Immunological Fingerprints of Controllers Developing Neutralizing HIV-1 Antibodies

Enrique Martin-Gayo; Ce Gao; Hsiao Rong Chen; Zhengyu Ouyang; Dhohyung Kim; Kellie E Kolb; Alex K Shalek; Bruce D Walker; Mathias Lichterfeld; Xu G Yu

doi:10.1016/j.celrep.2019.12.087

Immunological Fingerprints of Controllers Developing Neutralizing HIV-1 Antibodies

Cell Rep. 2020 Jan 28;30(4):984-996.e4. doi: 10.1016/j.celrep.2019.12.087.

Authors

Affiliations

¹ Ragon Institute of MGH, MIT, and Harvard, Boston, MA, USA; Universidad Autónoma de Madrid, Hospital de la Princesa, Madrid, Spain. Electronic address: enrique.martin@uam.es.
² Ragon Institute of MGH, MIT, and Harvard, Boston, MA, USA.
³ Ragon Institute of MGH, MIT, and Harvard, Boston, MA, USA; Department of Chemistry, MIT Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Ragon Institute of MGH, MIT, and Harvard, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁵ Ragon Institute of MGH, MIT, and Harvard, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA; Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA.
⁶ Ragon Institute of MGH, MIT, and Harvard, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA; Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA. Electronic address: xyu@mgh.harvard.edu.

Abstract

The induction of broadly neutralizing antibodies (bnAbs) is highly desired for an effective vaccine against HIV-1. Typically, bnAbs develop in patients with high viremia, but they can also evolve in some untreated HIV-1 controllers with low viral loads. Here, we identify a subgroup of neutralizer-controllers characterized by myeloid DCs (mDCs) with a distinct inflammatory signature and a superior ability to prime T follicular helper (Tfh)-like cells in an STAT4-dependent fashion. This distinct immune profile is associated with a higher frequency of Tfh-like cells in peripheral blood (pTfh) and an enrichment for Tfh-defining genes in circulating CD4⁺ T cells. Correspondingly, monocytes from this neutralizer controller subgroup upregulate genes encoding for chemotaxis and inflammation, and they secrete high levels of IL-12 in response to TLR stimulation. Our results suggest the existence of multi-compartment immune networks between mDCs, Tfh, and monocytes that may facilitate the development of bnAbs in a subgroup of HIV-1 controllers.

Keywords: B cell; CD4 T cell; HIV; RNAseq; bnAb; controller; dendritic cell; monocyte; neutralizer; systems biology.

MeSH terms

Adult
Aged
Antibodies, Neutralizing / immunology*
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
Cell Line
Cell Survival / immunology
Dendritic Cells / immunology*
Dendritic Cells / metabolism
Female
Gene Expression Regulation / immunology
HIV Antibodies / immunology*
HIV Infections / immunology*
HIV-1 / immunology*
Humans
Interleukin-12 / metabolism
Male
Middle Aged
Monocytes / immunology*
Monocytes / metabolism
RNA-Seq
STAT4 Transcription Factor / genetics
STAT4 Transcription Factor / metabolism
T-Lymphocytes, Helper-Inducer / immunology*
T-Lymphocytes, Helper-Inducer / metabolism
Th1 Cells / immunology
Th1 Cells / metabolism

Substances

Antibodies, Neutralizing
HIV Antibodies
STAT4 Transcription Factor
STAT4 protein, human
Interleukin-12

Abstract

MeSH terms

Substances

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