RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses

Abstract

SummaryHIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development.

A New Hope for CD56negCD16pos NK Cells as Unconventional Cytotoxic Mediators: An Adaptation to Chronic Diseases

“…This phenotype has been correlated with a loss of immunoregulatory cytotoxic activity (Schlums et al, 2015). Similar observations were made for HIV-positive individuals who had broadly reactive neutralizing antibodies (bnAbs), lower expression of IL12 and IL18 receptors and PLZF1 yet with higher expression of CD6 (Bradley et al, 2018), confirming an adaptive-like NK cell phenotype. In addition, HIV-positive individuals with bnABs had a higher proportion of CD56 neg CD16 pos NK, which was associated with better viral control.…”

Gene Regulatory Programs Conferring Phenotypic Identities to Human NK Cells

“…A major clinical goal is to harness these NK cell functions for tumor immunotherapy (Baggio et al, 2017;Johnson and Miller, 2018;Romee et al, 2016). In addition, NK cells have been implicated in the control of HIV infection either directly or by antibody-mediated lysis of infected cells (Bradley et al, 2018;Ramsuran et al, 2018). Although NK cells lack antigen-specific receptors, recent studies indicate that some responses are characterized by expansion and memory, features originally thought to be restricted to adaptive immunity.…”

Immune checkpoint modulation enhances HIV-1 antibody induction

“…Comparative analysis of cohorts of HIV-1 infected individuals who make bnAbs vs. those who do not have demonstrated subjects who make bnAbs during HIV-1 infection have higher levels of CD4+ T follicular helper (Tfh) cells 16,17 , lower levels of T regulatory cells, and a higher frequency of auto-antibodies compared to those who do not make bnAbs 17 . Recently, we demonstrated the association of dysfunctional NK cells with the ability to produce bnAbs in the setting of HIV-1 infection 18 . Thus, immunoregulatory abnormalities are associated with bnAb development in HIV-1-infected individuals, suggesting that transiently recreating the HIV-1-modified immunoregulatory milieu at the time of vaccination may be crucial to the induction of clonal lineages of bnAb B cells with full neutralization breadth 13,14,17 .…”