Development of glycan-binding broadly neutralizing antibody responses in HIV-1 infection

HIV-1包膜(Env)是中和抗体的唯一靶点，因此是疫苗开发的主要候选者。HIV-1在宿主免疫系统的作用下发生快速变异，导致env序列高度多样性，这对疫苗开发构成了重大挑战。然而，10-30%的HIV-1感染者在感染2-3年后会产生广谱中和抗体(BNAbs)，这些抗体能够中和大量的HIV-1毒株，这为实现具有广泛保护作用的HIV-1疫苗提供了一些希望。从慢性感染患者中分离出bNAbs，可以鉴定和鉴定HIV-1env的中和表位。然而，到目前为止，开发能够诱导bNAb的HIV-1疫苗的尝试都没有成功。因此，更详细地了解HIV-1 bNAbs在感染期间如何在体内进化，可能会为下一代HIV-1疫苗的开发提供见解。通过研究HIV-1感染者队列(SPARTAC)的纵向血清反应，我们已经确定了一名捐赠者(SJU捐赠者)，他开发了针对N332/V3表位Env的bNAbs。该供者感染了C型支原体病毒，感染后1-2年内产生了bNAbs。尽管产生了bNab反应，SJU捐赠者还是双重感染了第二种HIV-1病毒。这一供体为研究bNab的发育和研究bNab逃逸提供了一个重要的机会。对这些领域的进一步了解将有助于HIV-1免疫原的合理设计。

HIV-1 Envelope (Env) is the sole target for neutralizing antibodies and therefore the primary candidate for vaccine development. HIV-1 rapidly mutates in response to the host immune system leading to a high-diversity in Env sequence which represents a major challenge for vaccine development. However, 10-30% of HIV-1 infected patients after 2-3 years of infection will develop broadly neutralizing antibodies (bnAbs) that are capable of neutralizing a wide number of HIV-1 strains offering some promise that an HIV-1 vaccine with broad protection might be achieved. Isolation of bnAbs from chronically infected patients has allowed identification and characterisation of the neutralization epitopes on HIV-1 Env. However, attempts to develop an HIV-1 vaccine that is able to elicit bnAbs have thus far been unsuccessful. Therefore, a more detailed knowledge on how HIV-1 bnAbs evolve in vivo during infection may provide insights into development of next generation HIV-1 vaccines. Through studying longitudinal serum responses in a cohort (SPARTAC) of HIV-1 infected individuals, we have identified a donor (SJU donor) who developed bNAbs targeting the N332/V3 epitope Env. This donor was infected with a Clade C virus and developed bNAbs after 1-2 years after infection. Despite generation of a bnAb response, SJU donor became superinfected with a second HIV-1 virus. This donor presents an important opportunity to study bnAb development and study bnAb escape. Further understanding in these areas will aid in the rational design of HIV-1 immunogens.