With an aging HIV population, it is becoming increasingly difficult to disentangle central nervous system (CNS) injury due to HIV from that due to comorbidities such as vascular disease. A commonality between HIV infection and aging is that both can be considered inflammatory conditions; thus HIV and aging can be expected to have an additive, if not synergistic, negative effect on the CNS. The driver of CNS injury in HIV infected individuals on combination antiretroviral therapy (cART) is likely multifactorial, and may include HIV viral products, antiretrovirals CNS toxicity, traditional vascular risk factors and persistent CNS immune activation. Pro-inflammatory monocytes, such as those expressing tissue factor (TF+), are well-positioned to mediate both inflammation and coagulopathy, thus likely to play a role in CNS injury. TF+ monocytes are increased in HIV+ individuals, even in those on effective cART. Their ability to mediate both inflammation and coagulopathy can lead to dysregulation of the CNS microcirculation, followed by ischemia, and then to demyelination. This last effect is visible as white matter hyperintensities (WMH) in standard clinical MRI studies, for example FLAIR sequence. More advanced pulse sequences, such as diffusion weighted imaging, can provide quantitative measurements of abnormal white matter microstructure integrity even when there is no visible WMH on FLAIR. Well-treated HIV+ individuals are expected to have a very slow neurocognitive decline which is also reflected in small, neuroimaging changes overtime. Therefore, it may take several years for those imaging changes reflecting CNS injury to become quantifiable with standard methodology. We propose novel methodologies that reproducibly construct structural and functional connectomes across subjects and between populations, thus further improving our understanding in the evolution of HIV-associated CNS injury. These novel methods are based on a rigorous statistical approach which will provide the reliability needed to ascertain small changes overtime. We propose to implement these methodologies while investigating the role of TF+ monocytes, immune cells at the crossroad of inflammation and coagulopathy, thus likely involved in HIV-associated CNS injury, especially in an older population.
The specific aims listed below will be investigated in a three-year longitudinal cohort of 110 HIV+ participants and 110 HIV- age, gender and vascular risk factors matched controls. We have chosen a cohort that is primarily composed of participants age ?50 thus at greater risk of vascular disease.
Aim 1. To assess via novel methodologies the longitudinal changes in the trajectory of brain structural connectome and functional connectivity in HIV infected compared to HIV seronegative individuals in the context of intermediaries of inflammation and coagulopathy (soluble CD14 and CD163, D-dimer, soluble tissue factor and TF+ monocytes).
Aim 2. To assess the mediation effect of structural connectome, functional connectivity and cerebral cortical thickness on specific cognitive domains.

Public Health Relevance

Over a million people are thought to be HIV infected in the US and it has been projected that by 2015 more than half of all HIV+ individuals would over the age of 50. Aging and HIV infection increase the risk of cerebrovascular disease leading to abnormal brain structural and functional connectivity which are the underpinning of cognitive dysfunction. Our proposal is centered on applying novel methodologies that will allows us to measure reliably and robustly the trajectory of injury of the central nervous system (CNS) associated with HIV infection. Furthermore, we will assess the levels of intermediaries of inflammation and coagulation, in particular tissue factor positive monocytes and assess their relationship to CNS injury as measured by structural and functional connectivity. The information acquired will inform us not only on the extent of CNS injury but also on possible therapeutic targets for CNS injury such as tissue factor positive monocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
3R01MH118020-03S1
Application #
10228819
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rao, Vasudev
Project Start
2018-07-20
Project End
2021-04-30
Budget Start
2020-06-25
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627