In this Review, we have addressed some recent developments in the discovery and applications of anti-human immunodeficiency virus type- 1 (HIV-1) broadly neutralizing antibodies (bnAbs) isolated from infected adults and children. The recent developments in human antibody isolation technologies have led to the discovery of several highly potent anti-HIV-1 bnAbs. Herein, we have discussed the characteristics of recently identified bnAbs directed at distinct epitopes of HIV-1, in addition to the existing antibodies, from adults and children and have shed light on the benefits of multispecific HIV-1 bnAbs and their role in the design of polyvalent vaccines.

Cross-reactive epitopes (CREs) are similar epitopes on viruses that are recognized or neutralized by same antibodies. The S protein of SARS-CoV-2, similar to type I fusion proteins of viruses such as HIV-1 envelope (Env) and influenza hemagglutinin, is heavily glycosylated. Viral Env glycans, though host derived, are distinctly processed and thereby recognized or accommodated during antibody responses. In recent years, highly potent and/or broadly neutralizing human monoclonal antibodies (bnAbs) that are generated in chronic HIV-1 infections have been defined. These bnAbs exhibit atypical features such as extensive somatic hypermutations, long complementary determining region (CDR) lengths, tyrosine sulfation and presence of insertions/deletions, enabling them to effectively neutralize diverse HIV-1 viruses despite extensive variations within the core epitopes they recognize. As some of the HIV-1 bnAbs have evolved to recognize the dense viral glycans and cross-reactive epitopes (CREs), we assessed if these bnAbs cross-react with SARS-CoV-2. Several HIV-1 bnAbs showed cross-reactivity with SARS-CoV-2 while one HIV-1 CD4 binding site bnAb, N6, neutralized SARS-CoV-2. Furthermore, neutralizing plasma antibodies of chronically HIV-1 infected children showed cross neutralizing activity against SARS-CoV-2 pseudoviruses. Collectively, our observations suggest that human monoclonal antibodies tolerating extensive epitope variability can be leveraged to neutralize pathogens with related antigenic profile.

Protective antibody responses to human immunodeficiency virus (HIV)-1 infection evolve only in a fraction of infected individuals by developing broadly neutralizing antibodies (bnAbs) and/or effector functions such as antibody-dependent cellular cytotoxicity (ADCC). HIV-1 chronically infected adults and children on combination antiretroviral therapy (cART) showed a reduction in ADCC activity and improvement in HIV-1 specific neutralizing antibody (nAb) responses. Early initiation of cART in infected adults is found to be beneficial in reducing the viral load and delaying disease progression. Herein, we longitudinally evaluated the effect of cART on HIV-1 specific plasma ADCC and nAb responses in a cohort of 20 perinatally HIV-1 subtype-C infected infants and children ≤2 years of age, pre-cART and up to 1 year post-cART initiation. Significant reductions in HIV-1 specific plasma ADCC responses to subtype-C and subtype-B viruses and improvement in HIV-1 neutralization were observed in HIV-1 infected children 1 year post-cART initiation. A positive correlation between reduction in viral load and the loss of ADCC response was observed. This study provides information aiding the understanding of the effects of early initiation of cART on antibody effector functions and viral neutralization in HIV-1 infected children, which needs to be further evaluated in large cohorts of HIV-1 infected children on cART to plan future intervention strategies.

Background: Elite-neutralizer-derived HIV-1 envelopes (Envs), which induce broadly neutralizing antibodies (bnAbs), can inform HIV-1 vaccine design by serving as templates for bnAb-eliciting vaccines. Since single Env-based immunizations are insufficient to induce bnAb responses, sequential regimens using multivalent immunogens or Env cocktails hold greater promise. This underscores the need to develop stable Env trimers from diverse HIV-1 strains, particularly clade-C, which accounts for 50% of global infections and over 90% in India and South Africa. While various platforms exist to stabilize soluble Env trimers for use as antigenic baits and vaccines, stabilizing clade C trimers remains challenging. Methods: We stabilized an HIV-1 clade C trimer based on an Env isolated from a pediatric elite neutralizer (AIIMS_329) using multiple platforms, including SOSIP.v8.2, ferritin nanoparticles (NPs) and I53-50 two-component NPs, followed by characterization of their biophysical, antigenic, and immunogenic properties. Results: The stabilized 329 Envs showed binding to multiple HIV-1 bnAbs, with negligible binding to non-neutralizing antibodies. Negative-stain electron microscopy confirmed the native-like conformation of the Envs. Multimerization of 329 SOSIP.v8.2 on ferritin and two-component I53-50 NPs improved the affinity to HIV-1 bnAbs and showed higher immunogenicity in rabbits. Conclusions: The soluble 329 Env protein could serve as an antigenic bait, and multimeric 329 NP Envs are potential vaccine candidates.