The antibody response in HIV-1-infected donors Purpose of review Although the goal of preventive HIV vaccine design is primarily the induction of broadly neutralizing antibodies (bNAbs), recent evidence suggests that a protective response will also benefit from Fc effector functions. Here, we provide an update on the antibody response to HIV infection, including both Fab and Fc-mediated antibody responses. We also highlight recent studies showing the interplay between these functions, focusing primarily on studies published in the last year. Recent findings Identification and characterization of bNAb donors continues to provide insights into viral factors that are potentially translatable to vaccine design. Improved and more diverse measures of Fc effector function, and modulators thereof, are enabling a deeper understanding of their role in infection. New data providing mechanistic links between the innate and adaptive humoral immune responses are creating exciting opportunities for vaccine strategies, with the aim of eliciting a polyfunctional protective response. Summary New insights into the overall humoral response to HIV infection are defining diverse and synergistic mechanisms required for antibody protection from HIV through vaccination.

B-cell abnormalities in HIV-1 infection: roles for IgG3 and T-bet Purpose of review Numerous B-cell abnormalities in HIV-1 infection have been described over the past three decades yet have remained poorly defined mechanistically. We review recent studies that describe mechanisms of B-cell dysregulation in chronic HIV-1 infection associated with IgG3 and T-bet. Recent findings HIV-1 infection causes hypergammaglobulinemia and dysregulation of B-cell populations, including the expansion during chronic viremia of functionally impaired tissue-like memory (TLM) B cells. TLM B cells and B cells in other conditions of chronic activation and inflammation with similar phenotypes are characterized by increased expression of the transcription factor T-bet and preferential immunoglobulin class-switching to IgG3. However, defects in B-cell function during chronic HIV-1 viremia are also associated with the binding of soluble IgG3 to IgM-expressing B cells, with the highest intensities observed on TLM B cells. The consequence of IgG3 binding to TLM B cells is increased clustering of the IgM B-cell receptor and decreased response to stimulation. Summary The identification of T-bet and IgG3 as the regulators of B-cell function in chronic HIV-1 viremia could provide new targets for therapeutic intervention aimed at reversing the damaging effects of HIV-1-associated chronic immune activation.

Germinal centers B-cell reaction and T follicular helper cells in response to HIV-1 infection Purpose of review This review aims to summarize the recent findings on germinal center B-cell reaction and Tfh cells in HIV-1 infection, with particular emphasis on the spatial organization of the germinal center, follicular cell regulation, and cellular alterations resulting from HIV infection. Recent findings HIV-specific bNAbs are generated by iterative cycles of B-cell maturation supported by GC environment. Recent observations underline that germinal center structural alterations at the earliest stages of HIV infection could impact Tfh cell and germinal center B-cell homeostasis, thus preventing the rise of efficient humoral immunity. Moreover, despite ART treatment, HIV-derived antigens persist, particularly in follicular CD4+ T cells. Antigenic persistence and variability lead to unregulated chronic stimulation. In this context, regulation of the germinal center appears of special interest. In addition to follicular T-regulatory cells (Tfr), new potent regulators of germinal center reaction, such as follicular CD8 T and NK cells have been recently identified. Summary Altogether these new data provide a better understanding on how HIV infection severely impacts germinal center reaction. Here we propose several therapeutic approaches to promote the bNAb development in HIV-infected patients by improving the preservation of germinal center architecture and its regulation.

Systems serology for decoding infection and vaccine-induced antibody responses to HIV-1 Purpose of review Experimental and analytical advances have enabled systematic, high-resolution studies of humoral immune responses, and are beginning to define mechanisms of immunity to HIV. Recent findings High-throughput, information-rich experimental and analytical methods, whether genomic, proteomic, or transcriptomic, have firmly established their value across a diversity of fields. Consideration of these tools as trawlers in ‘fishing expeditions’ has faded as ‘data-driven discovery’ has come to be valued as an irreplaceable means to develop fundamental understanding of biological systems. Collectively, studies of HIV-1 infection and vaccination including functional, biophysical, and biochemical humoral profiling approaches have provided insights into the phenotypic characteristics of individual and pools of antibodies. Relating these measures to clinical status, protection/efficacy outcomes, and cellular profiling data using machine learning has offered the possibility of identifying unanticipated mechanisms of action and gaining insights into fundamental immunological processes that might otherwise be difficult to decipher. Summary Recent evidence establishes that systematic data collection and application of machine learning approaches can identify humoral immune correlates that are generalizable across distinct HIV-1 immunogens and vaccine regimens and translatable between model organisms and the clinic. These outcomes provide a strong rationale supporting the utility and further expansion of these approaches both in support of vaccine development and more broadly in defining mechanisms of immunity.

