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

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.National Institutes of Health (U.S.) (AI055332)National Institutes of Health (U.S.) (AI060354)National Institutes of Health (U.S.) (AI078526)National Institutes of Health (U.S.) (AI084794)National Institutes of Health (U.S.) (AI095985)National Institutes of Health (U.S.) (AI096040)National Institutes of Health (U.S.) (AI100148)National Institutes of Health (U.S.) (AI10063)Bill & Melinda Gates Foundation (OPP1033091)Bill & Melinda Gates Foundation (OPP1033115)Bill & Melinda Gates Foundation (OPP1040741)Bill & Melinda Gates Foundation (OPP1040753)Ragon Institute of MGH, MIT, and HarvardStavros S. Niarchos FoundationHoward Hughes Medical Institute (Investigator

Rapid Seeding of the Viral Reservoir Prior to SIV Viremia in Rhesus Monkeys

The viral reservoir represents a critical challenge facing HIV-1 eradication strategies1–5. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded very early following mucosal SIV infection of rhesus monkeys and prior to systemic viremia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10, and 14 following intrarectal SIVmac251 infection. Treatment on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later timepoints. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, following discontinuation of ART after 24 weeks of fully suppressive therapy, virus rebounded in all animals, although animals treated on day 3 exhibited a delayed viral rebound as compared with animals treated on days 7, 10 and 14. The time to viral rebound correlated with total viremia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded very early following intrarectal SIV infection of rhesus monkeys, during the “eclipse” phase, and prior to viremia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies

Intermediate Frequency AC Signal Analysis for Bionanosensor

Nanobiosensors are devices which incorporate nanomaterials to detect miniscule quantities of biological and chemical agents. The authors have already developed a novel bionanosensor (BNS) for quick, efficient, and precise detection of bacterial pathogens using the principles of CNT-DNA interaction and DNA hybridization. The detection ability of the (BNS) was observed to be independent of the device resistance. Two new methods (low-pass filter (LPF) and curve fitting (CF)) were developed for better analysis of the BNS. These methods successfully model the BNS. Evidence is provided to elucidate the success of the model, which can explain the DNA hybridization on the sensor surface. These models successfully demonstrated the detection of DNA hybridization versus nonhybridization. Thus, the models can not only help in better and efficient design and operation of the BNS, but can also be used to analyze other similar nanoscale devices

Production of Mucosally Transmissible SHIV Challenge Stocks from HIV-1 Circulating Recombinant Form 01_AE env Sequences

Simian-human immunodeficiency virus (SHIV) challenge stocks are critical for preclinical testing of vaccines, antibodies, and other interventions aimed to prevent HIV-1. A major unmet need for the field has been the lack of a SHIV challenge stock expressing circulating recombinant form 01_AE (CRF01_AE) env sequences. We therefore sought to develop mucosally transmissible SHIV challenge stocks containing HIV-1 CRF01_AE env derived from acutely HIV-1 infected individuals from Thailand. SHIV-AE6, SHIV-AE6RM, and SHIV-AE16 contained env sequences that were >99% identical to the original HIV-1 isolate and did not require in vivo passaging. These viruses exhibited CCR5 tropism and displayed a tier 2 neutralization phenotype. These challenge stocks efficiently infected rhesus monkeys by the intrarectal route, replicated to high levels during acute infection, and established chronic viremia in a subset of animals. SHIV-AE16 was titrated for use in single, high dose as well as repetitive, low dose intrarectal challenge studies. These SHIV challenge stocks should facilitate the preclinical evaluation of vaccines, monoclonal antibodies, and other interventions targeted at preventing HIV-1 CRF01_AE infection

Neutralization properties of SHIV stocks in TZM-bl assays^a.

<p>Neutralization properties of SHIV stocks in TZM-bl assays<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005431#t004fn001" target="_blank">^a</a>.</p

i.r. challenge with SHIV-AE6, SHIV-AE6RM, SHIV-AE16 stocks in rhesus monkeys.

<p>Twelve animals were challenged once with 1 ml of undiluted (A) SHIV-AE6 (n = 4), (B) SHIV-AE6RM (n = 4), and (C) SHIV-AE16 (n = 4) stocks by the i.r. route. The upper panel shows plasma viral loads, and the lower panel shows the percentage of CD4⁺ T cells in peripheral blood. The dotted line reflected the limit of detection of the assay (50 RNA copies/ml).</p

Summary of in vivo infectivity of SHIVs -AE6, -AE6RM, and -AE16 stocks in rhesus monkeys.

<p>Summary of in vivo infectivity of SHIVs -AE6, -AE6RM, and -AE16 stocks in rhesus monkeys.</p

HIV-1 ENV sequence characteristics.

<p>HIV-1 ENV sequence characteristics.</p

Summary of large-scale SHIV stocks^a.

<p>Summary of large-scale SHIV stocks<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005431#t003fn001" target="_blank">^a</a>.</p