Elsevier

Cytokine & Growth Factor Reviews

Volume 23, Issues 4–5, August–October 2012, Pages 207-214
Cytokine & Growth Factor Reviews

The role of cytokines in the pathogenesis and treatment of HIV infection

https://doi.org/10.1016/j.cytogfr.2012.05.007Get rights and content

Abstract

HIV immune activation plays an important role in the immunopathogenesis of the disease. The mechanisms driving this immune activation are partially defined and likely are the result of multiple factors. The introduction of combination antiretroviral therapy (cART) has improved the life expectancy of HIV infected individuals, however there is evidence that in the setting of “undetectable” HIV-RNA plasma levels, there is some level of persistent immune activation in these patients. A better understanding of the immune activation pathways should be of value in developing complementary therapies to restore the immune systems of patients with HIV infection. This review discusses the cytokine mediated pathways of immune activation of the CD4 and CD8 T cell pools during HIV infection.

Section snippets

Pathogenesis of HIV infection

HIV infection targets the immune system leading to a state of immunodeficiency in a setting of immune activation. The molecular mechanisms causing the pathogenesis of HIV infection are still incompletely understood and are probably a composite of multiple factors. The acute phase of HIV infection or SIV infected rhesus macaques (RM) is characterized by a substantial drop in peripheral CD4 T cell counts and a substantial depletion of memory CD4+ CCR5+ T cells [1], [2], [3], [4], [5]. In the

T cell immune activation

It is likely that multiple forces are responsible for the disruption of the immune systems of patients with HIV infection (Fig. 1). An unresolved paradox in patients with HIV infection is that while both CD4 and CD8 T cells are activated, one sees depletion of the CD4 T cell pool and expansion of the CD8 T cell pool. A direct cytopathic effect of HIV infection on CD4 T cells may explain part of this difference, however, the low number of cells actively infected at any given point makes this an

Cytokine and immune activation pathways

In the course of chronic HIV infection, homeostatic forces and HIV-induced inflammation differentially affect CD4 and CD8 T cell immune activation. These differences are reflected in the ways that these T cell pools respond to the inflammatory and homeostatic environments (Fig. 1).

Inflammation and biomarkers: IL-6, sCD14 and D-dimer

The introduction of cART has improved the life expectancy of HIV infected individuals. While antiretroviral therapies are capable of suppressing plasma levels of HIV to <50 copies/ml for extended periods of time, levels of viral replication return to baseline within weeks of stopping therapy and thus patients with HIV infection today face the likelihood of life-long therapy. An increasing body of data are clearly demonstrating that despite plasma levels of HIV that are “undetectable” there is

Dr. Marta Catalfamo received a Biochemistry degree at the National University of Tucuman. Argentina. She obtained her PhD degree in Immunology from the Autonomous University of Barcelona, Spain. She did her postdoctoral studies in human CD4 and CD8 T cell function, and she defined a new regulated secretory pathways for the chemokine RANTES. After completing her post-doctoral training at the National Cancer Institute, NIH, she joined as staff scientist at the Laboratory of Immunoregulation at

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    Dr. Marta Catalfamo received a Biochemistry degree at the National University of Tucuman. Argentina. She obtained her PhD degree in Immunology from the Autonomous University of Barcelona, Spain. She did her postdoctoral studies in human CD4 and CD8 T cell function, and she defined a new regulated secretory pathways for the chemokine RANTES. After completing her post-doctoral training at the National Cancer Institute, NIH, she joined as staff scientist at the Laboratory of Immunoregulation at NIAID, NIH. Her research focuses in understanding the cytokine-driven mechanisms of immune activation during HIV infection. Her work has delineated clear differences in the activation of CD4 and CD8 T cell pools in patients with HIV infection. Her studies are directed to address how the homeostatic response to CD4 T cell depletion and the inflammatory response to HIV infection affect the immune activation of CD4 and CD8 T cell subsets. Particularly, the interactions of the signaling pathways between IL-7 and Type I IFNs associated with these two environments.

    Dr. Cecile Le Saout obtained her Master's degree in Biology and Health in 2005 and her PhD degree in Immunology in 2009, from the University of Montpellier II, France. She joined the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases, NIH for post-doctoral training in 2010. Her research is focused on elucidating the molecular mechanisms of T cell immune activation during HIV infection, particularly the cross-talk between the cytokines associated with the homeostatic (IL-7) and the inflammatory (Type-I IFN) environments induced by HIV infection.

    H. Clifford Lane received his M.D. degree from the University of Michigan in 1976. He then completed an internship and residency at the University of Michigan Hospital, Ann Arbor, Michigan. In 1979, he came to the National Institutes of Health (NIH) as a clinical associate in the Laboratory of Immunoregulation (LIR) of the National Institute of Allergy and Infectious Diseases (NIAID). He is currently chief of the Clinical and Molecular Retrovirology Section of the LIR and the clinical director, director of the Division of Clinical Research and Deputy Director for Clinical Research and Special Projects of NIAID.

    He became one of the first investigators to study immunopathogenic mechanisms of HIV disease, ultimately making a series of observations that helped establish the field of HIV immunopathogenesis. In the clinical arena, he has studied innovative approaches to therapy and has used experimental therapeutic interventions as a means of furthering our understanding of HIV pathogenesis. Among other things, he has investigated the strategies of syngeneic bone marrow transplantation, adoptive transfer of lymphocytes, and role of the cytokines alpha interferon and IL-2 in the treatment of patients with HIV infection.

    1

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, Bldg 10 Room 11B07, Bethesda, MD 20892-1360, United States. Tel.: +1 301 443 8313; fax: +1 301 402 4097.

    2

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, Rm. 4-1479, MSC 1460, Bethesda, MD 20892-1360, United States. Tel.: +1 301 4966572; fax: +1 301 480 5560.

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