Generation and evaluation of clade C simian-human immunodeficiency virus challenge stocks.

UNLABELLED: The development of a panel of mucosally transmissible simian-human immunodeficiency virus (SHIV) challenge stocks from multiple virus clades would facilitate preclinical evaluation of candidate HIV-1 vaccines and therapeutics. The majority of SHIV stocks that have been generated to date have been derived from clade B HIV-1 env sequences from viruses isolated during chronic infection and typically required serial animal-to-animal adaptation for establishing mucosal transmissibility and pathogenicity. To capture essential features of mucosal transmission of clade C viruses, we produced a series of SHIVs with early clade C HIV-1 env sequences from acutely HIV-1-infected individuals from South Africa. SHIV-327c and SHIV-327cRM expressed env sequences that were 99.7 to 100% identical to the original HIV-1 isolate and did not require in vivo passaging for mucosal infectivity. These challenge stocks infected rhesus monkeys efficiently by both intrarectal and intravaginal routes, replicated to high levels during acute infection, and established chronic setpoint viremia in 13 of 17 (76%) infected animals. The SHIV-327cRM challenge stock was also titrated for both single, high-dose intrarectal challenges and repetitive, low-dose intrarectal challenges in rhesus monkeys. These SHIV challenge stocks should facilitate the preclinical evaluation of vaccines and other interventions aimed at preventing clade C HIV-1 infection. IMPORTANCE: We describe the development of two related clade C SHIV challenge stocks. These challenge stocks should prove useful for preclinical testing of vaccines and other interventions aimed at preventing clade C HIV-1 infection.

A multivalent clade C HIV-1 Env trimer cocktail elicits a higher magnitude of neutralizing antibodies than any individual component.

UNLABELLED: The sequence diversity of human immunodeficiency virus type 1 (HIV-1) presents a formidable challenge to the generation of an HIV-1 vaccine. One strategy to address such sequence diversity and to improve the magnitude of neutralizing antibodies (NAbs) is to utilize multivalent mixtures of HIV-1 envelope (Env) immunogens. Here we report the generation and characterization of three novel, acute clade C HIV-1 Env gp140 trimers (459C, 405C, and 939C), each with unique antigenic properties. Among the single trimers tested, 459C elicited the most potent NAb responses in vaccinated guinea pigs. We evaluated the immunogenicity of various mixtures of clade C Env trimers and found that a quadrivalent cocktail of clade C trimers elicited a greater magnitude of NAbs against a panel of tier 1A and 1B viruses than any single clade C trimer alone, demonstrating that the mixture had an advantage over all individual components of the cocktail. These data suggest that vaccination with a mixture of clade C Env trimers represents a promising strategy to augment vaccine-elicited NAb responses. IMPORTANCE: It is currently not known how to generate potent NAbs to the diverse circulating HIV-1 Envs by vaccination. One strategy to address this diversity is to utilize mixtures of different soluble HIV-1 envelope proteins. In this study, we generated and characterized three distinct, novel, acute clade C soluble trimers. We vaccinated guinea pigs with single trimers as well as mixtures of trimers, and we found that a mixture of four trimers elicited a greater magnitude of NAbs than any single trimer within the mixture. The results of this study suggest that further development of Env trimer cocktails is warranted.

Emergency Department utilisation: a natural experiment.

AIM: In February 2005 a new Emergency Department (ED) was opened at Waitakere Hospital in West Auckland, New Zealand. Part of the rationale for this was the expectation that it would reduce attendances to the four established EDs in the Auckland region. This study was undertaken to determine whether this happened. METHOD: A retrospective analysis of ED presentations to Auckland City, Starship and North Shore hospitals for the 2 years prior to the opening of Waitakere ED (February 2005) was conducted. This was compared with the attendances to all hospitals in the 2 years following the opening of the new ED. The effect of the opening of Waitakere ED on ED presentations to other hospitals was assessed using control charts. Presentations to Middlemore Hospital during the same time period were used as a control. RESULTS: ED attendance to hospitals in the Auckland District Health Board (DHB) area increased by 9% over the study period (Auckland Hospital = 13%, Starship Children's Hospital = 2%), similarly ED attendance to Middlemore Hospital increased by 6%, consistent with population growth. However ED attendance to hospitals in the Waitemata DHB area (North Shore and Waitakere Hospitals) increased by 74%, disproportionate to population growth (8%). CONCLUSION: The opening of a new ED may have contributed to an increase in total ED presentations seen within the region overall, with no corresponding reduction in attendances at neighbouring hospitals.