Approximately 37 million people worldwide are living with HIV. HIV enters the CNS within 10 days of peripheral infection, with development of HIV Associated Neurocognitive Disorders (HAND) in ~50% of infected people despite ART. This is due to host/viral inflammatory and toxic factors within the CNS promoting neuronal injury. Studies have shown increased risk and incidence of HIV infected Hispanics for HAND compared to Whites. Molecular mechanisms underlying this increased risk have not been extensively studied. One mechanism by which HIV enters the CNS is by transmigration of infected monocytes across the blood brain barrier (BBB), establishing CNS HIV reservoirs, and inducing inflammation and neurotoxicity. A mature monocyte subset expressing the LPS receptor, CD14, and Fc?III receptor, CD16, is key to HIV neuropathogenesis, increased in the peripheral blood of HIV-infected people, and preferentially infected with HIV. We showed that CD14+CD16+ monocytes from HIV-infected people transmigrate preferentially across our human BBB model to CCL2 and CXCL12, chemokines elevated in the CNS of HIV-infected people. We also showed that CD14+CD16+ monocytes from HIV-infected people with HAND transmigrate in greater numbers to CCL2 than those from people with normal cognition. We showed that an antagonist to CXCR7, a recently identified CXCL12 receptor on monocytes, blocks CXCL12-mediated transmigration of specifically CD14+CD16+ monocytes from HIV- infected people, and we propose this as a therapeutic target to reduce their entry into the CNS. HIV DNA copies/106 PBMC from HIV-infected people, specifically within CD14+CD16+ monocytes, correlate with HAND. Using cultured CD14+CD16+ monocytes, we showed that monocytes harboring HIV (HIV+) preferentially transmigrate across the BBB to CCL2 as compared to uninfected but HIV-exposed monocytes, and that this selective advantage is due, in part, to increased junctional proteins JAM-A and ALCAM. However, there are no studies addressing whether CXCL12-mediated transmigration of mature monocytes, nor whether CXCL12- mediated transmigration specifically of HIV+CD14+CD16+ monocytes, correlate with HAND in Hispanics. Monocytes contribute to peripheral immune activation in HIV-infected people. Once CD14+CD16+ monocytes enter the CNS, they produce host/viral toxic factors that promote neuronal damage and HAND. We hypothesize that: 1. In a select cohort of HIV-infected Hispanics on ART, Hispanics with HAND, compared to those with normal cognition, have a higher percent of peripheral CD14+CD16+ monocytes expressing CCL2, CXCL12, TNF-a, and/or IL-6, and have higher levels of these mediators; 2. CD14+CD16+ monocytes from this cohort, particularly those harboring HIV, will preferentially transmigrate to CXCL12, and this will correlate with HAND; 3. Preferential transmigration of HIV+ monocytes to CXCL12 will be blocked with antibodies to JAM-A and ALCAM, and an inhibitor to CXCR7; 4. Hispanics with HAND will have higher HIV DNA copies/106 PBMC compared to Whites with HAND, contributing to their increased risk for HAND. ! !

Public Health Relevance

More than 37 million people worldwide are infected with HIV. HIV enters the brain early after peripheral infection and despite antiretroviral therapy (ART) results in chronic neuroinflammation and the development of HIV Associated Neurocognitive Disorders (HAND) in more than 50% of infected people, of whom Hispanics have been shown to be at increased risk for development of HAND as compared to Whites. The goal of this proposal is to characterize mechanisms that mediate the increased risk of Hispanics to develop HAND by examining the functions of a specific peripheral blood mature monocyte subset that is key to HIV neuropathogenesis.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Stoff, David M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine, Inc
United States
Zip Code