This proposal seeks to define early changes to monocyte/macrophages (MO) phenotype and function induced during acute HIV infection (AHI) and to determine the role of timing of early initiation of combination antiretroviral therapy (cART in preventing long term HIV-induced alterations on MO profile and HIV infection of MO. In the context of initial exposure to HIV which establishes the central nervous system (CNS) reservoir of infection, the proposed aims will characterize persistent HIV reservoirs which could contribute to our understanding to develop innovative strategies to cure the body of HIV-1 infection. Changes to MO profile and the degree of MO HIV burden are closely linked to development of neurocognitive impairment (NCI). Because brain injury involving perturbed MO populations may occur very early upon exposure to HIV, understanding the natural history of MO perturbations in the earliest stages of HIV infection is critical to eradicating HIV and strategizing concepts of intervention. Alterations in monocyte homeostasis have profound clinical implications in chronic HIV and our lab has recently identified a perturbed phenotypic and functional MO profiles in chronic HIV that contributes to NCI as well as demonstrated that MO harbor high HIV burden that is associated with NCI. In collaboration with investigators of the NIH-funded RV254/SEARCH 010 cohort with over 100 AHI cases in Bangkok, Thailand, the proposed study presents a unique opportunity to define the earliest changes to monocytes during AHI by leveraging specimens and biological measurements including cerebrospinal fluid (CSF) inflammatory assessments and magnetic resonance spectroscopy (MRS) of the brain. We have established the timing of infection on average 2 weeks from onset of HIV exposure and defined the pattern of systemic and CSF cellular responses and HIV viral burden. We propose to define the earliest timepoint in AHI where MO features and viral burden rise to high levels resembling chronic infection and relate this to (1) early neuroinvasion that will be characterized by measurable circulating markers of CNS inflammation and by brain parenchymal inflammation as detected by MRS, (2) baseline viral penetration assessed by CSF/Plasma HIV viral load ratio and (3) assess the effects of early suppressive cART and telmisartan + cART intensification on MO inflammation.
This study will investigate the early changes to monocyte/macrophage phenotype and function during acute HIV infection that could be important in the development of cognitive impairment. We hypothesize that understanding these key mechanisms will be important for developing new paradigms for eradicating HIV.
|D'Antoni, Michelle L; Byron, Mary Margaret; Chan, Phillip et al. (2018) Normalization of Soluble CD163 Levels After Institution of Antiretroviral Therapy During Acute HIV Infection Tracks with Fewer Neurological Abnormalities. J Infect Dis 218:1453-1463|
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|Corley, Michael J; Dye, Christian; D'Antoni, Michelle L et al. (2016) Comparative DNA Methylation Profiling Reveals an Immunoepigenetic Signature of HIV-related Cognitive Impairment. Sci Rep 6:33310|