Biphasic CD8+ T-Cell Defense in Simian Immunodeficiency Virus Control by Acute-Phase Passive Neutralizing Antibody Immunization.
Identifying human immunodeficiency virus type 1 (HIV-1) control mechanisms by neutralizing antibodies (NAbs) is critical for anti-HIV-1 strategies. Recent in vivo studies on animals infected with simian immunodeficiency virus (SIV) and related viruses have shown the efficacy of postinfection NAb passive immunization for viremia reduction, and one suggested mechanism is its occurrence through modulation of cellular immune responses. Here, we describe SIV control in macaques showing biphasic CD8(+) cytotoxic T lymphocyte (CTL) responses following acute-phase NAb passive immunization. Analysis of four SIVmac239-infected rhesus macaque pairs matched with major histocompatibility complex class I haplotypes found that counterparts receiving day 7 anti-SIV polyclonal NAb infusion all suppressed viremia for up to 2 years without accumulating viral CTL escape mutations. In the first phase of primary viremia control attainment, CD8(+) cells had high capacities to suppress SIVs carrying CTL escape mutations. Conversely, in the second, sustained phase of SIV control, CTL responses converged on a pattern of immunodominant CTL preservation. During this sustained phase of viral control, SIV epitope-specific CTLs showed retention of phosphorylated extracellular signal-related kinase (ERK)(hi)/phosphorylated AMP-activated protein kinase (AMPK)(lo) subpopulations, implying their correlation with SIV control. The results suggest that virus-specific CTLs functionally boosted by acute-phase NAbs may drive robust AIDS virus control.



In early HIV infection, NAb responses are lacking and CTL responses are insufficient, which leads to viral persistence. Hence, it is important to identify immune responses that can successfully control such HIV replication. Here, we show that monkeys receiving NAb passive immunization in early SIV infection strictly control viral replication for years. Passive infusion of NAbs with CTL cross-priming capacity resulted in induction of functionally boosted early CTL responses showing enhanced suppression of CTL escape mutant virus replication. Accordingly, the NAb-infused animals did not show accumulation of viral CTL escape mutations during sustained SIV control, and immunodominant CTL responses were preserved. This early functional augmentation of CTLs by NAbs provides key insights into the design of lasting and viral escape mutation-free protective immunity against HIV-1 infection.
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.|The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Sumire
S
Iseda
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Naofumi
N
Takahashi
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.|The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Hugo
H
Poplimont
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Takushi
T
Nomura
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Sayuri
S
Seki
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.|The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Taku
T
Nakane
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Midori
M
Nakamura
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.|The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Shoi
S
Shi
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Hiroshi
H
Ishii
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Shota
S
Furukawa
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Shigeyoshi
S
Harada
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Taeko K
TK
Naruse
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Akinori
A
Kimura
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.|The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Tetsuro
T
Matano
AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan h-yamato@nih.go.jp.
Hiroyuki
H
Yamamoto
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000276:immunology / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014766:Viremia / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D014779:Virus Replication
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral