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Broadly neutralizing antibodies (bnAbs) targeting the human immunodeficiency virus-1 (HIV-1) have played a crucial role in elucidating and characterizing neutralization-sensitive sites on the HIV-1 envelope spike and in informing vaccine development. Continual advancements in identifying more potent bnAbs, along with their capacity to trigger antibody-mediated effector functions, coupled with modifications to extend their half-life, position them as promising candidates for both HIV-1 treatment and prevention. While current pharmacological interventions have made significant progress in managing HIV-1 infection and enhancing quality of life, no definitive cure or vaccines have been developed thus far. Standard treatments involve daily oral anti-retroviral therapy, which, despite its efficacy, can lead to notable long-term side effects. Recent clinical trial data have demonstrated encouraging therapeutic and preventive potential for bnAb therapies in both HIV-1-infected individuals and those without the infection. This review provides an overview of the advancements in HIV-1-specific bnAbs and discusses the insights gathered from recent clinical trials regarding their application in treating and preventing HIV-1 infection.

Antibodies, and notably immunoglobulins A (IgA), are paramount in mucosal tissues as protective immune effectors against invading pathogens and immunomodulators of the microbiota. Upon human immunodeficiency virus type 1 (HIV-1) infection, systemic and mucosal IgA antibody responses are triggered. While naturally produced serum HIV-1 envelope protein-specific IgA are quantitatively and qualitatively weaker than their IgG counterparts, they also possess antiviral properties including neutralization and Fc-dependent functions. IgA neutralizers can block HIV-1 mucosal transmission in animal models, indicating that their elicitation by vaccination would be an important component for preventing infection. Moreover, the first genuine IgA broadly HIV-1 neutralizing antibodies (bNAbs) were recently identified in certain individuals living with HIV-1. Vaccine-based induction of IgA bNAbs potentially protective at the mucosal level is therefore conceivable. Hence, research efforts must therefore be undertaken to better understand their development and functions. In this review, we present the general functions of IgA in homeostasis and antimicrobial immunity and discuss their involvement in the antibody responses against HIV-1. [ABSTRACT FROM AUTHOR]

Introduction: A limited subset of HIV-1 infected adult individuals typically after at least 2-3 years of chronic infection, develop broadly neutralizing antibodies (bnAbs), suggesting that highly conserved neutralizing epitopes on the HIV-1 envelope glycoprotein are difficult for B cell receptors to effectively target, during natural infection. Recent studies have shown the evolution of bnAbs in HIV-1 infected infants. Methods: We used bulk BCR sequencing (BCR-seq) to profile the B cell receptors from longitudinal samples (3 time points) collected from a rare pair of antiretroviralnaïve, HIV-1 infected pediatric monozygotic twins (AIIMS_329 and AIIMS_330) who displayed elite plasma neutralizing activity against HIV-1. Results: BCR-seq of both twins revealed convergent antibody characteristics including V-gene use, CDRH3 lengths and somatic hypermutation (SHM). Further, antibody clonotypes with genetic features similar to highly potent bnAbs isolated from adults showed ongoing development in donor AIIMS_330 but not in AIIMS_329, corroborating our earlier findings based on plasma bnAbs responses. An increase in SHM was observed in sequences of the IgA isotype from AIIMS_330. Discussion: This study suggests that children living with chronic HIV-1 can develop clonotypes of HIV-1 bnAbs against multiple envelope epitopes similar to those isolated from adults, highlighting that such B cells could be steered to elicit bnAbs responses through vaccines aimed to induce bnAbs against HIV-1 in a broad range of people including children. [ABSTRACT FROM AUTHOR]

The development of HIV prophylactic vaccines is facing an impasse, since all phase IIb/III clinical trials were halted in 2023 without demonstrating efficacy. Thus, the field is in need of developing novel immunogens and vaccination strategies that induce broadly neutralising antibodies together with potent Fc-dependent effector functions, as well as protective cross-reactive CD4+ and CD8+ T cell responses. Nucleic acid vaccines, particularly mRNA vaccines, have been one of the major groundbreaking advances in the current decade. Nucleic acid vaccines may help recalibrate the HIV vaccine field towards the use of delivery systems that allow the proper expression of immunogens as a sole antigen (i.e., membrane-bound trimeric envelope glycoproteins) or even to be displayed in a multiantigen platform that will be synthesised by the host. In this review, we will summarise how the multiple HIV vaccine strategies pursued in the last 40 years of HIV research have driven current vaccine development, which are the most relevant immunogens identified so far to induce balanced adaptive immune responses, and how they can benefit from the acceptance of nucleic acid vaccines in the market by reducing the limitations of previous delivery systems. The incorporation of nucleic acid vaccines into the current heterogeneous repertoire of vaccine platforms may represent an invaluable opportunity to reignite the fight against HIV. [ABSTRACT FROM AUTHOR]

IntroductionA limited subset of HIV-1 infected adult individuals typically after at least 2-3 years of chronic infection, develop broadly neutralizing antibodies (bnAbs), suggesting that highly conserved neutralizing epitopes on the HIV-1 envelope glycoprotein are difficult for B cell receptors to effectively target, during natural infection. Recent studies have shown the evolution of bnAbs in HIV-1 infected infants.MethodsWe used bulk BCR sequencing (BCR-seq) to profile the B cell receptors from longitudinal samples (3 time points) collected from a rare pair of antiretroviralnaïve, HIV-1 infected pediatric monozygotic twins (AIIMS_329 and AIIMS_330) who displayed elite plasma neutralizing activity against HIV-1.ResultsBCR-seq of both twins revealed convergent antibody characteristics including V-gene use, CDRH3 lengths and somatic hypermutation (SHM). Further, antibody clonotypes with genetic features similar to highly potent bnAbs isolated from adults showed ongoing development in donor AIIMS_330 but not in AIIMS_329, corroborating our earlier findings based on plasma bnAbs responses. An increase in SHM was observed in sequences of the IgA isotype from AIIMS_330.DiscussionThis study suggests that children living with chronic HIV-1 can develop clonotypes of HIV-1 bnAbs against multiple envelope epitopes similar to those isolated from adults, highlighting that such B cells could be steered to elicit bnAbs responses through vaccines aimed to induce bnAbs against HIV-1 in a broad range of people including children.

The development of HIV prophylactic vaccines is facing an impasse, since all phase IIb/III clinical trials were halted in 2023 without demonstrating efficacy. Thus, the field is in need of developing novel immunogens and vaccination strategies that induce broadly neutralising antibodies together with potent Fc-dependent effector functions, as well as protective cross-reactive CD4+ and CD8+ T cell responses. Nucleic acid vaccines, particularly mRNA vaccines, have been one of the major groundbreaking advances in the current decade. Nucleic acid vaccines may help recalibrate the HIV vaccine field towards the use of delivery systems that allow the proper expression of immunogens as a sole antigen (i.e., membrane-bound trimeric envelope glycoproteins) or even to be displayed in a multiantigen platform that will be synthesised by the host. In this review, we will summarise how the multiple HIV vaccine strategies pursued in the last 40 years of HIV research have driven current vaccine development, which are the most relevant immunogens identified so far to induce balanced adaptive immune responses, and how they can benefit from the acceptance of nucleic acid vaccines in the market by reducing the limitations of previous delivery systems. The incorporation of nucleic acid vaccines into the current heterogeneous repertoire of vaccine platforms may represent an invaluable opportunity to reignite the fight against HIV.

HIV-1 envelope glycoprotein (Env) conformation substantially impacts antibody-dependent cellular cytotoxicity (ADCC). Envs from primary HIV-1 isolates adopt a prefusion "closed" conformation, which is targeted by broadly neutralizing antibodies (bnAbs). CD4 binding drives Env into more "open" conformations, which are recognized by non-neutralizing Abs (nnAbs). To better understand Env-Ab and Env-CD4 interaction in CD4+ T cells infected with HIV-1, we simultaneously measured antibody binding and HIV-1 mRNA expression using multiparametric flow cytometry and RNA flow fluorescent in situ hybridization (FISH) techniques. We observed that env mRNA is almost exclusively expressed by HIV-1 productively infected cells that already downmodulated CD4. This suggests that CD4 downmodulation precedes env mRNA expression. Consequently, productively infected cells express "closed" Envs on their surface, which renders them resistant to nnAbs. Cells recognized by nnAbs were all env mRNA negative, indicating Ab binding through shed gp120 or virions attached to their surface. Consistent with these findings, treatment of HIV-1-infected humanized mice with the ADCC-mediating nnAb A32 failed to lower viral replication or reduce the size of the viral reservoir. These findings confirm the resistance of productively infected CD4+ T cells to nnAbs-mediated ADCC and question the rationale of immunotherapy approaches using this strategy., Importance: Antibody-dependent cellular cytotoxicity (ADCC) represents an effective immune response for clearing virally infected cells, making ADCC-mediating antibodies promising therapeutic candidates for HIV-1 cure strategies. Broadly neutralizing antibodies (bNAbs) target epitopes present on the native "closed" envelope glycoprotein (Env), while non-neutralizing antibodies (nnAbs) recognize epitopes exposed upon Env-CD4 interaction. Here, we provide evidence that env mRNA is predominantly expressed by productively infected cells that have already downmodulated cell-surface CD4. This indicates that CD4 downmodulation by HIV-1 precedes Env expression, making productively infected cells resistant to ADCC mediated by nnAbs but sensitive to those mediated by bnAbs. These findings offer critical insights for the development of immunotherapy-based strategies aimed at targeting and eliminating productively infected cells in people living with HIV.

