本期两篇论文在灵长类模型中对新一代广谱强效抗HIV-1单克隆抗体(mAbs)进行了测试,并取得了令人鼓舞的结果。二者都得出结论认为,它们的结果非常鼓励在人体中进行HIV-1的mAb疗法研究。
Dan Barouch等人发现,只注射具有广泛中合作用的强效抗HIV-1抗体PGT121以及采用各种不同的mAb“鸡尾酒”(将mAbs以不同方式混合使用),仅仅一个星期就能将感染了SHIV的恒河猴体内的这种病毒抑制到检测不出的水平。
Masashi Shingai等人报告说,将抗体3BNC117 和 10-1074一起使用,导致被SHIV慢性感染的恒河猴的血浆病毒血症受到强效抑制,效果持续几个星期。
生物谷推荐的英文摘要
Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys
Dan H. Barouch,James B. Whitney,Brian Moldt,Florian Klein,Thiago Y. Oliveira,Jinyan Liu,Kathryn E. Stephenson,Hui-Wen Chang,Karthik Shekhar,Sanjana Gupta,Joseph P. Nkolola,Michael S. Seaman,Kaitlin M. Smith,Erica N. Borducchi,Crystal Cabral,Jeffrey Y. Smith,Stephen Blackmore,Srisowmya Sanisetty,James R. Perry,Matthew Beck,Mark G. Lewis,William Rinaldi,Arup K. Chakraborty,Pascal Poignard,Michel C. Nussenzweig
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.
Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia
Masashi Shingai,Yoshiaki Nishimura,Florian Klein,Hugo Mouquet,Olivia K. Donau,Ronald Plishka,Alicia Buckler-White,Michael Seaman,Michael Piatak,Jeffrey D. Lifson,Dimiter Dimitrov,Michel C. Nussenzweig& Malcolm A. Martin
Neutralizing antibodies can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS1, 2, 3, 4. However, earlier studies of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies administered to infected individuals or humanized mice reported poor control of virus replication and the rapid emergence of resistant variants5, 6, 7. A new generation of anti-HIV-1 monoclonal antibodies, possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals8. These neutralizing antibodies target different regions of the HIV-1 envelope glycoprotein including the CD4-binding site, glycans located in the V1/V2, V3 and V4 regions, and the membrane proximal external region of gp41 (refs 9, 10, 11, 12, 13, 14). Here we have examined two of the new antibodies, directed to the CD4-binding site and the V3 region (3BNC117 and 10-1074, respectively), for their ability to block infection and suppress viraemia in macaques infected with the R5 tropic simian–human immunodeficiency virus (SHIV)-AD8, which emulates many of the pathogenic and immunogenic properties of HIV-1 during infections of rhesus macaques15, 16. Either antibody alone can potently block virus acquisition. When administered individually to recently infected macaques, the 10-1074 antibody caused a rapid decline in virus load to undetectable levels for 4–7days, followed by virus rebound during which neutralization-resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viraemia for 3–5weeks in some long-term chronically SHIV-infected animals with low CD4+ T-cell levels. A second cycle of anti-HIV-1 monoclonal antibody therapy, administered to two previously treated animals, successfully controlled virus rebound. These results indicate that immunotherapy or a combination of immunotherapy plus conventional antiretroviral drugs might be useful as a treatment for chronically HIV-1-infected individuals experiencing immune dysfunction.