A SINGLE INJECTION OF ANTI-HIV-1 ANTIBODIES PROTECTS AGAINST REPEATED SHIV CHALLENGES. Despite the success of potent anti-retroviral drugs in controlling HIV-1 infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 bNAbs can protect mice or macaques against a single high dose challenge with HIV or SIV/HIV chimeric viruses respectively, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Based on the relatively long-term protection conferred by Hepatitis A immune globulin, we tested the efficacy of a single injection (20mg/kg) of four anti-HIV-1 neutralizing monoclonal antibodies (MAbs) (VRC01, VRC01-LS, 3BNC117, and 10-1074) in blocking repeated weekly low dose virus challenges of the clade B SHIVAD8. Compared to control animals, which required 2 to 6 challenges (median=3 weeks) for infection, a single bNAb infusion prevented virus acquisition for up to 23 weeks. This effect depended on antibody potency and half-life. The highest levels of plasma neutralizing activity and correspondingly, the longest protection, were found in monkeys administered the more potent antibodies, 3BNC117 and 10 1074 (median=13 and 12.5 weeks respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median=8 weeks). The introduction of a mutation that extends antibody half-life into the Fc domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered in to populations at high risk for HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission. EARLY ANTIBODY THERAPY CAN INDUCE LONG LASTING CELLULAR IMMUNITY TO SHIV INFECTIONS. Highly potent and broadly neutralizing anti-HIV 1 antibodies (bNAbs) have recently been used to prevent and treat lentivirus infections in humanized mice, macaques and humans. To determine whether the administration of bNAbs during the acute SHIV infection of rhesus macaques might lead to long-term control of virus replication, animals challenged with SHIVAD8-EO by mucosal or intravenous routes, received a single 2-week course of 2 potent passively transferred bNAbs (3BNC117 and 10-1074). Following modulated acute phase viremia and its subsequent control, measurable virus rebound occurred between weeks 7 and 21 after infection, depending on bNAb half-life in vivo. However, in 6 of the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in these 6 controller macaques. Infusion of a depleting anti-CD8+ T cell mAb to the controller animals led to the rapid appearance of plasma viremia (10e5 to 10e7 viral RNA copies/ml); controller status was re-established in several monkeys when CD8+ T cell levels returned to pre-depletion levels. In contrast, macaques treated for 2 or for 15 weeks with combination anti-retroviral therapy (cART), beginning on day 3 after infection, experienced rebound of plasma viremia after treatment was interrupted. We conclude that passive immunotherapy during the acute SHIV infection differs from cART in that it facilitates the emergence of potent immunity able to durably suppress virus replication.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
Zip Code
Gautam, Rajeev; Nishimura, Yoshiaki; Gaughan, Natalie et al. (2018) A single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection. Nat Med 24:610-616
Wagh, Kshitij; Seaman, Michael S; Zingg, Marshall et al. (2018) Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections. PLoS Pathog 14:e1006860
Nishimura, Yoshiaki; Martin, Malcolm A (2017) Of Mice, Macaques, and Men: Broadly Neutralizing Antibody Immunotherapy for HIV-1. Cell Host Microbe 22:207-216
Doria-Rose, Nicole A; Altae-Tran, Han R; Roark, Ryan S et al. (2017) Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting. PLoS Pathog 13:e1006148
Nishimura, Yoshiaki; Gautam, Rajeev; Chun, Tae-Wook et al. (2017) Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543:559-563
Chen, Chia-Yen; Shingai, Masashi; Welbourn, Sarah et al. (2016) Antagonism of BST-2/Tetherin Is a Conserved Function of the Env Glycoprotein of Primary HIV-2 Isolates. J Virol 90:11062-11074
Hu, Xintao; Valentin, Antonio; Dayton, Frances et al. (2016) DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV. J Immunol 197:3999-4013
Gautam, Rajeev; Nishimura, Yoshiaki; Pegu, Amarendra et al. (2016) A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533:105-109
Francica, Joseph R; Sheng, Zizhang; Zhang, Zhenhai et al. (2015) Analysis of immunoglobulin transcripts and hypermutation following SHIV(AD8) infection and protein-plus-adjuvant immunization. Nat Commun 6:6565
Yamamoto, Takuya; Lynch, Rebecca M; Gautam, Rajeev et al. (2015) Quality and quantity of TFH cells are critical for broad antibody development in SHIVAD8 infection. Sci Transl Med 7:298ra120

Showing the most recent 10 out of 11 publications