Monocyte/macrophage-derived CC chemokines and their modulation by HIV-1 and cytokines: A complex network of interactions influencing viral replication and AIDS pathogenesis

Abstract

Monocytes/macrophages are cells of the innate arm of the immune system and exert important regulatory effects on adaptive immune response. These cells also represent major targets of HIV infection and one of the main reservoirs. Notably, macrophage-tropic viruses are responsible for the initial infection, predominate in the asymptomatic phase, and persist throughout infection, even after the emergence of dual-tropic and T-tropic variants. Functional impairment of HIV-infected macrophages plays an important role in the immune dysregulation typical of AIDS. Recent studies have underlined the pivotal role of chemokines, cytokines, and their receptors in HIV pathogenesis. It is becoming increasingly apparent that the expression level of chemokine receptors, serving as HIV coreceptors, influences the susceptibility of a CD4+ cell to viral infection and to certain HIV envelope-induced alterations in cellular functions. Numerous pathogens, including HIV, can stimulate the production of chemokines and cytokines, which in turn can modulate coreceptor availability, resulting in differential replication potential for R5 and X4 strains, depending on the microenvironment milieu. Thus, a complex network of interactions involving immune mediators produced by monocytes/macrophages and other cell types as a direct/indirect consequence of HIV infection is operative at all stages of the disease and may profoundly influence the extent of viral replication, dissemination, and pathogenesis.

M1 and M2a Polarization of Human Monocyte-Derived Macrophages Inhibits HIV-1 Replication by Distinct Mechanisms

“…This finding is consistent with previous reports showing that both IFN-␥ and TNF-␣ can down-regulate CD4, thereby limiting HIV-1 entry. In this regard, previous studies have also shown that IFN-␥ decreases CD4 expression in monocytes, whereas TNF-␣, either alone or in combination with IL-13, down-regulates CCR5 and CXCR4, as well as CD4, from the surface of MDM (16,44,45,48). Our study confirms and extends these observations to M1 MDM generated by the short-term costimulation with TNF-␣ plus IFN-␥.…”

“…Next, we investigated the effects of M1 and M2a polarization on the CCR5-binding chemokines CCL3, CCL4, and CCL5 that are potent inhibitors of R5 HIV-1 entry in CD4 ϩ T lymphocytes and MDM (16,48). Secretion of CCL3 and CCL4 was detected after 18 h of cytokine stimulation in all MDM cultures and was significantly up-regulated in M1 vs M2a MDM (25-fold in M1 vs ϳ2-fold in M2a-MDM for CCL3; 14-fold in M1 vs Ͻ2-fold in M2a for CCL4) (Fig.…”

CD4-Specific Transgenic Expression of Human Cyclin T1 Markedly Increases Human Immunodeficiency Virus Type 1 (HIV-1) Production by CD4+T Lymphocytes and Myeloid Cells in Mice Transgenic for a Provirus Encoding a Monocyte-Tropic HIV-1 Isolate

“…Chemokines produced by monocytes play an important role in influencing HIV-1 replication, spread of infection, and pathogenesis of disease (17). Localized production of MCP-1 is sufficient to induce the directed migration of monocytes into organs in vivo, as evidenced by the organ-specific influx of monocytes in mice that carry an MCP-1 transgene controlled by an organ-specific promoter (22,26).…”

HIV-1 exploits CCR5 conformational heterogeneity to escape inhibition by chemokines

“…This occurs via two mechanisms: sterically preventing the viral envelope glycoprotein gp120 from binding to the coreceptor and reducing cell surface coreceptor levels by inducing receptor down-regulation (5-7). They are secreted by a number of cell types and in particular immune cells including R5 HIV-1 target cells (6,8,9). The potential role of native CCR5 chemokines in blocking HIV-1 transmission and progression has been extensively studied (9)(10)(11)(12), but their efficacy as protective factors remains a matter of debate (13,14).…”