Pathologic natural killer cell subset redistribution in HIV-1 infection: new insights in pathophysiology and clinical outcomes

Abstract

Several lines of evidence indicate that the interaction of HIV-1 with NK cells markedly affects host immune responses and leads to a defective control of the virus. Until recently, it was generally believed that the absolute number of total circulating NK cells was decreased during the course of chronic and active phases of HIV-1 infection and that this explained, at least in part, the defective NK cell antiviral activities. However, scientific advances made over recent years have changed this concept and have clarified that HIV-1 viremia is associated with a pathologic redistribution rather than an absolute decrease in the number of circulating NK cells. In particular, the expansion of dysfunctional Siglec-7(neg) and/or CD56(neg) NK cell subsets expressing an aberrant repertoire of activating and inhibitory receptors has been associated with functional impairments of NK cells and with clinical outcomes of HIV-1 disease. Indeed, these pathologic NK cell populations often comprise the majority of NK cells in the presence of high levels of chronic HIV-1 viremia. The reasons for these NK cell aberrancies remain unknown, as freshly purified CD4(neg) NK cells are not productively infected by HIV-1. Disclosing the cellular and molecular mechanisms underlying such dysfunctions represents an important challenge of biomedical research, also considering that the presence of a rare KIR3DS1(pos) NK cell population represents a protective factor against HIV-1 disease progression. In this review, we will summarize the recent updates regarding NK cell pathophysiology during the course of HIV-1 infection.

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

“…It is likely that CD56 2 CD16 + cells arise from maturation of CD56 dim CD16 + NK cells. It will be of interest to determine whether CD56 + NK cells expressing low levels of FcRg, TCRz, and DAP12 represent a precursor stage toward losing CD56, similar to the reduction of SIGLEC-7 expression (33,34). Consistent with this concept, we have also observed a decreased expression of CD56 (data not shown) in addition to low CD16 expression within CD56 + NK cells from HIV-infected patients both on and off therapy.…”

High Frequencies of Polyfunctional CD8+NK Cells in Chronic HIV-1 Infection Are Associated with Slower Disease Progression

“…A number of reports have demonstrated phenotypic and functional changes in peripheral blood NK cells during HIV-1 infection in humans (16)(17)(18)(19)(20)(21). Progressive HIV-1 infection is associated with a decline in cytotoxic CD56 dim CD16 ϩ NK cells and an expansion of dysfunctional CD56 Ϫ CD16 ϩ NK cells (22,23). We have previously shown a decline of less differentiated and functionally more potent CD56 dim CD16 ϩ NK cells, which are either CD57…”

Evidence for the innate immune response as a correlate of protection in human immunodeficiency virus (HIV)-1 highly exposed seronegative subjects (HESN)

“…Progressive HIV disease is associated clearly with increasingly impaired NK responses and the selective depletion of CD56 dim NK cells during chronic HIV-1 infection [112][113][114][115]. The loss of CD56 dim NK cells, the main circulating NK subset that mediates cytotoxicity, results in the enrichment of CD56 null NK cells with decreased function [113,[116][117][118]. HIV-1 replication also results in the altered expression of inhibitory and activating receptors on NK cells further impairing the lytic potential of the remaining NK pool [119][120][121].…”