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Current Opinion in HIV and AIDS Jul 2019The review recalls recent findings regarding the induction of vaccinal effects by HIV-1 broadly neutralizing antibodies (bNAbs) and highlights potential therapeutic... (Review)
Review
PURPOSE OF REVIEW
The review recalls recent findings regarding the induction of vaccinal effects by HIV-1 broadly neutralizing antibodies (bNAbs) and highlights potential therapeutic strategies to exploit such immunomodulatory properties.
RECENT FINDINGS
Studies in different animal models have shown that mAbs can generate long-lasting protective immunity. Induction of this vaccinal effect by HIV-1 bNAbs has also been more recently reported in animal models of HIV-1 infection. Notably, bNAbs treatment of macaques infected with the chimeric simian-human immunodeficiency virus (SHIV) improved both humoral and cellular adaptive immune responses that contributed to disease control. Importantly, this concept has been extended to HIV-1-infected patients as enhancement of humoral responses was recently reported in HIV-1 patients treated with bNAbs. Studies aiming at elucidating the mechanisms underlying these immunomodulatory properties of bNAbs have identified a role for immune complexes in shaping immune responses against HIV-1. They also highlight different Fc (fragment crystallizable) region effector functions that might be required for the enhancement of HIV-1 immune responses upon bNAbs treatment.
SUMMARY
HIV-1 bNAbs can elicit protective adaptive immune responses through mechanisms involving multiple cellular and molecular actors of the immune system. Harnessing these mechanisms will be crucial to achieve protective immunity against HIV-1 infection by bNAbs.
Topics: Animals; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 30973419
DOI: 10.1097/COH.0000000000000555 -
The Lancet. HIV Oct 2023
Topics: Humans; HIV Infections; Broadly Neutralizing Antibodies; Acquired Immunodeficiency Syndrome; HIV Antibodies; HIV-1
PubMed: 37802563
DOI: 10.1016/S2352-3018(23)00172-8 -
Science Translational Medicine May 2023Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1...
Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1 remission. Autologous neutralizing antibodies (aNAbs) represent a key adaptive immune response in people living with HIV-1. We aimed to investigate the role of aNAbs in shaping post-ATI HIV-1 rebound variants. We performed single-genome amplification of HIV-1 from pre-ART and post-ATI plasma samples of 12 individuals who initiated ART early after infection. aNAb activity was quantified using pseudoviruses derived from the most common plasma variant, and the serum dilution that inhibited 50% of viral infections was determined. aNAb responses matured while participants were on suppressive ART, because on-ART plasma and purified immunoglobulin G (IgG) demonstrated improved neutralizing activity against pre-ART HIV-1 strains when compared with pre-ART plasma or purified IgG. Post-ATI aNAb responses exerted selective pressure on the rebounding viruses, because the post-ATI HIV-1 strains were more resistant to post-ATI plasma neutralization compared with the pre-ART virus. Several pre-ATI features distinguished post-treatment controllers from noncontrollers, including an infecting HIV-1 sequence that was more similar to consensus HIV-1 subtype B, more restricted proviral diversity, and a stronger aNAb response. Post-treatment control was also associated with the evolution of distinct N-glycosylation profiles in the HIV-1 envelope. In summary, aNAb responses appeared to mature after early initiation of ART and applied selective pressure on rebounding viruses. The combination of aNAb activity with select HIV-1 sequence and reservoir features identified individuals with a greater chance of post-treatment control.
Topics: Humans; Antibodies, Neutralizing; Anti-Retroviral Agents; HIV Infections; Proviruses; Immunoglobulin G; HIV Antibodies; Viral Load
PubMed: 37163616
DOI: 10.1126/scitranslmed.abq4490 -
Trends in Immunology Mar 2021'Reverse vaccinology 2.0' aims to rationally reproduce template antibody responses, such as broadly neutralizing antibodies against human immunodeficiency virus-1. While... (Review)
Review
'Reverse vaccinology 2.0' aims to rationally reproduce template antibody responses, such as broadly neutralizing antibodies against human immunodeficiency virus-1. While observations of antibody convergence across individuals support the assumption that responses may be replicated, the diversity of humoral immunity and the process of antibody selection are rooted in stochasticity. Drawing from experience with in vitro antibody engineering by directed evolution, we consider how antibody selection may be driven, as in germline-targeting vaccine approaches to elicit broadly neutralizing antibodies and illustrate the potential consequences of over-defining a template antibody response. We posit that the prospective definition of template antibody responses and the odds of replicating them must be considered within the randomness of humoral immunity.
Topics: Antibodies, Neutralizing; Antibody Formation; HIV Antibodies; HIV-1; Humans; Prospective Studies
PubMed: 33514459
DOI: 10.1016/j.it.2021.01.001 -
Cell Chemical Biology May 2022Highly active antiretroviral therapy currently used for HIV/AIDS has significantly increased the life expectancy of HIV-infected individuals. It has also improved the... (Review)
Review
Highly active antiretroviral therapy currently used for HIV/AIDS has significantly increased the life expectancy of HIV-infected individuals. It has also improved the quality of life, reduced mortality, and decreased the incidence of AIDS and HIV-related conditions. Currently, however, affected individuals are typically on a lifetime course of several therapeutic drugs, all with the potential for associated toxicity and emergence of resistance. This calls for development of novel, potent, and broad anti-HIV agents able to stop the spread of HIV/AIDS. Significant progress has been made toward identification of anti-HIV-1 broadly neutralizing antibodies (bNAbs). However, antibody-based drugs are costly to produce and store. Administration (by injection only) and other obstacles limit clinical use. In recent years, several highly promising small-molecule HIV-1 entry inhibitors targeting the epitopes of bNAbs have been developed. These newly developed compounds are the focus of the present article.
