Combined Effects of HLA-B*57/5801 Elite Suppressor CD8+ T Cells and NK Cells on HIV-1 Replication

Abstract

Elite controllers or suppressors (ES) are HIV-1 infected individuals who maintain undetectable viral loads without anti-retroviral therapy. The HLA-B * 57 allele is overrepresented in ES suggesting a role for HIV-specific CD8+ T cells in immune control. Natural killer (NK) cells also play a role in controlling viral replication, and genetic studies demonstrate that specific combinations of killer cell immunoglobulin-like receptor (KIR) alleles and HLA subtypes including HLA-B * 57 correlate with delayed progression to AIDS. While prior studies have shown that both HIV-specific CD8+ T cells and NK cells can inhibit viral replication in vitro, the interaction between these two effector cells has not been studied. We performed in vitro suppression assays using CD8+ T cells and NK cells from HLA-B * 57 ES either alone or in combination with each other. We found no evidence of antagonism or synergy between the CD8+ T cells and NK cells, suggesting that they have independent mechanisms of inhibition in vitro. Our data has implications for combined immunotherapy with CD8+ T cells and NK cells in HIV cure strategies.

Learning to Be Elite: Lessons From HIV-1 Controllers and Animal Models on Trained Innate Immunity and Virus Suppression

“…As expected, HIV-1 viremic control is positively correlated with percentage of NK cells ( 38 ) and HIV-1 protection is associated with specific KIR3DL1 allotypes in HLA-B*57-positive subjects ( 57 ). Additionally, NK cells from ECs can efficiently lyse HIV-1-infected CD4+ T cells independently of KIR3DS1 expression ( 36 ), suggesting other factors yet to be defined influence their unique antiviral activity. Moreover, the percentage of dysfunctional CD56-CD16+ NK cells, which are frequently observed in PLWH, was lower in ECs than viremic subjects ( 25 ).…”

Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers

“…Recent data underscore the relevance of immune-mediated selection mechanisms for driving a highly distinct viral reservoir configuration in these individuals, characterized by chromosomal locations of intact proviruses that display features of deep latency (4). While T cell-mediated responses, specifically when targeting highly networked viral epitopes, may play a key role in these selection processes ( 46), a contribution of innate immune cells appears increasingly obvious, as marked variations in quantity and quality have been reported for NK cells (47,48), pDCs (49)(50)(51), and, most frequently, for mDCs from controllers (11,12,52,53). Here, we extend these findings by showing a distinct expression pattern of OXPHOS and mTOR genes in mDCs from ECs, which was coupled with an enhanced oxidative and nonoxidative metabolic profile in response to TLR3 stimulation.…”

TCR-mimic bispecific antibodies to target the HIV-1 reservoir

“…Given the HA29- and HI12-scDb induced killing of peptide-pulsed cells, we tested whether scDbs could inhibit viral replication or induce direct lysis of infected cells using viral suppression assays ( 53 ). On infected cells, the level of specific peptide-MHC complexes is extremely low (54 copies of ALT/HLA-A*02:01 per cell) ( SI Appendix , Fig.…”