HIV-1 immunopathogenesis: how good interferon turns bad - PubMed (original) (raw)

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HIV-1 immunopathogenesis: how good interferon turns bad

Jean-Philippe Herbeuval et al. Clin Immunol. 2007 May.

Abstract

The hallmark of acquired immunodeficiency syndrome (AIDS) is the progressive loss of CD4+ T cells that results from infection with human immunodeficiency virus type-1 (HIV-1). Despite 25 years of AIDS research, questions remain concerning the mechanisms responsible for HIV-induced CD4+ T cell depletion. Here we briefly review the in vitro and in vivo literature concerning the protective role of interferon-alpha (IFN-alpha) in HIV/AIDS. We then develop a laboratory- and clinically supported model of CD4+ T cell apoptosis in which either infectious or noninfectious HIV-1 induces the production of type I interferon by plasmacytoid dendritic cells (pDC). The interferon produced binds to its receptor on primary CD4+ T cells resulting in membrane expression of the TNF-related apoptosis-inducing ligand (TRAIL) death molecule. The binding of infectious or noninfectious HIV-1 to CD4 on these T cells results in expression of the TRAIL death receptor 5 (DR5), leading to the selective death of HIV-exposed CD4+ T cells.

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Figures

Figure 1

Figure 1

Progressor. Model showing that either infectious or noninfectious HIV-1 binds to CD4 on pDC, resulting in their activation, type I interferon (IFN-α) production and migration from blood to lymphoid tissue. IFN-α binds to its receptor on CD4+ T cells, resulting in STAT-1/2-regulated expression of membrane TRAIL. The binding of HIV-1 to CD4 on CD4+ T cells is required for expression of the TRAIL death receptor 5 (DR5). Membrane TRAIL expressed by CD4+ T cells, or soluble TRAIL produced by monocytes (not shown) binds to DR5, resulting in CD4+ T cell apoptosis. Figure 1, Nonprogressor. Model showing that the pDC of nonprogressing patients who have low or undetectable plasma viral loads, do not produce IFN-α that is required for TRAIL expression on CD4+ T cells. The lack of viral particles may account for the fact that DR5 is not expressed on CD4+ T cells, which do not undergo apoptosis.

Figure 2

Figure 2

Comparison of protective and immunopathologic effects of IFN-α on HIV-1 infection. The

protective

effects include IFN-α-mediated inhibition of HIV-1 replication and formation of infectious viral particles, and the IFN-α-induced apoptosis of infected CD4+ T cells, resulting in the destruction of the source of new virus production. The

immunopathogenic

effect involves IFN-α-induced apoptosis of HIV-exposed but uninfected CD4+ T cells by the same mechanism that destroys HIV-infected CD4+ T cells. These uninfected, HIV-exposed, dying T helper cells include HIV-specific, as well CD4+ T helper cells that are specific for many pathogens. The protective/immunopathogic balance is statistically tipped in favor of immunopathogenesis, due to the fact that noninfectious HIV-1 particles has been estimated to outnumber infectious particles by a factor of 102-104. Definitions: pDC, plasma dendritic cells. CD123 and BDCA2 are pDC markers; CCR7: migration marker of pDC.

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References

    1. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, Douek DC. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004;200:749–59. - PMC - PubMed
    1. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, Hogan C, Boden D, Racz P, Markowitz M. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med. 2004;200:761–70. - PMC - PubMed
    1. Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, Reilly C, Carlis J, Miller CJ, Haase AT. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005;434:1148–52. - PubMed
    1. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 2005;434:1093–7. - PubMed
    1. Levy JA. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev. 1993;57:183–289. - PMC - PubMed

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