The ultimate goal of this proposal is to identify sites of HIV-1 (HIV) persistence in the CNS, evaluate the characteristics and dynamics of HIV in these sites and test a novel preclinical approach for eradicating these sites. Rationale: The major target cells for HIV infection and persistence are T-cells and macrophages. With cART therapy, the number of HIV infected T-cells in the blood has dropped to virtually undetectable levels;however, sites of persistent tissue-based HIV infection and the evolution of that infection in virally suppressed individuals have not been well defined. Discontinuation of cART leads to recurrence of HIV viremia with viral strains not represented by those defined in the rare blood T-cell reservoir, suggesting the existence of a heretofore undefined tissue-based HIV reservoir. HIV infected macrophages have been implicated as a major viral tissue based reservoir in patients with HIV associated dementia (HAD) and unique brain-specific forms of HIV have been found at high levels in HAD patient brains. In patients with cART-mediated complete regulation of peripheral blood detectable HIV brain disease has changed significantly and the milder cognitive dysfunction syndromes associated with HIV infection have now been defined as HIV-associated neurocognitive disorders (HAND). The role that HIV might play in HAND has not yet been determined. With the emergence of atherosclerosis as a significant comorbidity in HIV-infected patients, it appears that a variation of vascular dementia may be becoming more frequent, implicating a potentially new type of HIV-associated CNS pathogenesis. The goal of this program is to define the sites and subspecies of HIV present in CNS and peripheral tissues in patients with well documented histories of cART associated viral suppression. Given the likelihood that a significant reservoir of HIV will be found in macrophages, a novel therapeutic that inhibits infection of macrophages and regulates monocyte differentiation so as to block ongoing migration into diseased tissues will be tested in a variety of in-vitro systems including functional brain cell cultures.
Specific AIM 1 : To identify and characterize the systemic cellular and genetic basis for HIV-1 persistence in the CNS and other reservoirs in autopsy tissues from a virally suppressed cohort.
Specific AIM 2 : Evaluate macrophage-localized HIV-1 reservoir virus variants for growth and functional effects in human macrophage and brain neuron/astrocyte cultures, and test functional effects of PA300, a novel regulator of HIV infection inhibitor and macrophage differentiation in such assays. Studies proposed will allow a definitive description of the HIV reservoir in patients treated with cART and provide in vitro support for a novel therapeutic approach that addresses the macrophage specific component of this reservoir.
Patients treated for HIV infection with anti-retroviral drugs are not cured of HIV infection and are developing evidence for chronic brain diseases such as HIV associated neurocognitive dysfunction (HAND), these observations suggest the existence of a long lived reservoir of infected cells resistant to current treatment strategies. The focus of this project is to define the sites in the brain and body where such reservoirs could exist by evaluating autopsy tissues from patients who died even though their HIV blood level was low or undetectable and to test a component of this reservoir (HIV infected macrophages) for sensitivity to a novel drug, PA300, that kills HIV infected macrophages in test tube assays. The ultimate goal of this study will be to test whether a long lived macrophage based HIV reservoir may contribute to the brain abnormalities observed in patients with HAND and whether this population of cells can be killed thus regulating the presumed toxic environment in the brain that contributes to HAND pathogenesis.
|Fogel, Gary B; Lamers, Susanna L; Levine, Andrew J et al. (2015) Factors related to HIV-associated neurocognitive impairment differ with age. J Neurovirol 21:56-65|
|Lamers, Susanna L; Fogel, Gary B; Nolan, David J et al. (2014) HIV-associated neuropathogenesis: a systems biology perspective for modeling and therapy. Biosystems 119:53-61|