Exceptional post-treatment control associated with strong NK and Ï?É? cytotoxic T cells


BACKGROUND: Although ART is effective in suppressing viral replication, HIV persists in reservoirs and rebounds after stopping therapy. However, there are few patients, such as post-treatment controllers (PTC), who are able to maintain viral loads below detection limits without ART, being a realistic model for the HIV-functional-cure. We describe the mechanisms of control of an exceptional PTC (>15 years).
METHODS: A 59-year woman with sexually-acquired acute HIV-infection was included in the `Immune-mediated PHI trial´ (NCT00979706), involving several interventions: short course of low doses of CsA, IL-2, GM-CSF and Peg-a-IFN followed by analytical STI. Virological studies were performed: total and integrated HIV-1 DNA in CD4+ T-cells and rectal tissue, viral outgrowth assay (qVOA), HIV-1 infectivity in PBMC and CD4+ T-cells cultures and viral inhibitory activity (VIA) of autologous CD4+T-cells with NK and CD8+ T-cells. NK and T-cell phenotype was determined by flow-cytometry.HLA class I, Î?32CCR5 and NKG2C alleles were genotyped.
RESULTS: After antiretroviral and immunomodulatory treatment, the patient maintained undetectable viral load in plasma for 15 years. HIV-1 subtype was CFR_02AG, R5-tropic. We found a pronounced and progressive fall of the viral reservoir (VR): total HIV-DNA (from 4573.50 to 95.33 copies/106 CD4+T-cells) and integrated proviral DNA (from 85.37 to 5.25 copies/106 CD4+T-cells).VR in rectal biopsy was 3 HIV DNA total copies/106 cells and qVOA detected 1.61 UIMP at year 9. VIA assay showed strong inhibition of in vitro replication in co-cultures with autologous NK-cells or CD8+T-cells at 1:2 ratio (75% and 62%, respectively). Co-cultures with NK and CD8+T-cells resulted in 93% inhibition of HIV-replication. Higher levels of both NKG2C+-memory-like NK-cells and NKG2C+Ï?É?+T-cells than referenced data from untreated normal HIV-infected progressors were detected (46.2% versus 24.0% and 64.9% versus 19.7%, respectively). The patient has A*29:01/A*29:01, B*44:03/B*44:03, C*16:01/C*16:01 HLA-I, wt/wt CCR5 and wt/wt NKG2C alleles.
CONCLUSIONS: We describe the case of functional cure in a 59-years-old woman treated during PHI that has maintained undetectable viral load for 15 years without ART. Replication-competent HIV-1 could be isolated by qVOA. NKG2C+-memory-like NK-cells and Ï?É?+CD8+T-cells contribute to the control of viral-replication and functional-cure observed. Strategies able to expand these cells could help to achieve HIV-functional-cure.