occurred in HIV infected individuals, but often at earlier ages, and with the older HIV- infected individuals the most compromised. We hypothesize that chronic immune activation drives pDC senescence in HIV-infected subjects. In this study we will utilize two experimental cohorts to compare pDC from HIV seropositive and seronegative donors. The first group will be a cross-sectional study of ART- treated, HIV infected and uninfected adult subjects of different ages, while the second group will be a longitudinal study of individuals prior to initiation of ART and after 24 and 48 weeks of ART therapy. In the first aim, we will investigate the phenotype and function of pDC in these two groups. In the second aim, we will define the age- and HIV-related changes in the CD2+ subpopulation of pDC, which accumulate in the blood of aging individuals. Finally, in the third aim, we will examine the status of the bone marrow pDC and pDC precursors in older vs. young HIV-infected and uninfected individuals to determine how changes Together, our studies will provide much-needed information on the status of pDC in healthy aging and aging with HIV infection and may lead to identification of biomarkers for immune senescence and potential targets for therapeutic intervention.