Macrophages are terminally differentiated cells of the mononuclear phagocyte system that also encompasses dendritic cells, circulating blood monocytes, and committed myeloid progenitor cells in the bone marrow. Both macrophages and their monocytic precursors can change their functional state in response to microenvironmental cues exhibiting a marked heterogeneity. However, there are still uncertainties regarding distinct expression patterns of surface markers that clearly define macrophage subsets, particularly in the case of human macrophages. In addition to their tissue distribution, macrophages can be functionally polarized into M1 (proinflammatory) and M2 (alternatively activated) as well as regulatory cells in response to both exogenous infections and solid tumors as well as by systems biology approaches.

To investigate whether the CC-chemokine monocyte chemotactic protein (MCP)-1 could play a role in the pathogenesis of HIV infection of the central nervous system. This hypothesis was suggested by previous observations, including our finding of elevated cerebrospinal fluid (CSF) levels of this chemokine in patients with cytomegalovirus (CMV) encephalitis. CSF levels of MCP-1 were determined in 37 HIV-infected patients with neurological symptoms, and were compared with both the presence and severity of HIV-1 encephalitis at post-mortem examination and CSF HIV RNA levels. MCP-1 production by monocyte-derived macrophages was tested after in vitro infection of these cells by HIV. CSF MCP-1 levels were significantly higher in patients with (median, 4.99 ng/ml) than in those without (median, 1.72 ng/ml) HIV encephalitis. Elevated CSF MCP-1 concentrations were also found in patients with CMV encephalitis and with concomitant HIV and CMV encephalitis (median, 3.14 and 4.23 ng/ml, respectively). HIV encephalitis was strongly associated with high CSF MCP-1 levels (P = 0.002), which were also correlated to high HIV-1 RNA levels in the CSF (P = 0.007), but not to plasma viraemia. In vitro, productive HIV-1 infection of monocyte-derived macrophages upregulated the secretion of MCP-1. Taken together, these in vivo and in vitro findings support a model whereby HIV encephalitis is sustained by virus replication in microglial cells, a process amplified by recruitment of mononuclear cells via HIV-induced MCP-1.

Background. Microbial translocation contributes to immune activation and disease progression during chronic human immunodeficiency virus type 1 (HIV-

The capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines and other extracellular stimuli. In this study, we demonstrate that cytokine-induced polarization of human monocyte-derived macrophage (MDM) into either classical (M1) or alternatively activated (M2a) MDM is associated with a reduced capacity to support productive CCR5-dependent (R5) HIV-1 infection. M1 polarization was associated with a significant down-regulation of CD4 receptors, increased secretion of CCR5-binding chemokines (CCL3, CCL4, and CCL5), and a >90% decrease in HIV-1 DNA levels 48-h postinfection, suggesting that the inhibition occurred at an early preintegration step in the viral life cycle. In contrast, M2a polarization had no effect on either HIV-1 DNA or protein expression levels, indicating that inhibition occurred at a late/postintegration level in the viral life cycle. M2a inhibition was sustained for up to 72-h postinfection, whereas M1-effects were more short-lived. Most phenotypic and functional changes were fully reversible 7 days after removal of the polarizing stimulus, and a reciprocal down-regulation of M1-related chemokines and cytokines was observed in M2a MDM and vice versa. Since reversion to a nonpolarized MDM state was associated with a renewed capacity to support HIV replication to control levels, M1/M2a polarization may represent a mechanism that allows macrophages to cycle between latent and productive HIV-1 infection.

The immunosuppressive and antiinflammatory cytokine interleukin (IL) 10 selectively upregulates the expression of the CC chemokine receptors CCR5, 2, and 1 in human monocytes by prolonging their mRNA half-life. IL-10–stimulated monocytes display an increased number of cell surface receptors for, and better chemotactic responsiveness to, relevant agonists than do control cells. In addition, IL-10–stimulated monocytes are more efficiently infected by HIV BaL. This effect was associated to the enhancement of viral entry through CCR5. These data add support to an emerging paradigm in which pro- and antiinflammatory molecules exert reciprocal and opposing influence on chemokine agonist production and receptor expression.

Significance: A proportion of the variation in HIV-1 viral load in the infected population is influenced by host genetics. Using a large sample of infected individuals ( n = 6,315) with genome-wide genotype data, we sought to map genomic regions that influence HIV viral load and quantify their impact. We identified amino acid positions located in the binding groove of class I HLA proteins (HLA-A and -B) and SNPs in the chemokine (C-C motif) receptor 5 gene region that together explain 14.5% of the observed variation in HIV viral load. Controlling for these signals, we estimated that an additional 5.5% can be explained by common, additive genetic variation. Thus, we demonstrate that common variants of large effect explain the majority of the host genetic component of HIV viral load.