Natural killer cell regulation of the germinal center HIV neutralizing antibody response

Project Summary/Abstract:
HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines, but are generated in
approximately half of HIV-1-infected individuals after years of chronic infection. Definition of the mechanisms
that enable bnAb development during infection will pave the way for vaccination strategies capable of eliciting
bnAbs. Some reasons bnAbs are not readily induced are their requirement for high immunoglobulin gene
somatic hypermutation that requires successive rounds of B cell affinity maturation in germinal centers and
their limitation by host regulatory controls. We have recently identified that HIV-1-infected individuals who
developed bnAbs have more dysfunctional natural killer (NK) cells as well as higher frequencies of circulating
CD4+ T follicular helper (Tfh) cells that provide critical help to B cells. We further demonstrated that activated
NK cells from HIV-seronegative donors could reduce Tfh cell numbers and decrease B cell activity in NK-Tfh-
B cell co-cultures. These data led to the scientific premise of our proposal that NK cell dysregulation results in
reduced NK cell constraints on Tfh availability which contributes to bnAb development during HIV-1 infection.
This identified NK cells as a potential key regulator of the HIV-1 bnAb response. The overall objective of this
proposal is to test our central hypothesis that transient blockade of NK cell immunoregulatory activity will
create an immunological environment permissive for the development of HIV-1 bnAbs by increasing germinal
center T and B cell responses. This hypothesis is supported by results from a preliminary study we have
performed in rhesus macaques to address the effects of transient NK depletion on the response to HIV
Envelope vaccination, where an increase in germinal center Tfh and B cell frequencies was observed in
macaques that had NK cells depleted during HIV vaccination compared with HIV vaccinated animals without
NK cell depletion. Our specific aims will test the following hypotheses: (Aim 1) NK cells from HIV-1-infected
individuals generating bnAbs will have a more impaired immunoregulatory capacity than those from HIV-
infected individuals without bnAbs; (Aim 2) We will define the critical NK cell receptor-Tfh ligands important for
NK cell inhibition of Tfh and B cells; (Aim 3) Determine the mechanisms of transient NK cell depletion on the
germinal center HIV-1 neutralizing antibody response. This project is innovative because we have identified
that NK cell dysfunction contributes to HIV-1 bnAb development and have demonstrated in depletion of NK
cells improves germinal center activity after immunization. This contribution is significant because identifying
the molecular mechanisms and receptor-ligand interactions that mediate NK cell inhibition of Tfh and B cell
responses and determining the effect of NK cell depletion or receptor blockade on germinal center B cell a Tfh
cell repertoire and function in vivo will identify novel NK cell-targeting strategies that can be applied during
HIV-1 vaccination to improve immune responses.

Grant Number: 5R01AI147778-05
NIH Institute/Center: NIH
Principal Investigator: Todd Bradley