The neuroinflammatory responses to human immunodeficiency virus type 1 (HIV-1) coat proteins such as glycoprotein 120 (gp120) are considered to be responsible for HIV-associated distal sensory neuropathy. Accumulating evidence suggests that T-cell line tropic X4 gp120 increases macrophage infiltration into the peripheral nerves, and thereby induces neuroinflammation leading to pain. However, the mechanisms underlying X4 gp120-induced macrophage recruitment to the peripheral nervous systems remain unclear. We demonstrated that perineural application of X4 gp120 from HIV-120 strains IIIB and MN elicited mechanical hypersensitivity and spontaneous pain-like behaviors in mice. Furthermore, flow cytometry and immunohistochemical studies revealed increased infiltration of bone marrow-derived macrophages into the parenchyma of sciatic nerves and dorsal root ganglia (DRG) 7 days after gp120 IIIB or MN application. Chemical deletion of circulating macrophages using clodronate liposomes markedly suppressed gp120 IIIB-induced pain-like behaviors. In in vitro cell infiltration analysis, RAW 264.7 cell (a murine macrophage cell line) was chemoattracted to conditioned medium from gp120 IIIB-or MN treated cultured Schwann cells, but not to conditioned medium from these gp120-treated DRG neurons, suggesting the possible involvement of Schwann cell-derived soluble factors in macrophage infiltration. We identified using a gene expression array that CXCL1, a chemoattractant of macrophages and neutrophils, was increased in gp120 IIIB treated Schwann cells. Similar to gp120 IIIB or MN, peripheral neural application of recombinant CXCL1 elicited pain-like behaviors accompanied by macrophage infiltration to the peripheral nerves. Furthermore ,the repeated injection of CXCR2 (receptor for CXCL1) antagonist or CXCL1 neutralizing antibody prevented both pain-like behaviors and macrophage infiltration in gp120 IIIB treated mice. Thus, our findings newly define that Schwann cell-derived CXCL1, secreted in response to X4 gp120 IIIB exposure ,is responsible for macrophage infiltration into peripheral nerves ,and is thereby associated with pain-like behaviors in mice. We propose that communication between Schwann cells and macrophages may play a prominent role in the induction of X4 HIV-1-associated pain.
Mpumelelo Ntogwa, PhD in Clinical pharmacology and therapeutics, Kyoto University Japan. Master of Science (Msc) in Clinical pharmacology and therapeutics, Kyoto University Japan (2018). Graduated with a Bachelor of Pharmacy from University of Havana, Cuba (2008). Has 6 years working experience as a hospital pharmacist at Mahalapye District Hospital, Botswana (2009-2015). His interests in HIV-associated pain was triggered by previous experiences working with HIV patients who regularly experienced a debilitating type of pain in their hands and feet which turned out to be HIV-induced Distal Sensory Neuropathy (HIV DSN). He has spent the past 6 years trying to uncover the mechanisms underlying this condition.