Neutralizing antibodies (NAbs) can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS1–4. However, earlier studies of anti-HIV 1 NAbs administered to infected individuals or humanized mice, reported poor control of virus replication and the rapid emergence of resistant variants 5–7. A new generation of anti-HIV 1 monoclonal antibodies (mAbs), possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals 8. These NAbs target different regions of the HIV 1 envelope glycoprotein including the CD4 binding site (bs), glycans located in the V1/V2, V3, and V4 regions, and the membrane proximal external region of gp419–14. We have examined two of the new antibodies, directed to the CD4 bs and the V3 region (3BNC117 and 10-1074 respectively) for their ability to block infection and suppress viremia in macaques infected with the R5 tropic SHIVAD8 virus, 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 monkeys, the 10-1074 antibody caused a rapid decline in virus loads to undetectable levels for 4 to 7 days, followed by virus rebound during which neutralization resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viremia for 3 to 5 weeks in some long-term chronically SHIV infected animals with low CD4+ T cell levels. A second cycle of anti-HIV 1 mAb therapy, administered to two previously treated animals, successfully controlled virus rebound. These results suggest 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.

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Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques and humans1–12. To determine whether the administration of combination 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 10-107413,14). Viremia remained undetectable for 56–177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. 4 additional animals maintained their CD4+ T cell counts and very low levels of viremia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the 6 controller macaques. Infusion of a T cell depleting anti-CD8β mAb to the controller animals led to a specific decline in levels of CD8+ T cells and rapid reappearance of plasma viremia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy (cART), beginning on day 3 after infection, experienced sustained rebound plasma viremia when treatment was interrupted. We conclude that passive immunotherapy during the acute SHIV infection differs from cART in that it facilitates the emergence of potent CD8+ T cell immunity able to durably suppress virus replication.