Induction of Antibodies Binding to the Membrane Proximal External Region of gp36 of HIV-2

Abstract

Objective: The ability to induce neutralizing antibodies may be the most important feature of an antiretroviral vaccine, preventing infection of target cells and subsequent integration of the virus into the cellular genome where the virus may persist. Broadly neutralizing antibodies directed against conserved epitopes in the membrane proximal external region (MPER) of the transmembrane envelope (TM) protein gp41 of HIV-1 such as the monoclonal antibodies (mAb) 2F5 and mAb 4E10 have been found in infected individuals; however, all attempts to induce such antibodies failed. In individuals infected with HIV-2 such antibodies were not yet reported. Methods: Two recombinant proteins corresponding to the ectodomain of the TM protein gp36 of HIV-2 were produced, rats were immunized and sera were analyzed for binding and neutralizing antibodies. Results: Although binding antibodies were induced, none of the sera neutralized HIV-2. Most interestingly, epitope mapping showed specific binding of the antibodies to the MPER of gp36, to a region homologous to the binding site of the mAb 4E10 in gp41 of HIV-1. Conclusions: Although MPER-specific antibodies were induced by vaccination with gp36, these antibodies did not neutralize HIV-2. This is similar to the situation with HIV-1, but in contrast to that with gammaretroviruses.

Optimisation of expression and purification of the feline and primate foamy virus transmembrane envelope proteins using a 96 deep well screen

“…The TM proteins of the gammaretroviruses are small (15 kDa) and non-glycosylated, whereas the TM proteins of the foamy viruses are much larger (gp48), they contain seven to eight cysteines and are highly glycosylated [15]. This resembles the situation described for the lentiviral TM proteins of HIV-1 (gp41) and HIV-2 (gp36), which are also not soluble in aqueous solutions (our own unpublished observations and [46]). …”

“…Whereas induction of neutralising antibodies immunising with the ectodomain of the TM protein of gammaretroviruses was easily achieved [41-43] all attempts to obtain such antibodies for HIV-1 and HIV-2 using similar proteins also failed [46,48]. As already pointed out, the TM proteins of the gammaretroviruses are rather small and not glycosylated, whereas the TM proteins of HIV-1, HIV-2, FFV and PFV are Muehle et al, Figure 3 …”

Neutralization of porcine endogenous retrovirus by antibodies against the membrane-proximal external region of the transmembrane envelope protein

“…As it appears to be easy to induce neutralizing antibodies following immunization with the ectodomain of p15E of different gammaretroviruses (Fiebig et al , 2006; Kaulitz et al , 2011; Langhammer et al , 2006), the question remains as to why is it so difficult to obtain neutralizing antibodies when immunizing with the ectodomain of the TM proteins of lentiviruses such as HIV-1 (Law et al , 2007; Mantis et al , 2001; Nieva et al , 2011) and HIV-2 (Behrendt et al , 2012). Glycosylation, the interaction between the MPER and the lipid bilayer, and/or the conformation of the molecule may be important (Ma et al , 2011; Montero et al , 2008; Van Regenmortel, 2011).…”

Increased titers of neutralizing antibodies after immunization with both envelope proteins of the porcine endogenous retroviruses (PERVs)

“…Whereas in the case of these gammaretroviruses neutralizing antibodies against the transmembrane envelope protein could be easily induced, all attempts to obtain antibodies such as 2F5 and 4E10 broadly neutralizing HIV-1 failed [1-3,16]. In addition, attempts to induce neutralizing antibodies against HIV-2 [17], the feline foamyvirus (FFV) [18], and the primate foamy virus (PFV) (our unpublished data) immunizing with the transmembrane envelope protein also failed. There are some major differences between the transmembrane envelope proteins p15E of the gammaretroviruses and those of the lenti- and foamyviruses.…”