NKG2C⁺ memory‐like NK cells contribute to the control of HIV viremia during primary infection: Optiprim‐ANRS 147

Abstract

Natural-killer (NK) cells are important immune effectors during a viral infection. Latent CMV infection is widely spread and was demonstrated to shape the NK cell repertoire through the NKG2C receptor. An expansion of NKG2C+ NK cells has been reported during primary HIV infection (PHI), but their role is not known. We previously found a correlation between the maturation state of the NK cell compartment and a lower viral load by studying patients from the ANRS 147 Optiprim trial. We investigated here extensively the NKG2C+ NK cells at the time of PHI and its evolution after 3 months of early antiretroviral therapy (combination antiretroviral therapy (cART)). Multiparametric cytometry combined with bioinformatics was used to determine subsets. NKbright NKG2C+ progenitor, NKdim NKG2C+ effector and NKdim NKG2C+CD57+ memory-like populations were identified. Two groups of patients were unraveled according to the distribution of the NKG2C+ subsets skewed toward either progenitor/effector or memory-like phenotype. Patients with high NKG2C+CD57+ NK cell frequencies showed lower HIV-RNA, lower immune activation, higher pDC counts and reached more rapidly undetectable levels of HIV-RNA at M1 under cART. NKG2C+CD57+ NK cell frequency was the only factor strongly correlated to low viral load among other clinical features. While the patients were cytomegalovirus (CMV) infected, there was no sign of reactivation of CMV during PHI suggesting that memory-like NK cells were already present at the time of HIV infection and constituted a preexisting immune response able to contribute to natural control of HIV. This parameter appears to be a good candidate in the search of predictive markers to monitor HIV remission.

NK Cells in HIV-1 Infection: From Basic Science to Vaccine Strategies

“…HESN, exhibited higher frequency of Memory like NK cells compared with HIV infected individuals and also a positive correlation between memory NK cells and IgG titles for HCMV, which appears to be the trigger by these cells ( 101 ). Finally, HIV infected individuals showed a negative correlation between frequency of memory NK cells and viral load ( 102 ), suggesting that Memory-like subset might constitute a ready-armed immune cells able to contribute to natural control of viral load.…”

Memory responses of natural killer cells

“…Additional studies are needed to clarify if these instances of NKG2C + NK expansion in the absence of acute HCMV are due to cross-reactive antigens (either viral or viral-induced host) between CMV and these other infections, to the specific inflammatory milieu elicited, to (subclinical) CMV reactivation, or to some combination of these factors. Several studies have suggested that CMV reactivation and the subsequent expansion of NKG2C + NK cells may improve clinical outcomes for leukemia patients [77–80], and a recent study found that among CMV-seropositive patients newly infected with HIV, a higher frequency of NKG2C + CD57 + NK cells correlated with lower HIV viral load and more rapidly reaching undetectable viremia levels after combination antiretroviral therapy [81]. It will be of great interest to determine what clinical benefits there may be to patients that experience an expansion of the NKG2C + NK cell population in the setting of antiviral immunity against additional infections.…”

Vaccinating for natural killer cell effector functions

“…72,73 CD57 + NKG2C + memory-like NK cells are expanded in HIV-1/HCMV co-infected individuals, and these cells make a potential contribution to control of viremia during primary HIV infection. 74,75 Together with evidence that individuals with a degree of inherent resistance to HIVso-called elite controllers or slow progressorsmount stronger antibody-mediated NK cell activation and ADCC responses than more susceptible individuals, these studies suggest that NK cells may contribute to HIV protection and control. 76 NK cells have been implicated as antigenspecific effector cells after vaccination or infection of nonhuman primates with simian immunodeficiency virus (SIV); target cells pulsed with SIV vaccine antigen but not heterologous antigens can be lysed in vitro by splenic and hepatic NK cells from infected but not from uninfected animals.…”

“…NK cells from KIR3DL1/HLA‐Bw4 + or KIR2DL1/HLA‐C2 + donors show higher cytotoxicity against HIV‐infected targets in the presence of anti‐HIV gp120 antibody, highlighting the influence of NK cell education to HIV vaccine‐induced effector NK cells and potentially contributing to individual variability in vaccine outcomes . CD57 + NKG2C + memory‐like NK cells are expanded in HIV‐1/HCMV co‐infected individuals, and these cells make a potential contribution to control of viremia during primary HIV infection . Together with evidence that individuals with a degree of inherent resistance to HIV – so‐called elite controllers or slow progressors – mount stronger antibody‐mediated NK cell activation and ADCC responses than more susceptible individuals, these studies suggest that NK cells may contribute to HIV protection and control …”