Defective phagocytosis by human monocyte/macrophages following HIV-1 infection: underlying mechanisms and modulation by adjunctive cytokine therapy

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Abstract

Defective immunological function of cells of the macrophage lineage contributes considerably to the pathogenesis of HIV-1 infection. Impairment of phagocytosis of opportunistic pathogens such as Mycobacterium avium complex (MAC), Pneumocystis carinii, Toxoplasma gondii or Candida albicans by peripheral blood monocytes, tissue macrophages and monocyte-derived macrophages following in vivo and in vitro HIV-1 infection is well documented. The development of opportunistic infections due to these pathogens in HIV-infected individuals at late stages of disease is attributed to defective monocyte/macrophage function. The mechanisms whereby HIV-1 impairs phagocytosis are not well known. A number of phagocytic receptors normally mediate engulfment of specific opportunistic pathogens by cells of macrophage lineage; distinct mechanisms are triggered by pathogen–receptor binding to promote cytoskeletal rearrangements and engulfment. This review focuses on the signalling events occurring during Fcγ receptor- and complement receptor-mediated phagocytosis, and considers the mechanisms by which HIV-1 inhibits those signalling events. Since macrophage function is enhanced by cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-γ), the use of these immunomodulators is of potential interest as adjunctive immunotherapy in immunosuppressed individuals. In this review we present examples of clinical applications of GM-CSF and IFN-γ therapy for the treatment of opportunistic infections in HIV-infected individuals receiving antiretroviral drugs.

Introduction

Cells of macrophage lineage contribute to the pathogenesis of HIV-1 infection throughout the course of the disease (reviewed in Crowe, 1995). They express CD4 receptor (Crowe et al., 1987) and CCR5 co-receptor (Alkhatib et al., 1996) for HIV-1 entry, and hence are targets for macrophage (M)-tropic or R5 strains of HIV-1. Both blood monocytes and tissue macrophages can be infected with HIV-1, although monocytes are less susceptible than macrophages (Sonza et al., 1996), and persist in the circulation or tissues as viral reservoirs (Crowe et al., 1987, McElrath et al., 1989). Following HIV-1 infection, cells of macrophage lineage display impaired effector functions, including phagocytosis (Kedzierska et al., 2000), intracellular killing (Biggs et al., 1995) and cytokine production (reviewed in Kedzierska and Crowe, 2001). These defects contribute to the pathogenesis of AIDS by allowing reactivation and development of opportunistic infections with their attendant morbidity and mortality.

Although the treatment of HIV-infected individuals has improved with the introduction of highly active antiretroviral therapy (HAART), research into the pathogenesis of AIDS-related opportunistic infections is still important and relevant. HAART dramatically reduces the plasma viral load and increases CD4 T-cell numbers, thereby delaying progression of the disease and decreasing the occurrence of opportunistic infections (reviewed in Crowe and Sonza, 2000). Despite the clinical improvement associated with HAART, current antiviral drugs are not able to eradicate HIV-1 due to the persistence of the latent reservoirs of the virus (Ho, 1998). In patients receiving HAART who maintain undetectable viral loads for long periods, replication-competent HIV-1 can be recovered from resting CD4 T cells (Finzi et al., 1997) and peripheral blood monocytes (Crowe and Sonza, 2000). Viral reservoirs therefore represent a potentially life long persistence of replication-competent forms of HIV-1 that cannot be suppressed by current antiretroviral treatment.

Strains of HIV-1 that are resistant to reverse transcriptase and protease inhibitors arise in the majority of treated patients who have not adhered to treatment regimens or have low plasma drug levels for other reasons. Viral load rises as a result of the emergence of drug resistant HIV-1. Opportunistic infections are the major problem for patients failing HAART and are likely to increase, as resistance to antiretroviral drugs becomes more widespread. Therefore, an improved understanding of the mechanisms by which HIV-1 impairs cell-mediated immunity is important for the full control of HIV-1 disease progression.

Development of novel adjunctive immunotherapies able to control opportunistic pathogens is also needed. Although current drugs used for treatment of opportunistic infections are usually effective, drug resistance leading to persistent clinical symptoms continues to be recognised. Furthermore, some of the antibiotics used for the treatment of opportunistic infections (e.g. rifampicin) lower the blood levels of some antiretroviral drugs, and therefore must be used cautiously in combination with HAART. The use of immunomodulators such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or interferon-gamma (IFN-γ) for the treatment of opportunistic infections has been successful in a limited number of studies. This review outlines the overall impairment of phagocytic function by cells of macrophage lineage following HIV-1 infection, considers the mechanisms underlying such defective function and presents clinical examples of the use of adjunctive cytokine therapy combined with antiretroviral drugs and specific treatments for the management of opportunistic infections.

Section snippets

Defective phagocytosis by cells of macrophage lineage following HIV-1 infection

In immunocompetent individuals peripheral blood monocytes and tissue macrophages provide critical functions in the cell-mediated response to a variety of pathogens such as bacteria (Mycobacterium avium complex (MAC), Mycobacterium tuberculosis), parasites (Toxoplasma gondii, microsporidia) and fungi (Candida albicans, Cryptococcus neoformans, Pneumocystis carinii). Inefficient control of opportunistic pathogens contributes to the development of opportunistic infections in HIV-infected

Mechanisms underlying defective phagocytosis by cells of macrophage lineage

The mechanisms whereby HIV-1 impairs phagocytosis are not well known. There are a number of phagocytic receptors, and engulfment of specific opportunistic pathogens is often receptor-specific (reviewed in Greenberg, 1995). Complement receptors (C'Rs) are generally responsible for MAC uptake (Schlesinger and Horwitz, 1991) and Fcγ receptors (FcγRs) mediate phagocytosis of opsonised T. gondii (Joiner et al., 1990). Most studies have shown that HIV-1 infection results in either elevated or

Use of immunomodulators for the treatment of opportunistic infections in HIV-infected individuals

The function of cells of macrophage lineage is influenced by their state of activation, which in turn is initiated by exposure to growth factors and cytokines. The key monocyte/macrophage immunomodulators are GM-CSF and IFN-γ. Those cytokines are of potential interest as adjuvants to drug therapy to accelerate immunoreconstitution and protection against a variety of opportunistic pathogens in immunosuppressed individuals.

Summary

Monocytes and macrophages are distinct cell populations that differ in the expression of surface receptors, cytokine/chemokine production and their susceptibility to HIV-1 infection. We therefore propose that there are different mechanisms underlying defective phagocytosis in those two cell populations. Since only a small proportion of blood monocytes (0.001–1%) is infected with HIV-1, the high level of inhibition of phagocytosis in monocytes obtained from HIV-infected individuals may reflect

Acknowledgements

We would like to thank Geza Paukovics for his flow cytometric expertise and HiuTat Chan for stimulating discussions.

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