Gammadelta T cell immune manipulation during chronic phase of simian-human immunodeficiency virus infection [corrected] confers immunological benefits.
Vgamma2Vdelta2 T cells, a major human gammadelta T cell subset, recognize the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by mycobacteria and some opportunistic pathogens, and they contribute to innate/adaptive/homeostatic and anticancer immunity. As initial efforts to explore Vgamma2Vdelta2 T cell-based therapeutics against HIV/AIDS-associated bacterial/protozoal infections and neoplasms, we investigated whether a well-defined HMBPP/IL-2 therapeutic regimen could overcome HIV-mediated immune suppression to massively expand polyfunctional Vgamma2Vdelta2 T cells, and whether such activation/expansion could impact AIDS pathogenesis in simian HIV (SHIV)-infected Chinese rhesus macaques. While HMBPP/IL-2 coadministration during acute or chronic phase of SHIV infection induced massive activation/expansion of Vgamma2Vdelta2 T cells, the consequences of such activation/expansions were different between these two treatment settings. HMBPP/IL-2 cotreatment during acute SHIV infection did not prevent the increases in peak and set-point viral loads or the accelerated disease progression seen with IL-2 treatment alone. In contrast, HMBPP/IL-2 cotreatment during chronic infection did not exacerbate disease, and more importantly it could confer immunological benefits. Surprisingly, although viral antigenic loads were not increased upon HMBPP/IL-2 cotreatment during chronic SHIV infection, HMBPP activation of Vgamma2Vdelta2 T cells boosted HIV Env-specific Ab titers. Such increases in Abs were sustained for >170 days and were immediately preceded by increased production of IFN-gamma, TNF-alpha, IL-4, and IL-10 during peak expansion of Vgamma2Vdelta2 T cells displaying memory phenotypes, as well as the short-term increased effector function of Vgamma2Vdelta2 T cells and CD4(+) and CD8(+) alphabeta T cells producing antimicrobial cytokines. Thus, HMBPP/Vgamma2Vdelta2 T cell-based intervention may potentially be useful for combating neoplasms and HMBPP-producing opportunistic pathogens in chronically HIV-infected individuals.
Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
Zahida
Z
Ali
Lin
L
Yan
Nicholas
N
Plagman
Armin
A
Reichenberg
Martin
M
Hintz
Hassan
H
Jomaa
Francois
F
Villinger
Zheng W
ZW
Chen
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D002908:Chronic Disease; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D008253:Macaca mulatta / Q000276:immunology; D010755:Organophosphates / Q000276:immunology* / Q000494:pharmacology; D012367:RNA, Viral / Q000097:blood; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000628:therapy*; D015302:Simian Immunodeficiency Virus; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D019562:Viral Load
C467061:4-hydroxy-3-methyl-2-butenyl diphosphate; D000914:Antibodies, Viral; D007376:Interleukin-2; D010755:Organophosphates; D012367:RNA, Viral; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma