Polyfunctional CD4 ⁺ T-Cell Induction in Neutralizing Antibody-Triggered Control of Simian Immunodeficiency Virus Infection

Abstract

Rapid depletion of memory CD4؉ T cells and delayed induction of neutralizing antibody (NAb) responses are characteristics of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. Although it was speculated that postinfection NAb induction could have only a limited suppressive effect on primary HIV replication, a recent study has shown that a single passive NAb immunization of rhesus macaques 1 week after SIV challenge can result in reduction of viral loads at the set point, indicating a possible contribution of postinfection NAb responses to virus control. However, the mechanism accounting for this NAb-triggered SIV control has remained unclear. Here, we report rapid induction of virus-specific polyfunctional T-cell responses after the passive NAb immunization postinfection. Analysis of SIV Gag-specific responses of gamma interferon, tumor necrosis factor alpha, interleukin-2, macrophage inflammatory protein 1␤, and CD107a revealed that the polyfunctionality of Gag-specific CD4 ؉ T cells, as defined by the multiplicity of these responses, was markedly elevated in the acute phase in NAb-immunized animals. In the chronic phase, despite the absence of detectable NAbs, virus control was maintained, accompanied by polyfunctional Gagspecific T-cell responses. These results implicate virus-specific polyfunctional CD4؉ T-cell responses in this NAb-triggered virus control, suggesting possible synergism between NAbs and T cells for control of HIV/SIV replication.

Biphasic CD8 + T-Cell Defense in Simian Immunodeficiency Virus Control by Acute-Phase Passive Neutralizing Antibody Immunization

“…Most of the animals had been used for our previous experiments, and their viral loads in the early phase were previously reported (17,19,20). In the present study, we conducted a longterm follow-up and in-depth analysis on T-cell responses throughout the period of observation (up to approximately 2 years).…”

“…The present study used frozen peripheral blood mononuclear cell (PBMC) samples derived from Burmese rhesus macaques (Macaca mulatta) for retrospective analysis of SIV-specific T-cell responses. Previous SIV mac239 challenge experiments using the animals (17,19,20) were conducted at the Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), with the help of the Corporation for Production and Research of Laboratory Primates. These studies were approved by the Committee on the Ethics of Animal Experiments of NIBIOHN under the guidelines for animal experiments at NIBIOHN and the National Institute of Infectious Diseases, which are in accordance with the Guidelines for Proper Conduct of Animal Experiments established by the Science Council of Japan (http://www.scj.go.jp/ja/info/kohyo/pdf/kohyo-20-k16-2e .pdf).…”

“…In certain cases, nonsterile viremia control after the decline of infused NAbs occurs when administration is performed in an earlier time frame (3,6,14,15). One feasible explanation is modulation of cellular immunity through Fc receptor-mediated functions (16) involving innate (8) and adaptive effectors (17). In considering these, the question is how cellular immune responses specifically undergo functional modulation by NAb passive immunization.…”

“…In the model, we intravenously administered polyclonal neutralizing anti-SIV IgG at day 7 post-SIV challenge. This was associated with immediate cell-associated viral-RNA accumulation in CD1c ϩ myeloid dendritic cells (DCs), subsequent elevation of SIV Gag-specific polyfunctional CD4 ϩ T-cell responses, enhanced in vitro virus-suppressive activity in CD8 ϩ cells, and set point viremia control (3,17). Set point viral loads were undetectable (less than 4 ϫ 10 2 viral-RNA copies/ml) in four of the six NAb-infused macaques and 1 ϫ 10 3 to 4 ϫ 10 3 copies/ml in the remaining two.…”

Association of Major Histocompatibility Complex Class I Haplotypes with Disease Progression after Simian Immunodeficiency Virus Challenge in Burmese Rhesus Macaques

“…We examined SIV infections in four groups of Burmese rhesus macaques having MHC-I haplotypes 90-120-Ia (A) (n ϭ 6), 90-010-Ie (E) (n ϭ 6), 90-120-Ib (B) (n ϭ 4), and 90-088-Ij (J) (n ϭ 4). Macaques R02-007, R06-037, R07-001, R07-004, R07-009, R01-011, R06-038, R06-001, R02-004, R04-014, and R06-022, which were used as controls in previous experiments (49,53,58), were included in the present study. The determination of MHC-I haplotypes was based on the family study in combination with the reference strand-mediated conformation analysis (RSCA) of Mamu-A and Mamu-B genes as described previously (31).…”