CBER Research Projects

Project Title

Regulation of Cytokine Expression by HIV: Potential Points of Therapeutic Intervention

Principal Investigator

K.A. Clouse-Strebel

Laboratory

Laboratory of Cell Biology; Division of Monoclonal Antibodies; Office of Therapeutics Research and Review

Project Summary

Macrophages play a critical role in the pathogenesis of HIV infection, both as targets for virus replication and as sources of multifunctional cytokines. Our early studies showed that normal human monocytes stimulated with the HIV-1 envelope protein, gp120, produce the HIV-modulatory cytokines, TNF-a, IL-1b, IL-6 and GM-CSF (JI 1991) and the potent vasoactive peptide, ET-1 (JI 1993). Our studies with monocyte derived macrophages (MDM) revealed that HIV-1 infection fails to induce these latter cytokines in vitro, but consistently induces M-CSF production with a kinetics paralleling virus replication (JI 1995). M-CSF facilitates differentiation and increases the susceptibility of MDM to HIV infection by enhancing expression of the HIV receptors, CD4 and CCR5. We determined the viral specificity of M-CSF production in MDM using a panel of single-stranded RNA viruses, including HIV-1, HIV-2, measles and respiratory syncytial viruses (MV & RSV) and found that only monocytropic strains of HIV-1 (JI 2000) and HIV-2 caused enhanced production of M-CSF. Chemokines, such as MIP-1a/b and MCP-1, were also produced by HIV-1 infected MDM, but not HIV-2, suggesting that both chemokines and M-CSF are needed to establish a viral reservoir or that chemokine production may correlate with pathogenicity (in prep, 2001). Our other studies using anti-retroviral agents (AZT and Ritonavir) suggest that virus replication and M-CSF production are inextricably linked in HIV-infected MDM, such that inhibition of one leads to comcommitant inhibition of the other (AIDS, submitted). Since HIV arose from cross-species transmission of SIV and progressed from a benign to highly pathogenic disease with initial infections targeting MDM, we are investigating the ability of SIV to infect primary human macrophages and induce M-CSF and other cytokines or chemokines. Using primary isolates, we are finding that SIV from multiple lineages are able to replicate in human MDM. Ongoing studies will determine receptor usage and cytokine production to obtain insight into pathogenic determinants of these lentiviruses for the human population with the hope of identifying novel targets for therapeutic intervention.

Since astrocytes surround HIV-producing cells in the brain, which might influence virus replication, we studied their effect on HIV expression in human MDM. Co-culture of HIV-infected MDM with primary human astrocytes resulted in reduced HIV replication mediated in part by an unidentified astrocyte secreted factor (AIDS 1999) in addition to expression of inducible nitric oxide synthase (iNOS) and production of NO by astrocytes (Blood 1999). Our data suggest that astrocytes play a pivotal role in determining the course of neurologic HIV disease via production of HIV modulating cytokines and expression of iNOS/NO. It also leads us to speculate that neurologic damage observed in HIV disease may ensue from prolonged, high level production of NO by astrocytes, which may reflect a host attempt to inhibit virus replication.

Publications

• Blood 1999 Mar 15;93(6):1843-1850
  Human Immunodeficiency Virus-1-Infected Macrophages Induce Inducible Nitric Oxide Synthase and Nitric Oxide (NO) Production in Astrocytes: Astrocytic NO as a Possible Mediator of Neural Damage in Acquired Immunodeficiency Syndrome.
  Hori K, Burd PR, Furuke K, Kutza J, Weih KA, Clouse KA
  Pub Med

• AIDS 1999 May 7;13(7):751-8
  Human astrocytes inhibit HIV-1 expression in monocyte-derived macrophages by secreted factors.
  Hori K, Burd PR, Kutza J, Weih KA, Clouse KA
  Pub Med

• J Immunol 1993 May 15;150(10):4601-9
  Potent stimulation of monocytic endothelin-1 production by HIV-1 glycoprotein 120.
  Ehrenreich H, Rieckmann P, Sinowatz F, Weih KA, Arthur LO, Goebel FD, Burd PR, Coligan JE, Clouse KA
  Pub Med

• J Immunol 1991 Nov 1;147(9):2892-901
  The HIV-1 gp120 envelope protein has the intrinsic capacity to stimulate monokine secretion.
  Clouse KA, Cosentino LM, Weih KA, Pyle SW, Robbins PB, Hochstein HD, Natarajan V, Farrar WL
  Pub Med

• J Virol 1995 Dec;69(12):7699-711
  Augmentation of virus secretion by the human immunodeficiency virus type 1 Vpu protein is cell type independent and occurs in cultured human primary macrophages and lymphocytes.
  Schubert U, Clouse KA, Strebel K
  Pub Med

• J Biomed Sci 2001 May-Jun;8(3):290-6
  Identification of a potential hiv-induced source of bystander-mediated apoptosis in t cells: upregulation of trail in primary human macrophages by hiv-1 tat.
  Zhang M, Li X, Pang X, Ding L, Wood O, Clouse K, Hewlett I, Dayton AI
  Pub Med

• J Immunol 1995 May 15;154(10):5528-35
  Endogenous macrophage CSF production is associated with viral replication in HIV-1-infected human monocyte-derived macrophages.
  Gruber MF, Weih KA, Boone EJ, Smith PD, Clouse KA
  Pub Med

Last Updated: 4/1/2002

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Date created: September 24, 2003

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