A role for antibodies in natural HIV control Purpose of review Rare patients naturally control HIV replication without antiretroviral therapy. Understanding the mechanisms implicated in natural HIV control will inform the development of immunotherapies against HIV. Elite controllers are known for developing efficient antiviral T-cell responses, but recent findings suggest that antibody responses also play a significant role in HIV control. We review the key studies that uncovered a potent memory B-cell response and highly functional anti-HIV antibodies in elite controllers, and explore the mechanisms that may account for the distinct properties of their humoral response. Recent findings Elite controllers maintain a large HIV-specific memory B-cell pool that is sustained by efficient T follicular helper function. Neutralizing antibody rarely show high titers in controllers, but seem capable, at least in certain cases, of neutralizing contemporaneous viral strains. In addition, elite controllers display a unique HIV-specific antibody profile in terms of isotype, antigen specificity, and glycosylation pattern, resulting in polyfunctional antibody effector functions that may promote infected cell lysis and prime effectors of the antiviral immune response. Summary Lessons from elite controller studies argue for the importance of integrating the many parameters defining a polyfunctional antibody response when evaluating candidate vaccines and immunotherapeutic approaches directed at HIV.

HIV-1 antibodies in prevention of transmission Purpose of review To present the data that suggest that antibodies to HIV may prevent HIV-1 infection. Recent findings Many human monoclonal broadly neutralizing antibodies (bnAbs) have been isolated over the last decade. Numerous experiments of passive immunization in nonhuman primate models have allowed to accumulate strong evidences that bnAbs, opposed to nonneutralizing antibodies, are the best candidates to prevent HIV-1 infection. bnAbs counteract HIV-1 by both blocking the virus at the portal of entry and clearing rapidly viral foci established at distance after dissemination of the virus following infection. Cocktails of bnAbs or modified bi/trispecific antibodies will be necessary to counter the large and evolving antigenic diversity of the HIV-1 species. Two large multicenter phase IIb clinical trials have been initiated. Even if they are not conducted with the most recent and most potent bnAb, the results which are expected in 2022 will inform us on the real potency of bnAbs at preventing HIV-1 acquisition in the real life. Summary If these trials demonstrate the efficacy of bnAbs, they will open the trail toward new strategies for preexposure prophylaxis, eventually postexposure prophylaxis and prevention of mother-to-child transmission.

Correlates of broadly neutralizing antibody development Purpose of review Broadly neutralizing antibodies (bnAbs) are considered a key component of an effective HIV-1 vaccine, but despite intensive efforts, induction of bnAbs by vaccination has thus far not been possible. Potent bnAb activity is rare in natural infection and a deeper understanding of factors that promote or limit bnAb evolution is critical to guide bnAb vaccine development. This review reflects on recent key discoveries on correlates of bnAb development and discusses what further insights are needed to move forward. Recent findings An increasing number of parameters have been implicated to influence bnAb development in natural infection. Most recent findings highlight a range of immune factors linked with bnAb evolution. Novel approaches have brought exciting progress in defining signatures of the viral envelope associated with bnAb activity. Summary Focused efforts of recent years have unraveled a multiply layered process of HIV-1 bnAb development. As it is understood today, bnAb evolution can be triggered and influenced by a range of factors and several different pathways may exist how bnAb induction and maturation can occur. To capitalize on the gained knowledge, future research needs to validate factors to identify independent drivers of bnAb induction to advance vaccine design.

Coevolution of HIV-1 and broadly neutralizing antibodies Purpose of review Exploring the molecular details of the coevolution of HIV-1 Envelope with broadly neutralizing antibodies (bNAbs) in infected individuals over time provides insights for vaccine design. Since mid-2017, the number of individuals described in such publications has nearly tripled. New publications have extended such studies to new epitopes on Env and provided more detail on previously known sites. Recent findings Studies of two donors – one of them an infant, the other with three lineages targeting the same site – has deepened our understanding of V3-glycan-directed lineages. A V2-apex-directed lineage showed remarkable similarity to a lineage from a previously described donor, revealing general principles for this class of bNAbs. Understanding development of CD4 binding site antibodies has been enriched by the study of a VRC01-class lineage. Finally, the membrane-proximal external region is a new addition to the set of epitopes studied in this manner, with early development events explored in a study of three lineages from a single donor. Summary These studies provide templates for immunogen design to elicit bNAbs against a widened set of epitopes, generating new directions in the quest for an HIV vaccine.

Targeting broadly neutralizing antibody precursors: a naïve approach to vaccine design Purpose of review It is believed that broadly neutralizing antibodies (bNAbs) will be an important component of an effective HIV-1 vaccine. Several immunogens have been designed that can target specific precursor B cells as a first step in a vaccine strategy to elicit bNAbs. Recent findings Germline-targeting immunogens have been developed that specifically engage precursors of reproducible classes of anti-HIV antibodies, such as VRC01-class and apex-directed bNAbs. However, these precursors represent only a small portion of the immune repertoire and any antigen will inherently present off-target epitopes to the immune system that may confound bNAb development. Novel animal models are being utilized to understand the competitive fitness of bNAb precursors in the context of immunization with germline-targeting immunogens. In parallel, immunogen design efforts are being pursued to favor the development of bNAb responses over off-target responses following immunization. New studies of bNAb precursor interactions with glycosylated Env variants can inform prime-boost regimens geared towards accelerating bNAb development. Summary Germline-targeting immunogens hold promise as a first step in eliciting a bNAb response through vaccination. A better understating of how efficiently germline-targeting immunogens can specifically target rare bNAb precursors is emerging. In addition, a more comprehensive structure-based understanding of critical barriers to bNAb elicitation, as well as commonalities between bNAb classes can further inform vaccine design.