NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection

Abstract

Increasing evidence supports the notion that the innate immune response, and in particular, natural killer cells play a central role in determining the quality of the host immune response to infection. In this review we highlight recent evidence that suggests that NK cells influence the clinical fate of HIV-infected individuals.

Figure 1. Kinetics of the immune response to viral infections

The immune response to infection is a step-wise process that begins with the release of type 1 interferons. This is followed by the production of interleukin-15 (IL-15) that induces rapid proliferation of NK cells. It is believed that NK cells contribute the early containment of viral replication as well as the rapid secretion of pro-inflammatory cytokines and chemokines that drive a Th1-biased immune response, resulting in the rapid potentiation of virus-specific CD8+ T cell responses. These CD8+ T cell responses maintain control over viral replication throughout the chronic phase of infection, and finally decline in function as viral replication escalates in late disease.

Figure 2. Both Innate and Adaptive Receptors interact with HLA-B27 presenting the HIV-1 Gag epitope KRWIIMGLNK

Several receptors expressed on cells of both the innate and adaptive immune system interact with the complex formed by HLA-B27 and the KRWIIMGLNK peptide on the surface of infected cells. All 3 of these interactions may synergistically or independently place immune selection pressure on this highly conserved region of the virus that selects for escape variants only in individuals that express HLA-B27.

Figure 3. Stages of NK cell development

A simplified diagram of the steps and interactions of hematopoetic cells that lead to NK cell lineage commitment. An NK cell experiences dynamic interactions with the stroma during development, which requires both physical contact and secreted factors to induce the maturation of a fully functional NK cell.

Figure 4. Differences in NK cell receptor expression of CD56bright and CD56dim NK cells

CD56bright and CD56dim NK cells represent 10 and 90% of circulating NK cells, respectively. These two NK cell subsets have different functional roles in the response to infection or malignant cells. CD56bright NK cells express high levels of activating receptors (NKp30, NKp44, NKp46, NKG2D) and the inhibitory receptor NKG2A, which control the release of large quantities of cytokines and chemokines. In contrast, CD56dim NK cells express a vast array of both inhibitory (red) and activating (green) receptors that modulate their cytolytic function.