Natural Killer Cells in Perinatally HIV-1-Infected Children Exhibit Less Degranulation Compared to HIV-1-Exposed Uninfected Children and Their Expression of KIR2DL3, NKG2C, and NKp46 Correlates with Disease Severity

Abstract

NK cells play an integral role in the innate immune response by targeting virally infected and transformed cells with direct killing and providing help to adaptive responses through cytokine secretion. Whereas recent studies have focused on NK cells in HIV-1-infected adults, the role of NK cells in perinatally HIV-1-infected children is less studied. Using multiparametric flow cytometric analysis, we assessed the number, phenotype, and function of NK cell subsets in the peripheral blood of perinatally HIV-1-infected children on highly active antiretroviral therapy and compared them to perinatally exposed but uninfected children. We observed an increased frequency of NK cells expressing inhibitory killer Ig-like receptors in infected children. This difference existed despite comparable levels of total NK cells and NK cell subpopulations between the two groups. Additionally, NK cell subsets from infected children expressed, with and without stimulation, significantly lower levels of the degranulation marker CD107, which correlates with NK cell cytotoxicity. Lastly, increased expression of KIR2DL3, NKG2C, and NKp46 on NK cells correlated with decreased CD4+ T-lymphocyte percentage, an indicator of disease severity in HIV-1- infected children. Taken together, these results show that HIV-1-infected children retain a large population of cytotoxically dysfunctional NK cells relative to perinatally exposed uninfected children. This reduced function appears concurrently with distinct NK cell surface receptor expression and is associated with a loss of CD4+ T cells. This finding suggests that NK cells may have an important role in HIV-1 disease pathogenesis in HIV-1-infected children.

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

“…), we interpret that NK cells can contribute to both resistance against infection and to viral control once infected (Table 3). Together with data illustrating increased activation [10,20,91] and function [6,19] of NK cells in HESNs, these results suggest that NK cells fit the model of a candidate cell type whose retained function and heightened activation status may contribute to both control over HIV-1 replication and resistance to HIV-1 in HESN subjects.…”

“…• Vertical transmission Children exposed to HIV-1 through carriage from HIV-1-infected mother HIV-1-specific T cell responses [11] Heightened innate immune cell activity [10,12] Oral exposure • Breastfeeding • Discordant couples (oral sex)…”

“…Heightened NK activation marker (CD69) expression and increased NK cell degranulation (CD107a) are two NK cell surface changes associated with resistance to infection in several independent cohorts of HESN subjects, including perinatally exposed children born to HIV-1-infected mothers [10] and HESN i.v. drug users from Ho Chi Minh City, Vietnam [91].…”

NKG2C Deletion Is a Risk Factor of HIV Infection

“…In addition, we have found that NKG2C and NKG2A expression is correlated to HIV viral load, similar to the findings of Ballan et al and Zeddou et al, respectively. 19,21 As only + / + individuals were used in our comparison, it can be suggested that HIV infection itself impacts the level of receptor expression. Therefore, the level of NKG2C and NKG2A expression will depend not only on a patient's genotype, but also on the extent of viremia.…”

Infection with Vpr-Positive Human Immunodeficiency Virus Type 1 Impairs NK Cell Function Indirectly through Cytokine Dysregulation of Infected Target Cells

“…In vivo analyses indicate that NK cells from patients with HIV-1 viremia are defective in target cell lysis compared to those from aviremic or uninfected control subjects (15,26). Disease severity in HIV-1 is associated with altered expression of different NK receptors and ligands, as shown by different studies (7,9,25,29,48). HIV-1 viral antigens have been shown to dysregulate NK cell function and its interaction with other accessory cells in the absence of direct infection through a multidirectional network of cytokines (26,27,39).…”