Broadly neutralizing antibodies (bnAbs) targeting the human immunodeficiency virus-1 (HIV-1) have played a crucial role in elucidating and characterizing neutralization-sensitive sites on the HIV-1 envelope spike and in informing vaccine development. Continual advancements in identifying more potent bnAbs, along with their capacity to trigger antibody-mediated effector functions, coupled with modifications to extend their half-life, position them as promising candidates for both HIV-1 treatment and prevention. While current pharmacological interventions have made significant progress in managing HIV-1 infection and enhancing quality of life, no definitive cure or vaccines have been developed thus far. Standard treatments involve daily oral anti-retroviral therapy, which, despite its efficacy, can lead to notable long-term side effects. Recent clinical trial data have demonstrated encouraging therapeutic and preventive potential for bnAb therapies in both HIV-1-infected individuals and those without the infection. This review provides an overview of the advancements in HIV-1-specific bnAbs and discusses the insights gathered from recent clinical trials regarding their application in treating and preventing HIV-1 infection., Competing Interests: The authors declare that no competing interest exists.

Antibodies, and notably immunoglobulins A (IgA), are paramount in mucosal tissues as protective immune effectors against invading pathogens and immunomodulators of the microbiota. Upon human immunodeficiency virus type 1 (HIV-1) infection, systemic and mucosal IgA antibody responses are triggered. While naturally produced serum HIV-1 envelope protein-specific IgA are quantitatively and qualitatively weaker than their IgG counterparts, they also possess antiviral properties including neutralization and Fc-dependent functions. IgA neutralizers can block HIV-1 mucosal transmission in animal models, indicating that their elicitation by vaccination would be an important component for preventing infection. Moreover, the first genuine IgA broadly HIV-1 neutralizing antibodies (bNAbs) were recently identified in certain individuals living with HIV-1. Vaccine-based induction of IgA bNAbs potentially protective at the mucosal level is therefore conceivable. Hence, research efforts must therefore be undertaken to better understand their development and functions. In this review, we present the general functions of IgA in homeostasis and antimicrobial immunity and discuss their involvement in the antibody responses against HIV-1.

Individuals who clear primary hepatitis C virus (HCV) infections clear subsequent reinfections more than 80% of the time, but the mechanisms are poorly defined. Here, we used HCV variants and plasma from individuals with repeated clearance to characterize longitudinal changes in envelope glycoprotein E2 sequences, function, and neutralizing antibody (NAb) resistance. Clearance of infection was associated with early selection of viruses with NAb resistance substitutions that also reduced E2 binding to CD81, the primary HCV receptor. Later, peri-clearance plasma samples regained neutralizing capacity against these variants. We identified a subset of broadly NAbs (bNAbs) for which these loss-of-fitness substitutions conferred resistance to unmutated bNAb ancestors but increased sensitivity to mature bNAbs. These data demonstrate a mechanism by which neutralizing antibodies contribute to repeated immune-mediated HCV clearance, identifying specific bNAbs that exploit fundamental vulnerabilities in E2. The induction of bNAbs with these specificities should be a goal of HCV vaccine development. [Display omitted] • Public substitutions in HCV E2 arose independently in multiple cleared infections • E2 substitutions selected by NAbs led to viral fitness loss • These substitutions conferred hypersensitivity to some broadly neutralizing antibodies • NAbs targeting these vulnerable E2 sites should be a goal of HCV vaccine development Frumento et al. identify a mechanism of antibody-mediated antiviral protection by which neutralizing antibodies evolve to select and then exploit deleterious escape mutations in the HCV envelope glycoprotein E2. These mutations selected by unmutated ancestor broadly neutralizing antibodies (bNAbs) can confer hypersensitivity to mature bNAbs and loss of viral replication fitness, contributing to repeated immune-mediated clearance of HCV infection. [ABSTRACT FROM AUTHOR]