Targeting γδ T Cells For Immunotherapy of HIV Disease

Abstract

Disruption of circulating γδ T-cell populations is an early and common outcome of HIV infection. T-cell receptor (TCR)-γ2δ2 cells (expressing the Vγ2 and Vδ2 chains of the γδ TCR) are depleted, even though they are minimally susceptible to direct HIV infection, and exemplify indirect cell depletion mechanisms that are important in the progression to AIDS. Among individuals with common or normally progressing HIV disease, the loss of TCR-γ2δ2 cells has a broad impact on viral immunity, control of opportunistic pathogens and resistance to malignant disease. Advanced HIV disease can result in complete loss of TCR-γ2δ2 cells that are not recovered even during antiretroviral therapy with complete virus suppression. However, normal levels of TCR-γ2δ2 were observed among natural virus suppressors (low or undetectable virus without antiretroviral therapy) irrespective of their MHC haplotype, consistent with their disease-free status. The pattern of loss and recovery of TCR-γ2δ2 cells revealed their unique features and functional capacities, and encourage the development of immune-based therapies to activate and expand this T-cell subset. New research has identified drugs that might reconstitute the TCR-γ2δ2 population, recover their functional contributions, and improve control of HIV replication and disease. Here, we review research on HIV and TCR-γδ T cells to highlight the consequences of depleting this subset and the unique features of TCR-γδ biology that argue in favor of clinical strategies to reconstitute this T-cell subset in individuals with HIV/AIDS. Keywordsγδ T cell; AIDS; bisphosphonates; cancer; HIV; IL-2; immunotherapy; phosphoantigen T-cell receptors & cell typesMammalian genomes encode two alternate sets of T-cell receptor (TCR) genes. Helper (CD4 + ) and cytotoxic (CD8 + ) T cells express a heterodimeric TCR composed of one α and one β chain. TCR-αβ cell clones recognize peptide epitopes associated with MHC class I or II molecules on cell surfaces. MHC recognition and specific patterns of transcription factor expression dictate whether individual clones develop into CD8 + or one of several CD4 + subsets [1].The requirement for MHC in antigen presentation restricts TCR-αβ cells' recognition to epitopic peptides that include anchor residues appropriate for binding to individual MHCs.

HIV envelope-mediated, CCR5/α4β7-dependent killing of CD4-negative γδ T cells which are lost during progression to AIDS

“…55 In advanced HIV disease, V␥2V␦2 T are HIV R5 ENV KILLS ␥␦ T CELLS VIA CCR5/␣4␤7 5829 BLOOD, 24 NOVEMBER 2011 ⅐ VOLUME 118, NUMBER 22 For personal use only. on May 11, 2018.…”

Heterogeneous yet stable Vδ2 (+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals

“…Mycobacterium tuberculosis (19) and Plasmodium falciparum (20), often expanding to >50% of total blood T cells (21), and show responses to both HIV (22) and influenza (23). Vδ2 (+) T cells also kill a spectrum of malignant cells that includes leukemias and lymphomas and solid tumors such as renal cell, breast, prostate, and colorectal carcinomas (24).…”

Effect of Highly Active Antiretroviral Therapy on T-Cell Sub-population Profile in Human Immunodeficiency Virus-1 Infected Patients

“…Polyclonally activated Vδ1 cells from HIV-infected donors were also cytotoxic for normal CD4 + T cells. The Vδ1 subset is often expanded in HIV-infected individuals, which inverts the Vδ2:Vδ1 cell ratio, possibly due to microbial products that accumulate in blood when mucosal boundaries fail and allow microbial translocation [71]. In the study of T-reg cells groups, older HIV + subjects had a total T-reg percent that is 2.8% (p=0.02) higher than among younger HIV + , older HIV − and younger HIV − subjects.…”

“…ϒδ T cells population are minor constituents in the peripheral blood but provide a high contribution to the immune compartment of the gastrointestinal mucosa [13], likely representing the first defense against pathogens crossing this surface. In the mucosa, they constitute up to 50% of all lymphocytes population and approximately 10% of lymphocytes in the lamina propria [14][15][16].…”

“…This dysfunction is primarily within the Vδ2 ϒδ T-cell subset which decreased overall level in the blood and a reduced Th1 cytokine production but significant expansion of Vδ1 cells observed [13]. Infection with human immunodeficiency virus (HIV) disrupts the balance among ϒδT cell subsets, with increasing Vδ1 + T cells and substantial depletion of circulating Vδ2 T cells [15,103]. Patients treated with HAART exhibited a partial restoration in their ϒδT-cell Th1 cytokine response that was intermediate between the responses of the uninfected and HIV + patients [14,104].…”