Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jun;86(12):6986-93.
doi: 10.1128/JVI.00569-12. Epub 2012 Apr 11.

Frequent and strong antibody-mediated natural killer cell activation in response to HIV-1 Env in individuals with chronic HIV-1 infection

Christina F Thobakgale  1 , Lena Fadda, Kimberly Lane, Ildiko Toth, Florencia Pereyra, Suzane Bazner, Thumbi Ndung'u, Bruce D Walker, Eric S Rosenberg, Galit Alter, Mary Carrington, Todd M Allen, Marcus Altfeld
Affiliations

Frequent and strong antibody-mediated natural killer cell activation in response to HIV-1 Env in individuals with chronic HIV-1 infection

Christina F Thobakgale et al. J Virol. 2012 Jun.

Abstract

Natural killer (NK) cells play a critical role in the control of HIV-1 infection, and NK cells that respond to HIV-1 peptides have been recently described. However, the mechanisms by which NK cells recognize HIV-1 antigens are not fully understood. We investigated NK cell activation in response to HIV-1 peptides during early and chronic HIV-1 clade B infection using a whole-blood assay and multiparameter flow cytometry. Antibody-mediated NK cell activation in response to HIV-1 peptides was not detected in HIV-1-uninfected individuals. In contrast, 79% of individuals with chronic infection and 22% of individuals with early infection had detectable gamma interferon (IFN-γ) NK cell responses to HIV-1 antigens (P < 0.00001). IFN-γ- and tumor necrosis factor alpha (TNF-α)-producing NK cells most frequently targeted Env gp120 (median of 4% and range of 0 to 31% of all NK cells). NK cells rarely targeted other HIV-1 proteins such as Gag, Pol, and Nef. Antibody-mediated NK cell responses to peptides mapped predominantly to Env protein, required the presence of plasma or plasma IgG, and resulted in lower CD16 expression on NK cells, suggesting an antibody-mediated activation of NK cells. Further studies are needed to assess the consequences of these antibody-mediated NK cell responses for HIV-1 disease progression and vaccine-induced protection from infection.

PubMed Disclaimer

Figures

Fig 1
Fig 1
Proteins targeted by antibody-mediated NK cell responses in HIV-1-infected individuals. NK cell IFN-γ (A) and TNF-α (B) responses to HIV-1 peptide pools in all studied HIV-1-infected individuals (n = 74) irrespective of disease or treatment status (C). P values in panels A and B indicate the overall P value obtained from comparison of all the HIV regions using the one-way ANOVA test, and subsequent comparisons between the groups were done using the Mann-Whitney test and are discussed in the Results section. Abbreviations on the x axis in panel C refer to different patient groups as outlined in Table 1.
Fig 2
Fig 2
Proteins targeted by CD8+ T cell responses in HIV-1-infected individuals. CD8+ IFN-γ (A) and TNF-α (B) T cell responses to HIV-1 peptide pools in all studied HIV-1-infected individuals (n = 74) irrespective of disease or treatment status (C). P values in panels A and B indicate the overall P value obtained from comparison of all the HIV regions using the one-way ANOVA test, and subsequent comparisons between the groups were done using the Mann-Whitney test and are discussed in Results. Abbreviations on the x axis in panel C refer to different patient groups as outlined in Table 1.
Fig 3
Fig 3
NK cell responses to HIV-1 peptides require IgG or the presence of plasma. (A) Representative example of the antibody-mediated NK cell responses following stimulation with gp120 peptide pool in whole blood, isolated PBMCs in the absence of plasma, and PBMCs with autologous plasma added back at varying dilutions. Simultaneous measurement of IFN-γ-producing (A) and TNF-α-producing (B) NK cells to the gp120 peptide pool in six individuals—in whole blood, PBMCs without plasma, and PBMCs with plasma at a 1:5 dilution. (C) Degranulation assessment of NK cells in 4 individuals—in whole blood, PBMCs without plasma, and PBMCs with plasma at a 1:5 dilution. (D) Measurement of NK cell responses in infected individuals (n = 4)—in PBMCs with or without plasma IgG following stimulation with the gp120 peptide pool. (E) Assessment of antibody-mediated NK cell responses to the gp120 peptide pool using plasma and PBMCs derived from HIV-1-infected donors (n = 4) and healthy donors (n = 4).
Fig 4
Fig 4
Receptor expression profiles of cytokine-producing and -nonproducing NK cells. Receptor profiles and activation markers in IFN-γ-producing and -nonproducing NK cells in responder subjects following gp120 stimulation. Subjects were assessed for the following NK receptors and markers: CD16 (n = 10), NKp46, KIR (n = 11), NKG2A (n = 12), NKG2D, CD57, and CD7 (n = 9).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Addo MM, et al. 2003. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J. Virol. 77:2081–2092 - PMC - PubMed
    1. Alter G, et al. 2011. HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476:96–100 - PMC - PubMed
    1. Alter G, Malenfant JM, Altfeld M. 2004. CD107a as a functional marker for the identification of natural killer cell activity. J. Immunol. Methods 294:15–22 - PubMed
    1. Alter G, et al. 2007. Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J. Immunol. Methods 204:3027–3036 - PMC - PubMed
    1. Altfeld M, Fadda L, Frleta D, Bhardwaj N. 2011. DCs and NK cells: critical effectors in the immune response to HIV-1. Nat. Rev. Immunol. 11:176–186 - PMC - PubMed

Publication types