An HIV-1 Broadly Neutralizing Antibody from a Clade C-Infected Pediatric Elite Neutralizer Potently Neutralizes the Contemporaneous and Autologous Evolving Viruses

Abstract

Broadly neutralizing antibodies (bNAbs) have demonstrated protective effects against HIV-1 in primate studies and recent human clinical trials. Elite neutralizers are potential candidates for isolation of HIV-1 bNAbs. The coexistence of bNAbs such as BG18 with neutralization-susceptible autologous viruses in an HIV-1-infected adult elite controller has been suggested to control viremia. Disease progression is faster in HIV-1-infected children than in adults. Plasma bNAbs with multiple epitope specificities are developed in HIV-1 chronically infected children with more potency and breadth than in adults. Therefore, we evaluated the specificity of plasma neutralizing antibodies of an antiretroviral-naive HIV-1 clade C chronically infected pediatric elite neutralizer, AIIMS_330. The plasma antibodies showed broad and potent HIV-1 neutralizing activity with >87% (29/33) breadth, a median inhibitory dilution (ID50) value of 1,246, and presence of N160 and N332 supersite-dependent HIV-1 bNAbs. The sorting of BG505.SOSIP.664.C2 T332N gp140 HIV-1 antigen-specific single B cells of AIIMS_330 resulted in the isolation of an HIV-1 N332 supersite-dependent bNAb, AIIMS-P01. The AIIMS-P01 neutralized 67% of HIV-1 cross-clade viruses, exhibited substantial indels despite limited somatic hypermutations, interacted with native-like HIV-1 trimer as observed in negative stain electron microscopy, and demonstrated high binding affinity. In addition, AIIMS-P01 neutralized the coexisting and evolving autologous viruses, suggesting the coexistence of vulnerable autologous viruses and HIV-1 bNAbs in the AIIMS_330 pediatric elite neutralizer. Such pediatric elite neutralizers can serve as potential candidates for isolation of novel HIV-1 pediatric bNAbs and for understanding the coevolution of virus and host immune response. IMPORTANCE More than 50% of the HIV-1 infections globally are caused by clade C viruses. To date, there is no effective vaccine to prevent HIV-1 infection. Based on the structural information of the currently available HIV-1 bNAbs, attempts are under way to design immunogens that can elicit correlates of protection upon vaccination. Here, we report the isolation and characterization of an HIV-1 N332 supersite-dependent bNAb, AIIMS-P01, from a clade C chronically infected pediatric elite neutralizer. The N332 supersite is an important epitope and is one of the current HIV-1 vaccine targets. AIIMS-P01 potently neutralized the contemporaneous and autologous evolving viruses and exhibited substantial indels despite low somatic hypermutations. Taken together with the information on infant bNAbs, further isolation and characterization of bNAbs contributing to the plasma breadth in HIV-1 chronically infected children may help provide a better understanding of their role in controlling HIV-1 infection.

Viral Characteristics Associated with Maintenance of Elite Neutralizing Activity in Chronically HIV-1 Clade C-Infected Monozygotic Pediatric Twins

“…Chronically HIV-1-infected children have been shown to have potent plasma bnAbs with diverse epitope specificities (5,6). In our pediatric cohort of antiretroviral-naive HIC-1 clade C (HIV-1C)-infected children previously characterized for plasma antibody responses (6,(13)(14)(15)(16)(17)(18), we identified a pair of chronically infected antiretroviral-naive HIV-1C-infected children, AIIMS_329 and AIIMS_330, defined herein as genetically identical twins by their identical HLA phenotypes, who had acquired the infection at birth by vertical transmission. Both twins AIIMS_329 and AIIMS_330 developed potent plasma neutralizing antibodies (nAbs), with the latter showing elite neutralizing activity since the first sampling.…”

“…Binding ELISAs. MPER, RSC3, and RSC3Δ371I/P363N ELISAs were performed as described previously (16). Briefly, 96-well ELISA plates (Corning, USA) were coated with 2 g/ml of the RSC3 and RSC3Δ371I/ P363N proteins and the MPER-B and MPER-C peptides overnight at 4°C.…”

Harnessing early life immunity to develop a pediatric HIV vaccine that can protect through adolescence

“…During natural infection, bNabs develop only in 10% to 30% of the HIV-infected adults after several years of infection and are associated with extensive SHM and affinity maturation [ 38 , 39 ]. In contrast, HIV-infected children can develop broad neutralization earlier than adults [ 40 – 43 ] and exhibit increase in neutralization breadth and potency over time [ 41 , 44 ]. Moreover, compared to adults, where plasma neutralization breadth is driven by antibodies of limited specificities, neutralization breadth in children is often achieved via polyclonal epitope specificity [ 40 , 45 ].…”

Plasma neutralizing antibodies in an infant with interclade HIV-1 superinfection preferentially neutralize superinfecting HIV-1 strains

“…Though a prolonged exposure to viral antigens has been implicated as a necessity for the induction of bnAbs in HIV-1 infected adults, potent plasma bnAbs have been found in infected infants as early as one-year post-infection (1)(2)(3)(4)(5)(6). Further, the bnAbs isolated from infected children show features atypical of adult bnAbs suggesting the factors governing bnAb induction in infants are different than those in adults, providing an impetus to better characterize pediatric HIV-1 humoral immunity (7,8). In a recently reported cohort of 51 HIV-1 infected infants recruited in acute/early stages of infection and screened for plasma neutralization activity against a global panel of twelve heterologous viruses, we had identified a 54-weeks old perinatally HIV-1 infected infant AIIMS709 with two highly divergent and unlinked HIV-1 isolates (24% genetic difference in the env gene between the two contemporaneous circulating viral isolates which is analogous to the difference observed between two distinct clades) who was presumed to be superinfected (5).…”