Journal Article

Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Blackmore, Stephen, Smith, Kaitlin M., Oliveira, Thiago Y., Liu, Jinyan, Beck, Matthew, Chang, Hui-Wen, Shekhar, Karthik, Whitney, James B., Nkolola, Joseph P., Klein, Florian, Borducchi, Erica N., Nussenzweig, Michel C., Rinaldi, William, Gupta, Sanjana, Smith, Jeffrey Y., Moldt, Brian, Barouch, Dan H., Cabral, Crystal, Burton, Dennis R., Seaman, Michael S., Sanisetty, Srisowmya, Lewis, Mark G., Chakraborty, Arup K., Perry, James R., Poignard, Pascal, Stephenson, Kathryn E.

2013

Overview

Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian–human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans. Treatment of SHIV-infected monkeys with potent broadly neutralizing anti-HIV-1 monoclonal antibodies resulted in rapid control of viral replication in both peripheral blood and tissues; viral rebound was linked to decreasing antibody concentrations and not the generation of escape mutations, and setpoint viral load following viral rebound remained lower than the initial baseline viral load. Monoclonal antibodies in HIV therapy Two papers published this week test the new generation of broad and potent anti-HIV1 monoclonal antibodies (mAbs) in primate models with promising results, both concluding that their results strongly encourage the investigation of mAb therapy for HIV-1 in humans. Dan Barouch et al . show that a single infusion of the potent, broadly neutralizing anti-HIV-1 antibody PGT121, as well as various mAb cocktails, suppress the virus to undetectable levels in just a week in SHIV-infected rhesus monkeys. Masashi Shingai et al . report that co-administration of the antibodies 3BNC117 and 10-1074 results in potent suppression of plasma viraemia lasting for several weeks in chronically SHIV-infected macaques.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/255/1901 / 631/326/596/1787 / Acquired immune deficiency syndrome / AIDS / AIDS treatment / Animals / Antibodies, Monoclonal - therapeutic use / Antibodies, Neutralizing - therapeutic use / Deoxyribonucleic acid / DNA / DNA, Viral - blood / Health aspects / HIV / HIV Antibodies - immunology / HIV infection / HIV-1 - immunology / Host-parasite relationships / Human immunodeficiency virus / Humanities and Social Sciences / Immune system / Lymph nodes / Lymphocytes / Macaca mulatta / Medical research / Medicine, Experimental / Methods / Monoclonal antibodies / multidisciplinary / Mutation / Physiological aspects / Plasma / Prevention / Rhesus monkey / Science / Simian Acquired Immunodeficiency Syndrome - therapy / Simian Immunodeficiency Virus - physiology / Studies / T-Lymphocytes - immunology / Viremia - therapy