Topics: Antibodies, Neutralizing; Broadly Neutralizing Antibodies; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Humans; Quality of Life; env Gene Products, Human Immunodeficiency Virus
PubMed: 35353988
DOI: 10.1016/j.chembiol.2022.03.009 -
Journal of Chemical Information and... Jan 2022The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of...
The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of HIV infection. Understanding the b12-gp120 binding mechanism under physiological conditions may assist the development of more broadly effective antibodies. In this work, the main conformations and interactions between the receptor-binding domain (RBD) of spike glycoprotein gp120 of HIV-1 and the IgG1-b12 mAb are studied. Accelerated molecular dynamics (aMD) and ab initio hybrid molecular dynamics have been combined to determine the most persistent interactions between the most populated conformations of the antibody-antigen complex under physiological conditions. The results show the most persistent receptor-binding mapping in the conformations of the antibody-antigen interface in solution. The binding-free-energy decomposition reveals a small enhancement in the contribution played by the CDR-H3 region to the b12-gp120 interface compared to the crystal structure.
Topics: Amino Acid Sequence; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Immunoglobulin G
PubMed: 34971312
DOI: 10.1021/acs.jcim.1c01143 -
Archives of Virology Jan 2021This review argues that the three popular concepts of design, rationality and reductionism, which guided vaccine research for many years, actually contributed to the... (Review)
Review
This review argues that the three popular concepts of design, rationality and reductionism, which guided vaccine research for many years, actually contributed to the inability of vaccinologists to develop an effective HIV vaccine. The strong goal-directed intentionality inherent in the concept of design together with excessive confidence in the power of rational thinking convinced investigators that the accumulated structural knowledge on HIV epitopes, derived from crystallographic studies of complexes of neutralizing antibodies bound to HIV Env epitopes, would allow them to rationally design complementary immunogens capable of inducing anti-HIV protective antibodies. This strategy failed because it was not appreciated that the structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not represent structures present in the free disordered molecules before they had interacted. In addition, reductionist thinking led investigators to accept that biology could be reduced to chemistry, and this made them neglect the fundamental difference between chemical antigenicity and biological immunogenicity. As a result, they did not investigate which inherent constituents of immune systems controlled the induction of protective antibodies and focused instead only on the steric complementarity that exists between bound epitopes and paratopes.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Epitopes; HIV; HIV Antibodies; Humans
PubMed: 33251565
DOI: 10.1007/s00705-020-04884-0 -
Science (New York, N.Y.) Dec 2019Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of...
Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer-based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.
Topics: AIDS Vaccines; Adoptive Transfer; Amino Acid Sequence; Animals; B-Lymphocytes; Broadly Neutralizing Antibodies; Complementarity Determining Regions; Directed Molecular Evolution; Disease Models, Animal; HEK293 Cells; HIV Antibodies; Humans; Immunogenicity, Vaccine; Mice; Mice, Knockout; Precursor Cells, B-Lymphoid; env Gene Products, Human Immunodeficiency Virus
PubMed: 31672916
DOI: 10.1126/science.aax4380 -
Science (New York, N.Y.) Dec 2022Clinical trial shows that an HIV vaccine can elicit rare antibodies, but there is more to do.
Clinical trial shows that an HIV vaccine can elicit rare antibodies, but there is more to do.
Topics: Humans; AIDS Vaccines; Broadly Neutralizing Antibodies; Genes, Immunoglobulin; Germ Cells; HIV Antibodies; HIV-1; Immunoglobulins; Vaccination; Randomized Controlled Trials as Topic
PubMed: 36454831
DOI: 10.1126/science.adf3722 -
Monoclonal Antibodies in... Dec 20221F7 is a monoclonal antibody that recognizes an idiotypic determinant expressed on primate antibodies binding to HIV-1 and hepatitis C proteins. This monoclonal antibody... (Review)
Review
1F7 is a monoclonal antibody that recognizes an idiotypic determinant expressed on primate antibodies binding to HIV-1 and hepatitis C proteins. This monoclonal antibody was used as a tool to dissect the immune response in humans infected with HIV-1 and hepatitis B. Furthermore, 1F7 was also used to manipulate the immune response against HIV-1 in macaques. The generation of a monoclonal antibody describing a network suggests similar antibodies could be developed as tools to dissect entangled networks in autoimmune diseases and allergic reactions. This review discusses the body of work done with 1F7 in the light of contemporary immunology.
Topics: Animals; Humans; HIV Antibodies; Antibodies, Monoclonal; Immunoglobulin Idiotypes; HIV-1
PubMed: 36520586
DOI: 10.1089/mab.2022.0003