Natural Killer Cells in Human Immunodeficiency Virus-1 Infection: Spotlight on the Impact of Human Cytomegalovirus

Human cytomegalovirus (HCMV) has been closely associated with the human race across evolutionary time. HCMV co-infection is nearly universal in human immunodeficiency virus-1 (HIV-1)-infected individuals and remains an important cofactor in HIV-1 disease progression even in the era of effective antiretroviral treatment. HCMV infection has been shown to have a broad and potent influence on the human immune system and has been linked with the discovery and characterization of adaptive natural killer (NK) cells. Distinct NK-cell subsets, predominately expressing the activating receptor NKG2C and the marker of terminal differentiation CD57, expand in response to HCMV. These NK-cell populations engaged in the long-lasting interaction with HCMV, in addition to characteristic but variable expression of surface receptors, exhibit reduced expression of signaling proteins and transcription factors expressed by canonical NK cells. Broad epigenetic modifications drive the emergence and persistence of HCMV-adapted NK cells that have distinct functional characteristics. NKG2C+ NK-cell expansions have been observed in HIV-1 infected patients and other acute and chronic viral infections being systematically associated with HCMV seropositivity. The latter is potentially an important confounding variable in studies focused on the cellular NK-cell receptor repertoire and functional capacity. Here, focusing on HIV-1 infection we review the evidence in favor of “adaptive” changes likely induced by HCMV co-infection in NK-cell subsets. We highlight a number of key questions and how insights into the adaptive behavior of NK cells will inform new strategies exploiting their unique properties in the fight against HIV-1

Shared immunotherapeutic approaches in HIV and hepatitis B virus: combine and conquer

Purpose of review: The aim of this study was to identify similarities, differences and lessons to be shared from recent progress in HIV and hepatitis B virus (HBV) immunotherapeutic approaches. Recent findings: Immune dysregulation is a hallmark of both HIV and HBV infection, which have shared routes of transmission, with approximately 10% of HIV-positive patients worldwide being coinfected with HBV. Immune modulation therapies to orchestrate effective innate and adaptive immune responses are currently being sought as potential strategies towards a functional cure in both HIV and HBV infection. These are based on activating immunological mechanisms that would allow durable control by triggering innate immunity, reviving exhausted endogenous responses and/or generating new immune responses. Recent technological advances and increased appreciation of humoral responses in the control of HIV have generated renewed enthusiasm in the cure field. Summary: For both HIV and HBV infection, a primary consideration with immunomodulatory therapies continues to be a balance between generating highly effective immune responses and mitigating any significant toxicity. A large arsenal of new approaches and ongoing research offer the opportunity to define the pathways that underpin chronic infection and move closer to a functional cure

Systemic inflammation and residual viraemia in HIV-positive adults on protease inhibitor monotherapy: a cross-sectional study.

Increased levels of markers of systemic inflammation have been associated with serious non-AIDS events even in patients on fully suppressive antiretroviral therapy. We explored residual viremia and systemic inflammation markers in patients effectively treated with ritonavir-boosted protease inhibitor monotherapy (PImono)

NK cells: a double-edged sword in chronic hepatitis B virus infection.

There is natural enrichment of NK cells in the human liver and this intrahepatic predominance underscores their potential importance in the control of infections with hepatotropic viruses such as hepatitis B virus (HBV). The contribution of innate components during chronic HBV infection has been a relatively under-investigated area. However, recent data have highlighted that NK cells are capable of exerting antiviral and immunoregulatory functions whilst also contributing to the pathogenesis of liver injury via death receptor pathways. We will present an overview of current knowledge regarding the complex biology of NK cells in the context of their antiviral versus pathogenic role in chronic hepatitis B as a clinically relevant avenue for further investigation

Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection

NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-gamma in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-gamma production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56 bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-gamma. Blockade of IL-10 +/- TGF-beta restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-gamma, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-gamma persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-beta blockade

Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection

Human cytomegalovirus (HCMV) co-infection is highly prevalent within HIV-1 cohorts and is an important cofactor in driving ongoing immune activation, even during effective antiretroviral treatment. HCMV infection has recently been associated with expansion of adaptive-like natural killer (NK) cells, which harbor epigenetic alterations that impact on their cellular function and phenotype. The influence of HCMV co-infection on the considerable heterogeneity among NK cells and their functional responses to different stimuli was assessed in a cohort of HIV-1-infected individuals sampled during different stages of infection, compared with healthy subjects stratified according to HCMV serostatus. Our data demonstrate a reshaping of the NK cell pool in HIV-1 infection of HCMV-seropositive individuals, with an accentuated peripheral transition of CD56dim NK cells toward a mature CD57+ CD85j+ NKG2C+ NKG2A− phenotype. Lack of PLZF further distinguishes adaptive NK cells from other NK cells expressing CD57 or NKG2C. PLZF− NK cells from HIV-infected individuals had high expression of CD2, were Siglec-7 negative and exhibited downregulation of key signaling molecules, SYK and FcεRI-γ, overwhelmingly displaying features of adaptive NK cells that correlated with HCMV serum Ab levels. Notably this adaptive-like signature was detected during early HIV-1 infection and persisted during treatment. Adaptive-like NK cell subsets in HIV-1-infected individuals displayed enhanced IFN-γ production following Fc receptor triggering compared with their conventional NK cell counterparts, and their ability to produce TNF-α and degranulate was preserved. Together, these data suggest that HMCV infection/reactivation, a hallmark of HIV-1 infection, plays a role in driving a relative expansion of NK cells with adaptive features during HIV-1 infection. The identification of selective NK subsets with retained effector activity in HIV-1-infected subjects raises the possibility of developing therapeutic strategies that exploit specific NK subpopulations to achieve better HIV-1 control

Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo

This work was supported by funding from The NIHR Academic Clinical Fellowship scheme and a Wellcome Trust Clinical Research Training fellowship (107389/Z/15/Z) awarded to USG; a Wellcome Trust Senior Investigator award (101848/Z/ 13/Z) to MKM and a Barts and The London Charity award (No. 723/1795) to PTFK

Thermodynamic mapping of effector protein interfaces with RalA and RalB.

RalA and RalB are members of the Ras family of small G proteins and are activated downstream of Ras via RalGEFs. The RalGEF-Ral axis represents one of the major effector pathways controlled by Ras and as such is an important pharmacological target. RalA and RalB are approximately 80% identical at the amino acid level; despite this, they have distinct roles both in normal cells and in the disease state. We have used our structure of RalB-RLIP76 to guide an analysis of Ral-effector interaction interfaces, creating panels of mutant proteins to probe the energetics of these interactions. The data provide a physical mechanism that underpins the effector selective mutations commonly employed to dissect Ral G protein function. Comparing the energetic landscape of the RalB-RLIP76 and RalB-Sec5 complexes reveals mutations in RalB that lead to differential binding of the two effector proteins. A panel of RLIP76 mutants was used to probe the interaction between RLIP76 and RalA and -B. Despite 100% sequence identity in the RalA and -B contact residues with RLIP76, differences still exist in the energetic profiles of the two complexes. Therefore, we have revealed properties that may account for some of the functional separation observed with RalA and RalB at the cellular level. Our mutations, in both the Ral isoforms and RLIP76, provide new tools that can be employed to parse the complex biology of Ral G protein signaling networks. The combination of these thermodynamic and structural data can also guide efforts to ablate RalA and -B activity with small molecules and peptides.Captain Stephanos FoundationThis is the author accepted manuscript. The final version is available from the American Chemical Society via http://dx.doi.org/10.1021/bi501530