Research Article: Consistent elicitation of cross-clade HIV-neutralizing responses achieved in guinea pigs after fusion peptide priming by repetitive envelope trimer boosting

Date Published: April 17, 2019

Publisher: Public Library of Science

Author(s): Cheng Cheng, Kai Xu, Rui Kong, Gwo-Yu Chuang, Angela R. Corrigan, Hui Geng, Kurt R. Hill, Alexander J. Jafari, Sijy O’Dell, Li Ou, Reda Rawi, Ariana P. Rowshan, Edward K. Sarfo, Mallika Sastry, Kevin O. Saunders, Stephen D. Schmidt, Shuishu Wang, Winston Wu, Baoshan Zhang, Nicole A. Doria-Rose, Barton F. Haynes, Diana G. Scorpio, Lawrence Shapiro, John R. Mascola, Peter D. Kwong, Aftab A. Ansari.


The vaccine elicitation of broadly neutralizing responses is a central goal of HIV research. Recently, we elicited cross-clade neutralizing responses against the N terminus of the fusion peptide (FP), a critical component of the HIV-entry machinery. While the consistency of the elicited cross-clade neutralizing responses was good in mice, it was poor in guinea pigs: after seven immunizations comprising either envelope (Env) trimer or FP coupled to a carrier, serum from only one of five animals could neutralize a majority of a cross-clade panel of 19 wild-type strains. Such a low response rate—only 20%—made increasing consistency an imperative. Here, we show that additional Env-trimer immunizations could boost broad FP-directed neutralizing responses in a majority of immunized animals. The first boost involved a heterologous Env trimer developed from the transmitted founder clade C strain of donor CH505, and the second boost involved a cocktail that combined the CH505 trimer with a trimer from the BG505 strain. After boosting, sera from three of five animals neutralized a majority of the 19-strain panel and serum from a fourth animal neutralized 8 strains. We demonstrate that cross-reactive serum neutralization targeted the FP by blocking neutralization with soluble fusion peptide. The FP competition revealed two categories of elicited responses: an autologous response to the BG505 strain of high potency (~10,000 ID50), which was not competed by soluble FP, and a heterologous response of lower potency, which was competed by soluble FP. While the autologous response could increase rapidly in response to Env-trimer boost, the heterologous neutralizing response increased more slowly. Overall, repetitive Env-trimer immunizations appeared to boost low titer FP-carrier primed responses to detectable levels, yielding cross-clade neutralization. The consistent trimer-boosted neutralizing responses described here add to accumulating evidence for the vaccine utility of the FP site of HIV vulnerability.

Partial Text

The induction of immune responses capable of neutralizing a substantial portion of circulating HIV-1 strains has been a major goal of vaccine research. Unlike influenza virus, where the majority of variation is found in animal reservoirs and the circulating diversity in humans is <1% of the viral genome, the circulating diversity in humans of HIV-1 is roughly 30% at the amino-acid level [1]. This level of diversity is much greater than the circulating diversity found with most other viruses; indeed, it is estimated that the diversity of HIV-1 in a single individual infected for six years is roughly equivalent to the annual diversity of circulating influenza sequences world-wide [2]. In addition to genetic variation, the trimeric envelope (Env) glycoprotein of HIV-1 uses conformational masking and an evolving glycan shield to evade neutralizing antibody [3, 4]. Together, these immune evasion mechanisms have confounded HIV vaccine efforts. While vaccine-induced neutralization has been achieved for autologous virus [5–8], where the neutralized strain is the same strain from which the immunogen was developed, vaccine-induced neutralization of heterologous strains has only been achieved sporadically in select animals [9, 10]. The vaccine elicitation of sera capable of neutralizing diverse strains of HIV-1 has been a long-sought goal. Tantalizing neutralization results have been achieved against the FP site of HIV-1 vulnerability. However, these results needed improvements in breadth, potency, and consistency. Here we show that additional Env trimer boosting can enhance the consistency of neutralization titers in animals previously primed with FP coupled to a carrier protein. Prior to additional boosting, broad responses were clearly seen in only one animal (CGP701-5) on a 19-strain panel, and after boosting in three of five animals: CGP701-1, -3 and -5. Furthermore, after assessment on a 60-strain panel, fingerprint analysis could detect evidence of a characteristic FP-directed response, even in the animal CGP701-2, which showed no evidence of heterologous response on the 19-strain panel.   Source: