CD163, a monocyte- and macrophage-specific scavenger receptor, is shed during activation as soluble CD163 (sCD163). We have previously demonstrated that monocyte expansion from bone marrow with simian immunodeficiency virus (SIV) infection correlated with plasma sCD163, the rate of AIDS progression, and the severity of macrophage-mediated pathogenesis. Here, we examined sCD163 in human immunodeficiency virus (HIV) infection. sCD163 was elevated in the plasma of individuals with chronic HIV infection (>1 year in duration), compared with HIV-seronegative individuals. With effective antiretroviral therapy (ART), sCD163 levels decreased in parallel with HIV RNA levels but did not return to HIV-seronegative levels, suggesting the presence of residual monocyte/macrophage activation even with plasma viral loads below the limit of detection. In individuals with early HIV infection (≤1 year in duration), effective ART resulted in decreased sCD163 levels that were comparable to levels in HIV-seronegative individuals. sCD163 levels in plasma were positively correlated with the percentage of CD14+CD16+ monocytes and activated CD8+HLA-DR+CD38+ T lymphocytes and were inversely correlated with CD163 expression on CD14+CD16+ monocytes. With ART interruption in subjects with early HIV infection, sCD163 and plasma virus levels spiked but rapidly returned to baseline with reinitiation of ART. This study points to the utility of monocyte- and macrophage-derived sCD163 as a marker of HIV activity that links viral replication with monocyte and macrophage activation. These observations underscore the significance of monocyte and macrophage immune responses with HIV pathogenesis.

Objective: Here we evaluated whether neurocognitive disorders in HIV-infected individuals on effective antiretroviral therapy (ART) are associated with persistent monocyte activation as indexed by levels of soluble CD163 (sCD163), shed by monocyte/macrophages. Design: Chronically, HIV-infected individuals were examined at two consecutive visits median [interquartile range (IQR)] 16 (7–32) months apart. All patients were on ART and durably virologically suppressed (plasma HIV RNA <50 copies/ml) at all visits. Thirty-four age-matched HIV-seronegative patients were used as controls. Methods: A global deficit score (GDS) was calculated based on comprehensive neuropsychological assessment according to standard methods. Neuropsychological and medical data were used to assign neurocognitive status according to published guidelines for HIV-associated neurocognitive disorders (HAND) as follows: neuropsychologically normal (NP-nml), asymptomatic neuropsychological impairment (ANI) and minor neurocognitive disorder (MND). sCD163 in plasma and cerebrospinal fluid was measured using ELISA. Results: GDS-impaired patients had higher plasma sCD163 than those who were not impaired [median (IQR) 1401 ng/ml (1057–2258) versus 955 ng/ml (586–1313); Wilcoxon P = 0.028]. Patients with MND (N = 6) had significantly higher plasma sCD163 than ANI (P = 0.04) or NP-nml (P = 0.02). Whereas plasma sCD163 levels dropped in patients who were stably GDS-unimpaired after the first visit (P < 0.032), levels remained elevated in those who remained GDS-impaired (P = 0.50). Interpretation: These findings are consistent with persistent monocyte/macrophage activation in neurophysiologically impaired HIV-infected individuals despite virally suppressive ART. Overall, these observations underscore the significance of monocyte/macrophage immune responses in HIV, persistent monocyte activation in HAND and the value of sCD163, as a plasma marker of neurocognitive impairment.

Cells of the myeloid lineage are significant targets for human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in monkeys. Monocytes play critical roles in innate and adaptive immunity during inflammation. We hypothesize that specific subsets of monocytes expand with AIDS and drive central nervous system (CNS) disease. Additionally, there may be expansion of cells from the bone marrow through blood with subsequent macrophage accumulation in tissues driving pathogenesis. To identify monocytes that recently emigrated from bone marrow, we used 5-bromo-2′-deoxyuridine (BrdU) labeling in a longitudinal study of SIV-infected CD8+ T lymphocyte depleted macaques. Monocyte expansion and kinetics in blood was assessed and newly migrated monocyte/macrophages were identified within the CNS. Five animals developed rapid AIDS with differing severity of SIVE. The percentages of BrdU+ monocytes in these animals increased dramatically, early after infection, peaking at necropsy where the percentage of BrdU+ monocytes correlated with the severity of SIVE. Early analysis revealed changes in the percentages of BrdU+ monocytes between slow and rapid progressors as early as 8 days and consistently by 27 days post infection. Soluble CD163 (sCD163) in plasma correlated with the percentage of BrdU+ monocytes in blood, demonstrating a relationship between monocyte activation and expansion with disease. BrdU+ monocytes/macrophages were found within perivascular spaces and SIVE lesions. The majority (80–90%) of the BrdU+ cells were Mac387+ that were not productively infected. There was a minor population of CD68+BrdU+ cells (<10%), very few of which were infected (<1% of total BrdU+ cells). Our results suggest that an increased rate of monocyte recruitment from bone marrow into the blood correlates with rapid progression to AIDS, and the magnitude of BrdU+ monocytes correlates with the severity of SIVE. Human immunodeficiency virus (HIV) and the closely related simian immunodeficiency virus (SIV) can infect monocyte/macrophages, which enter and accumulate in the brain leading to neuronal dysfunction. Monocyte/macrophages exit the bone marrow, transit through the blood and enter the central nervous system (CNS). What triggers these cells to traffic is undefined, but it occurs in normal non-infected conditions at a rate that is accelerated with viral infection. Here, we used 5-bromo-2′-deoxyuridine (BrdU) injection and incorporation into the DNA of monocytes prior to their departure from the bone marrow. We found that the percentage of BrdU+ monocytes leaving the bone marrow 24 hours after injection increased in animals that rapidly succumbed to AIDS and correlated with the severity of SIV encephalitis (SIVE). Differences in BrdU labeled monocytes in slow and rapid progressors were revealed as early as 8 days and were consistent by 27 days post infection. Soluble CD163, shed by activated monocyte/macrophages, directly correlated with BrdU+ monocyte expansion. Our study provides new insights into the development of HIV-related CNS disease and underscores the importance of monocyte/macrophage recruitment from the bone marrow as an AIDS defining event.