Targeting NK Cells for HIV-1 Treatment and Reservoir Clearance

Abstract

Combined antiretroviral therapy (cART) can inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and reduce viral loads in the peripheral blood to undetectable levels. However, the presence of latent HIV-1 reservoirs prevents complete HIV-1 eradication. Several drugs and strategies targeting T cells are now in clinical trials, but their effectiveness in reducing viral reservoirs has been mixed. Interestingly, innate immune natural killer (NK) cells, which are promising targets for cancer therapy, also play an important role in HIV-1 infection. NK cells are a unique innate cell population with features of adaptive immunity that can regulate adaptive and innate immune cell populations; therefore, they can be exploited for HIV-1 immunotherapy and reservoir eradication. In this review, we highlight immunotherapy strategies for HIV infection that utilize the beneficial properties of NK cells.

Innate lymphoid cells—Underexplored guardians of immunity

“…Several strategies are currently used to enhance NK cytotoxicity in the context of refractory viral infections. A combination of NK cell activation by the IL-15 super-agonist ALT-803, anti-CD16-fusion antibodies or vaccines with antiretroviral therapy (ART) are in clinical studies to treat HIV infections [ 75 , 76 ]. NK cell therapies offer several advantages when compared to T cell-based approaches.…”

Natural killer cells and their exosomes in viral infections and related therapeutic approaches: where are we?

“…NK cell therapy has some limitations; for example, unlike T cells and B cells, NK cells do not have specificity, and the proliferation and viability of these cells are limited in vivo. To overcome these limitations, some interesting immunotherapy approaches were suggested, such as bispecific (BiKEs) and trispecific (TriKEs) killer cell engagers [ 239 ]. BiKEs that bind to CD16A on NK cells and HIV-1 envelope glycoprotein-expressing cells could kill the infected cells.…”

“…Autologous NK cells or haploidentical healthy donors’ NK cells can be considered for transferring the NK cells in virus-infected patients. One of the major limitations of this aim is the low count of NK cells in peripheral blood [ 239 ]. Additionally, the cytotoxicity of these NK cells is low.…”

“…In addition to peripheral blood, NK cells can be obtained from induced pluripotent stem cells, umbilical cord stem cells, and bone marrow [ 239 ]. CYNK-001 is a group of NK cells derived from umbilical cord stem cells.…”

Effective innate immune response in natural HIV-1 controllers. Can mimicking lead to novel preventive and cure strategies against HIV-1?

“…NK cells can be activated through cytokines in the environment or directly by some TLR agonists, and its ADCC activity can be promoted by the presence of neutralizing antibodies [63]. Several studies have described that the stimulation of NK cells with IL-15 improves ADCC activity, natural cytotoxicity and IFN-g production in vitro in PLWH on antiretroviral therapy [64,65].…”