NK cell responses to HIV infection

Natural killer (NK) cells are the cytolytic cells of the innate immune system. Their array of activating and inhibitory receptors interact with ligands present on target cells to regulate their killer activity. Healthy target cells express high levels of MHC-I, which engage the inhibitory KIR and NKG2A receptors on NK cells, preventing the NK cell from releasing pore-forming perforin and apoptosis-inducing granzymes to kill the target cell (left). HIV infection causes down regulation of MHC-I, which releases inhibition by KIR/NKG2A molecules, triggering the NK cell to kill the target and produce antiviral cytokines/chemokines. Along with stress ligand stimulation of activating NK receptors (aNKRs), these methods to recognize and kill the infected target represent innate NK cell function. In addition, HIV-specific antibodies can recognize the HIV envelope that is expressed on the surface of infected cells and trigger CD16 on NK cells, resulting in antibody-dependent cellular cytotoxicity (ADCC). Together, these innate and ADCC functions allow NK cells to kill HIV-infected targets.

CTL responses to HIV infection

CD8+ cytotoxic T lymphocytes (CTLs) are the killer cells of the adaptive immune system. T cell receptors (TCRs) recognize viral peptides presented on host MHC-I molecules, resulting in CTL formation of an immunological synapse with the infected cell. In this structure, perforin and granzymes are delivered to the target, killing the infected cell. Secondary to this effector function is proliferation to replenish the pool of killer cells and production of antiviral cytokines and pro-inflammatory chemokines to coordinate downstream immunity. The virus attempts to escape the CTL response by down regulating cell surface MHC-I, but TCR signaling is sensitive enough to detect low levels of these protein complexes. Additional methods to escape CTL responses include mutation of viral peptides to prevent detection by the TCR (reviewed in Collins, et al., 2020, Nat Rev Immunol).

HIV-infected Macrophage

Macrophages become infected with HIV and have been found in multiple tissues, including the brain and the urethra. They resist the cytopathic effects of HIV (forming long-lived reservoirs), store virus within the virus-containinig compartment (VCC), protected from antibodies, seed new infections with CD4+ T cells through virological synapses, and promote inflammation and neurological disease in people living with HIV. We and others have found that macrophages resist killing by CTL and NK cells, even when NK cell responses are boosted using HIV-specific antibodies that recognize infected macrophages. These methods of resistance are a major focus of the lab.