According to WHO and UN reports, in 2014 an estimated 34 million persons worldwide were living withHIV. In addition to compromising the immune system, HIV can also infect the CNS early during thedisease, leading to devastating neurological consequences (NeuroAIDS). A growing body of evidenceindicates that neurological damage in NeuroAIDS is triggered not by the active viral replication but by thetransmigration of HIV-infected leukocytes into the brain and the associated neuroinflammation. While it iswell established that HIV uses host-encoded proteins to facilitate viral infection, replication andtransmigration into the CNS, specific host factors involved in the pathogenesis of NeuroAIDS are stillextremely poorly understood. Our laboratory recently identified pannexin-1 channels as essentialcomponents of the HIV life cycle in immune cells as well as in the pathogenesis of NeuroAIDS. Inparticular, we and others have demonstrated that pannexin-1 channel opening facilitates multiple steps ofHIV-mediated CNS compromise, including: (1) regulation of CCR5 surface aggregation and trafficking inresponse to HIV infection; (2) HIV entry by direct regulation of the channel opening and subsequentrelease of intracellular ATP, auto-activating purinergic receptors; (3) release of intracellular factors suchas ATP that promote inflammation; (4) monocyte differentiation and maturation in response to chemokinesand/or HIV; (5) increased expression of several adhesion molecules required for leukocytes totransmigrate across the BBB; (6) neuroinflammation. We also found that ATP compromises BBB integrityand function, and our analysis of a large number of patient samples suggests that circulating ATP may bea biomarker of CNS disease. Our preliminary data indicate that different ethnic groups carry specificpannexin-1 polymorphisms and have differential expression and opening of this channel, potentiallyunderlying, at least in part, the observed variation in susceptibility to HIV infection and NeuroAIDS amongdifferent ethnicities. Our recent preliminary data indicate that circulating ATP concentrations and theircorrelation with CNS compromise are also ethnicity related. Importantly, pannexin-1 channels haveexcellent potential as a therapeutic target because (1) their opening can be effectively blocked in vivousing several pannexin-1 channel blockers, including a specific mimetic peptide we recently designed;and (2) these channels mostly exist in a closed state under physiological conditions, minimizing potentialside effects. This proposal is designed to define the mechanisms linking pannexin-1 channel opening toHIV receptor expression, trafficking, and function (Aim 1), leukocyte differentiation and transmigration intothe CNS (Aim 2), and the role of neuroinflammatory factors released through the channel in BBB andCNS function (Aim 3). Finally, in Aim 4 we will examine the role of pannexin-1 channels in two animalmodels. Together, these experiments will reveal the role of an important new host factor in NeuroAIDS.
|Effective start/end date||8/1/17 → 5/31/22|
- National Institutes of Health (NIH)