Suppression of HIV Replication by CD8+ Regulatory T-Cells in Elite Controllers

Abstract

We previously demonstrated in the Chinese macaque model that an oral vaccine made of inactivated SIV and Lactobacillus plantarum induced CD8+ regulatory T-cells, which suppressed the activation of SIV+CD4+ T-cells, prevented SIV replication, and protected macaques from SIV challenges. Here, we sought whether a similar population of CD8+ T-regs would induce the suppression of HIV replication in elite controllers (ECs), a small population (3‰) of HIV-infected patients with undetectable HIV replication. For that purpose, we investigated the in vitro antiviral activity of fresh CD8+ T-cells on HIV-infected CD4+ T-cells taken from 10 ECs. The 10 ECs had a classical genomic profile: all of them carried the KIR3DL1 gene and 9 carried at least 1 allele of HLA-B:Bw4-80Ile (i.e., with an isoleucine residue at position 80). In the nine HLA-B:Bw4-80Ile-positive patients, we demonstrated a strong viral suppression by KIR3DL1-expressing CD8+ T-cells that required cell-to-cell contact to switch off the activation signals in infected CD4+ T-cells. KIR3DL1-expressing CD8+ T-cells withdrawal and KIR3DL1 neutralization by a specific anti-killer cell immunoglobulin-like receptor (KIR) antibody inhibited the suppression of viral replication. Our findings provide the first evidence for an instrumental role of KIR-expressing CD8+ regulatory T-cells in the natural control of HIV-1 infection.

Intragastric Administration of Lactobacillus plantarum and 2,2′-Dithiodipyridine-Inactivated Simian Immunodeficiency Virus (SIV) Does Not Protect Indian Rhesus Macaques from Intrarectal SIV Challenge or Reduce Virus Replication after Transmission

“…As mentioned above, it is possible that this discrepancy was caused by the different immunogenetic responses elicited in the two subspecies of RMs by the same vaccine. Note that the strong CD8 regulatory T cell activity that prevents CD4 ϩ T cell activation and thus suppresses SIV replication that was discovered in vaccinated Chinese RMs by Andrieu and Lu has also been found in the so-called "elite controllers," a rare population (Ͻ1/100) of HIV-infected individuals who maintain undetectable viral loads without antiretroviral therapy (20). It is therefore possible that Indian RMs are not the appropriate model for studying the effects of an oral suppressive vaccine (such as iSIV-L. plantarum), as they do not have a genetic background allowing a suppressive/regulatory CD8 ϩ T cell response.…”

Pre-infection transcript levels of FAM26F in peripheral blood mononuclear cells inform about overall plasma viral load in acute and post-acute phase after simian immunodeficiency virus infection

“…Perhaps conspicuous gene expression differences are not the hallmark that distinguishes CNAR(+) and CNAR(–) CD8 + T-cells but rather the equipment with distinct polymorphic genes. In this respect, a recent report has uncovered mechanisms underlying cell-contact-mediated CNAR (Lu et al , 2016) by showing that particular regulatory CD8 + T-cells in carriers of KIR3DL1 and HLA-B : Bw4-80Ile can suppress viral replication in CD4 + T-cells. However, in the interaction of the specialized subset of CD8 + cells with CD4 + cells, FAM26F could play a role, and a low expression may contribute to a reduced activation of CD4 + T-cells.…”

Recent Advances in Antigen-Specific Immunotherapies for the Treatment of Multiple Sclerosis

“…Both Tregs are considered important in MS due to the exhibition of unique characteristics. Subsets of CD8+ Tregs that have been indicated to suppress immune responses and disease progression via distinct mechanisms have been identified by a unique expression of molecules like CD122, CD28, CD102 and HLA-G [ 2 , 39 , 40 ]. In addition, Th2 cells secreting cytokines like IL-4, IL-5, and IL-13, are considered to be able to downregulate the activity of pro-inflammatory cells [ 27 ].…”