Potent and Broadly Reactive HIV-2 Neutralizing Antibodies Elicited by a Vaccinia Virus Vector Prime-C2V3C3 Polypeptide Boost Immunization Strategy

Abstract

Human immunodeficiency virus type 2 (HIV-2) infection affects about 1 to 2 million individuals, the majority living in West Africa, Europe, and India. As for HIV-1, new strategies for the prevention of HIV-2 infection are needed. Our aim was to produce new vaccine immunogens that elicit the production of broadly reactive HIV-2 neutralizing antibodies (NAbs). Native and truncated envelope proteins from the reference HIV-2ALI isolate were expressed in vaccinia virus or in bacteria. This source isolate was used due to its unique phenotype combining CD4 independence and CCR5 usage. NAbs were not elicited in BALB/c mice by single immunization with a truncated and fully glycosylated envelope gp125 (gp125t) or a recombinant polypeptide comprising the C2, V3, and C3 envelope regions (rpC2-C3). A strong and broad NAb response was, however, elicited in mice primed with gp125t expressed in vaccinia virus and boosted with rpC2-C3. Serum from these animals potently neutralized (median 50% neutralizing titer, 3,200) six of six highly divergent primary HIV-2 isolates. Coreceptor usage and the V3 sequence of NAb-sensitive isolates were similar to that of the vaccinating immunogen (HIV-2ALI). In contrast, NAbs were not reactive on three X4 isolates that displayed major changes in V3 loop sequence and structure. Collectively, our findings demonstrate that broadly reactive HIV-2 NAbs can be elicited by using a vaccinia virus vector-prime/rpC2-C3-boost immunization strategy and suggest a potential relationship between escape to neutralization and cell tropism.

HIV-2 A-subtype gp125C2-V3-C3 mutations and their association with CCR5 and CXCR4 tropism

“…Specifically, recombinant polypeptides representing the gp125 (rpC2-C3) in infected patients, Marcelino and colleagues did not detect reactive IgG antibodies [50]. Similar results were observed with X4-tropic viruses that were resistant to neutralization in a vaccinia virus vector-prime/rpC2-C3-polypeptideboost vaccination strategy [40]. In the first study, the authors examined nonspecific and Env-specific IgA and IgG responses in acute and chronic HIV-2 infection [50], while in the other work, the same team used a mouse model to investigate the immunogenicity and neutralizing response elicited when a recombinant HIV-2 envelope proteins was administered [40].…”

“…2, Table S1). Coherently, these signatures were already observed in different primary R5 HIV-2 group A isolate [40]. Furthermore, we show the presence of position I320 V3 , which characterizes the R5 cluster with a valine mutation, a signature that is robustly associated with the A378P C3 mutation (P = 8.27e -18 ; u = 0.70, bootstrap = 0.79).…”

“…These two positions were not neighbors in the predicted conformational C2-V3-C3 structure [41]. On the other hand, the Q366N C3 mutation was present in one of two patients in which IgG antibodies were not detected [50] and in several X4-tropic viruses that were resistant to neutralization by vaccination [40]. Effectively, this last position could play a supporting role in co-receptor interaction and was possibly also observed in an R5 cluster (Fig.…”

“…Fourteen X4-tropic virus mutations (T309S V3 , V311I V3 , L319R V3 , I320R V3 , S323G V3 , 324-325insR V3 , P325F V3 , 325-326insHS V3 , R32 9K V3 , K338E C3 , Q346R C3 , V353M C3 , T361V C3 and K371E C3 ) formed a very strong and highly significant subcluster (bootstrap value = 0.99). Some of these mutations, like the associated positions 319, 320, 323 and 338, have been observed previously [40,50]. Specifically, recombinant polypeptides representing the gp125 (rpC2-C3) in infected patients, Marcelino and colleagues did not detect reactive IgG antibodies [50].…”

“…Although little is known about the role of the HIV-2 env glycoproteins in humoral immunity, it seems that the gp125 V3 region of HIV-2 may contain broadly neutralizing epitopes [38][39][40]. Paradoxically, it could be concealed within the envelope complex, possibly due to a physical interaction with gp125 C2 and C3 domains [41].…”