CD4+ T-cell help enhances NK cell function following therapeutic HIV-1 vaccination.
Increasing data suggest that NK cells can mediate antiviral activity in HIV-1-infected humans, and as such, novel approaches harnessing the anti-HIV-1 function of both T cells and NK cells represent attractive options to improve future HIV-1 immunotherapies. Chronic progressive HIV-1 infection has been associated with a loss of CD4(+) T helper cell function and with the accumulation of anergic NK cells. As several studies have suggested that cytokines produced by CD4(+) T cells are required to enhance NK cell function in various infection models, we hypothesized that reconstitution of HIV-1-specific CD4(+) T-cell responses by therapeutic immunization would restore NK cell activity in infected individuals. Using flow cytometry, we examined the function of CD4(+) T cells and NK cells in response to HIV-1 in subjects with treated chronic HIV-1 infection before and after immunization with an adjuvanted HIV-1 Gp120/NefTat subunit protein vaccine candidate provided by GlaxoSmithKline. Vaccination induced an increased expression of interleukin-2 (IL-2) by Gp120-specific CD4(+) T cells in response to HIV-1 peptides ex vivo, which was associated with enhanced production of gamma interferon (IFN-γ) by NK cells. Our data show that reconstitution of HIV-1-specific CD4(+) T-cell function by therapeutic immunization can enhance NK cell activity in HIV-1-infected individuals.


OBJECTIVE
NK cells are effector cells of the innate immune system and are important in the control of viral infection. Recent studies have demonstrated the crucial role played by NK cells in controlling and/or limiting acquisition of HIV-1 infection. However, NK cell function is impaired during progressive HIV-1 infection. We recently showed that therapeutic immunization of treated HIV-1-infected individuals reconstituted strong T-cell responses, measured notably by their production of IL-2, a cytokine that can activate NK cells. The current study suggests that reconstitution of T-cell function by therapeutic vaccination can enhance NK cell activity in individuals with chronic HIV-1 infection. Our findings provide new insights into the interplay between adaptive and innate immune mechanisms involved in HIV-1 immunity and unveil opportunities to harness NK cell function in future therapeutic vaccine strategies to target HIV-1.
Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
Stephanie
S
Jost
Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
Phillip John
PJ
Tomezsko
Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
Keith
K
Rands
Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
Ildiko
I
Toth
Infectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
Mathias
M
Lichterfeld
Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA Infectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
Rajesh Tim
RT
Gandhi
Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Hamburg, Germany maltfeld@partners.org.
Marcus
M
Altfeld
D016915:AIDS Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015696:Gene Products, tat / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000628:therapy*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D014611:Vaccination / Q000379:methods; D022223:Vaccines, Subunit / Q000276:immunology / Q000627:therapeutic use; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D016915:AIDS Vaccines; D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D007376:Interleukin-2; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; C514793:gp120 protein, Human immunodeficiency virus 1; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D007371:Interferon-gamma