In vivo monocyte depletion in acute SIV infection

Ursula Esser, University of California, Davis
Molecular Biology

Monocytes and macrophages play a central role in the pathogenesis of human immunodeficiency virus (HIV)- associated dementia. They represent prominent targets for HIV infection and are thought to facilitate viral neuroinvasion and neuroinflammatory processes. However many aspects regarding monocyte brain recruitment in HIV infection remain undefined. The nonhuman primate model for Acquired Immunodeficiency Syndrome (AIDS) is uniquely suited to examine the role of monocytes in the pathogenesis of AIDS-associated encephalitis. Using this model, we recently demonstrated central nervous system (CNS) trafficking of dye- labeled monocytes in acute simian immunodeficiency virus (SIV) infection and showed that monocyte brain entry coincided with viral neuroinvasion. Here, we hypothesize that peripheral blood monocyte depletion during the acute infection phase prevents monocyte brain entry and viral neuroinvasion. Our approach to deplete blood monocytes will utilize administration of clodronate liposomes that will be taken up by phagocytic cells in the peripheral circulation when administered intravenously. In monocyte-depleted, acutely SIV-infected animals, we anticipate both absence of monocyte trafficking into the CNS and virus import into the brain. Upon treatment interruption, we expect increased bone marrow output during SIV infection, faster kinetics of recovery of blood monocyte numbers in peripheral blood and higher setpoint of absolute monocyte numbers compared to uninfected control animals.

Our findings are anticipated to dissect the role of monocytes in acute SIV infection in an animal model for AIDS. This proposed novel approach of monocyte depletion, jointly with currently ongoing cell trafficking studies in our laboratory, is expected to elucidate the role of monocytes for virus import into the brain and disruption of blood-CSF and blood-brain barrier functions in primates, as well as capacity of circulating monocytes to produce proinflammatory markers and to migrate into the CNS.

Significance Identifying the characteristics of circulating, activated monocytes during acute SIV infection and defining mechanism(s) of early brain infiltration could lead to novel drug targeting and treatment options that inhibit CNS trafficking by targeting specific monocyte subsets or their migratory signals as well as possible release of monocyte precursors into the peripheral blood pool. Development of such treatment options is particularly critical in the era of highly active anti-retroviral therapy (HAART), which is associated with neurological disease in many HIV+ patients here in California and elsewhere, based on higher life expectancy and poor drug accessibility across the CNS barrier.