Mycobacterium tuberculosis Recall Antigens Suppress HIV-1 Replication in Anergic Donor Cells via CD8+ T Cell Expansion and Increased IL-10 Levels

Abstract

Mycobacterium tuberculosis (MTb) is the leading cause of death in the setting of AIDS. MTb enhances the pathogenicity and accelerates the course of HIV disease and, furthermore, infection with HIV-1 increases the risk of reactivation or reinfection with MTb. In this study, we show that host-specific recall responses to one pathogen, MTb, has a direct effect upon the regulation of a second pathogen, HIV-1. Using cells from immunocompetent former tuberculosis (TB) patients who displayed either a persistently positive (responsive) or negative (anergic), delayed-type hypersensitivity (DTH) reaction to intradermal injection of purified protein derivative (PPD), we investigated the effect of recall Ags to MTb upon the replication of HIV-1 primary isolates in vitro. We show that HIV-1 replication of a T cell-tropic isolate was significantly impaired in MTb-stimulated PBMC from PPD-anergic donors. Furthermore, these donors displayed a significant increase in CD8+ T cells and IL-10 levels and lower levels of IL-2 and TNF-α relative to PPD-responsive donors in response to PPD stimulation. Strikingly, CD8+ T cell depletion and blocking of IL-10 significantly increased HIV-1 replication in these PPD-anergic donors, indicating that an immunosuppressive response to MTb recall Ags inhibits HIV-1 replication in PPD-anergic individuals. Therefore, immunotherapeutic approaches aimed at recapitulating Ag-specific MTb anergy in vivo could result in novel and effective approaches to inhibit HIV-1 disease progression in MTb/HIV-1 coinfection.

IL-10–producing and naturally occurring CD4+ Tregs: limiting collateral damage

“…TNF, which is critical in controlling MTb infection, enhances HIV replication. Conversely, IL-10 and the presence of IL-10 Tregs, which blunt immune responses to MTb antigens, inhibited HIV-1 replication in an ex vivo experimental model, in part via their inhibition of TNF production (80). On the other hand, recent work demonstrated that CD25 + CD4 + Tregs from PBMCs of asymptomatic HIV-infected individuals regulate HIV-1 specific immune responses in a cell-contact dependent, IL-10-independent, manner (21).…”

“…Recent studies demonstrated that the relative levels of IL-10 and TNF elicited in MTb recall responses that have a direct impact on HIV-1 replication levels (80). TNF, which is critical in controlling MTb infection, enhances HIV replication.…”

“…In the human, IL-10 produced by Tregs obtained from immunocompetent tuberculosis patients who displayed no T cell-mediated skin reactivity to subcutaneous injection of purified protein derivative injection inhibited the proliferation of alloreactive T cells and their production of IFN-γ and TNF in vitro (19,79,80). In this case IL-10 may operate via inhibition of IL-10-sensitive APCs, such as DCs and macrophages, which may have been activated in the context of the innate immune response and/or via a direct effect on the T cell.…”

“…The relative levels of IL-10 and IFN-γ produced by T cells are thus an important determinant of the balance between clearance and persistent infection with certain pathogens such as MTb (19,63,(78)(79)(80), Mycobacterium avium (81), L. major (82)(83)(84), L. monocytogenes (85) and T. gondii (69). Like TNF, IFN-γ is reciprocally regulated by IL-10 (27) and is critical in the clearance of MTb (86,87).…”

Antigenic Stimulation Specifically Reactivates the Replication of Archived Simian Immunodeficiency Virus Genomes in Chronically Infected Macaques

“…The relative importance of viral adaptation through increased viral fitness and resistance to host immune responses is still a matter of debate (2,15,18,28,30). However, spatial and temporal analyses of viral quasispecies demonstrated that viral evolution is not only related to adaptation but also results from stochastic events such as a antigen induced activation of viral transcription (3,5,6,9,10,20,41).The long-term persistence of HIV/SIV is principally attributed to the presence of latently infected CD4 ϩ T cells in which the virus is transcriptionally silent (22,27,39). HIV/SIV replication is essentially confined to the immunocompetent structures of secondary lymphoid organs such as the germinal centers of the lymph nodes and spleen or the intestinal Peyer's patches (31,32,48,49).…”