HIV-1 immunopathogenesis: how good interferon turns bad

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.

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

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.