Virus-driven Inflammation Is Associated With the Development of bNAbs in Spontaneous Controllers of HIV.
Understanding the mechanism(s) by which broadly neutralizing antibodies (bNAbs) emerge naturally following infection is crucial for the development of a protective vaccine against human immunodeficiency virus (HIV). Although previous studies have implicated high viremia and associated immune activation as potential drivers for the development of bNAbs, here we sought to unlink the effect of these 2 parameters by evaluating the key inflammatory predictors of bNAb development in HIV-infected individuals who spontaneously control HIV in the absence of antiretroviral therapy ("controllers").



The breadth of antibody-mediated neutralization against 11 tier 2 or 3 viruses was assessed in 163 clade B spontaneous controllers of HIV. Plasma levels of 17 cytokines were screened in the same set of subjects. The relationship of the inflammatory signature was assessed in the context of viral blips or viral RNA levels in peripheral blood or gastrointestinal biopsies from aviremic controllers (<50 copies RNA/mL) and in the context of viral sequence diversity analysis in the plasma of viremic controllers (<50-2000 copies RNA/mL).



A unique inflammatory profile, including high plasma levels of CXCL13, sCD40L, IP10, RANTES, and TNFα, was observed in HIV controllers who developed bNAbs. Interestingly, viral load and tissue viremia, but not intermittent viral blips, were associated with these cytokine profiles. However, viral diversity was not significantly associated with increased breadth in controllers.



These results suggest that low antigenic diversity in the setting of a unique inflammatory profile associated with antigen persistence may be linked to the evolution of neutralizing antibody breadth.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard,  Cambridge, MA, USA.
Anne-Sophie
AS
Dugast
Department of Biological Engineering, MIT, Cambridge, Massachusetts, USA.
Kelly
K
Arnold
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard,  Cambridge, MA, USA.
Giuseppe
G
Lofano
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard,  Cambridge, MA, USA.
Sarah
S
Moore
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard,  Cambridge, MA, USA.
Michelle
M
Hoffner
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, USA.
Melissa
M
Simek
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, USA.|Department of Immunology and Microbial Science, The Scripps Research Institute, CA, USA.|International AIDS Vaccine Initiative, New York, USA.
Pascal
P
Poignard
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Michael
M
Seaman
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard,  Cambridge, MA, USA.
Todd J
TJ
Suscovich
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard,  Cambridge, MA, USA.
Florencia
F
Pereyra
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard,  Cambridge, MA, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Bruce D
BD
Walker
Department of Biological Engineering, MIT, Cambridge, Massachusetts, USA.
Doug
D
Lauffenburger
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard,  Cambridge, MA, USA.
Douglas S
DS
Kwon
AIDS and Cancer Virus Program, Leidos Biomedical Research Inc. Frederick National Laboratory, Frederick, Maryland, USA.
Brandon F
BF
Keele
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard,  Cambridge, MA, USA.
Galit
G
Alter
D057134:Antibodies, Neutralizing / Q000097:blood*; D016207:Cytokines / Q000097:blood; D006678:HIV / Q000276:immunology*; D015483:HIV Antibodies / Q000097:blood*; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007413:Intestinal Mucosa / Q000821:virology; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load
D057134:Antibodies, Neutralizing; D016207:Cytokines; D015483:HIV Antibodies; D012367:RNA, Viral
inflammation; neutralizing antibodies; HIV vaccine