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Expert Review of Vaccines Nov 2019: Despite intensive research efforts, there is still no effective prophylactic vaccine available against HIV-1. Currently, substantial efforts are devoted to the... (Review)
Review
: Despite intensive research efforts, there is still no effective prophylactic vaccine available against HIV-1. Currently, substantial efforts are devoted to the development of vaccines aimed at inducing broadly neutralizing antibodies (bNAbs), which are capable of neutralizing most HIV-1 strains. All bNAbs target the HIV-1 envelope glycoprotein (Env), but Env immunizations usually only induce neutralizing antibodies (NAbs) against the sequence-matched virus and not against other strains.: We describe the different strategies that have been explored to improve the breadth and potency of anti-HIV-1 NAb responses. The discussed strategies include the application of engineered Env immunogens, optimization of (bNAb) epitopes, different cocktail and sequential vaccination strategies, nanoparticles and nucleic acid-based vaccines.: A combination of the strategies described in this review and future approaches are probably needed to develop an effective HIV-1 vaccine that can induce broad, potent and long-lasting NAb responses.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Antibody Formation; HIV Antibodies; HIV-1; Humans; Treatment Outcome; env Gene Products, Human Immunodeficiency Virus
PubMed: 31791150
DOI: 10.1080/14760584.2019.1690458 -
[The affinity maturation, characteristics and application of HIV-1 broadly neutralizing antibodies].Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Feb 2022Hundreds of broadly neutralizing antibodies(bNAbs) were successfully isolated from long-term nonprogression(LTNP) of human immunodeficiency virus type 1(HIV-1) infected...
Hundreds of broadly neutralizing antibodies(bNAbs) were successfully isolated from long-term nonprogression(LTNP) of human immunodeficiency virus type 1(HIV-1) infected individuals. Some bNAbs were illustrated could reduce the viral load and the risk of HIV-1 infection. Today, HIV-1 bNAbs are at the center of vaccine development and passive immunization treatment. Usually, the activity of neutralizing antibodies depends on the epitope. The affinity of neutralizing antibodies also plays a vital role in its inhibitory effect. Multiple affinity maturation in vivo actually provides the broad and potent neutralizing activity of HIV-1 bNAbs. When high affinity HIV-1 bNAbs applied in clinic, it can help immune system to remove virus with lower dosage and fewer side effect. While affinity maturation, HIV-1 bNAbs shows unique characteristics, such as extensive of somatic hypermutation(SHM), in-frame insertion and deletion and long CDR 3 region of heavy chain. The key points in the progress that HIV-1 bNAbs affinity maturation will help us understand the relationship between antibodies neutralizing capability and its characteristics.It also potentially provide a reference to design effective HIV-1 immunogen.
Topics: Antibodies, Neutralizing; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 35184454
DOI: 10.3760/cma.j.cn112150-20210623-00606 -
Current HIV Research 2021The diagnosis of HIV infection is important among different groups. Moreover, combination antiretroviral therapy is used to treat HIV-1, but it cannot eradicate the... (Comparative Study)
Comparative Study
BACKGROUND
The diagnosis of HIV infection is important among different groups. Moreover, combination antiretroviral therapy is used to treat HIV-1, but it cannot eradicate the infection. Thus, the development of therapeutic vaccines, along with antiretroviral therapy, is recommended. This study evaluates the values of four HIV proteins as antigen candidates in therapeutic vaccine design as well as a possible diagnostic marker for HIV infection in humans.
METHODS
In this study, the HIV-1 Tat and Rev regulatory proteins and structural Gp120 and p24 proteins were generated in E. coli expression system. Their immunogenicity was evaluated in BALB/ c mice using homologous and heterologous prime/boost strategies. Moreover, the detection of anti- HIV IgG antibodies against these recombinant proteins was assessed in untreated (Naïve/ HIV-infected), treated, and drug-resistant patients compared to the healthy (control) group as a possible diagnostic marker for HIV infection.
RESULTS
In humans, our results showed that among HIV-1 proteins, anti-Gp120 antibody was not detected in treated individuals compared to the healthy (control) group. The levels of anti-Gp120 antibody were significantly different between the treated group and Naïve as well as drug-resistant subjects. Moreover, the level of anti-p24 antibody was significantly lower in the treated group than the Naive group. In mice, the results of immunization indicated that the Rev antigen could significantly induce IgG2a, IgG2b, and IFN-γ secretion aimed at Th1 response as well as Granzyme B generation as CTL activity in comparison with other antigens. Furthermore, the heterologous DNA prime/ protein boost regimen was more potent than the homologous regimen for stimulation of cellular immunity.
CONCLUSION
Briefly, the levels of both anti-Gp120 and anti-p24 antibodies can be considered for the diagnosis of the HIV-infected individuals in different groups compared to the healthy group. Moreover, among four recombinant proteins, Rev elicited Th1 cellular immunity and CTL activity in mice as an antigen candidate in therapeutic vaccine development.
Topics: AIDS Vaccines; Animals; Biomarkers; HIV Antibodies; HIV Antigens; HIV Infections; Healthy Volunteers; Humans; Mice; Mice, Inbred BALB C; Models, Animal; Vaccination; Viral Structural Proteins
PubMed: 33243125
DOI: 10.2174/1570162X18999201125212131 -
Bulletin of Experimental Biology and... Apr 2022HIV-1 env-pseudoviruses are a useful tool in the search for antiviral drugs (entry inhibitors) and evaluation of the efficacy of HIV-1 vaccines. Given the high genetic...
HIV-1 env-pseudoviruses are a useful tool in the search for antiviral drugs (entry inhibitors) and evaluation of the efficacy of HIV-1 vaccines. Given the high genetic variability of HIV-1, it is necessary to regularly update the panels of pseudoviruses in accordance with the emergence of new strains. Based on genetic variants of HIV-1 circulating in the regions of the Siberian Federal District, 13 HIV-1 env-pseudoviruses of recombinant form CRF63_02A and subtype A6 were obtained. Most pseudoviruses have been shown to be sensitive to neutralization by bnAbs VRC01, PGT126, and 10E8, moderately sensitive to bnAbs PG9 and 4E10, and resistant to bnAbs 2G12, PG16, and 2F5. All obtained variants of pseudoviruses are CCR5-tropic.
Topics: Antibodies, Neutralizing; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans; Neutralization Tests
PubMed: 35501651
DOI: 10.1007/s10517-022-05466-7 -
Frontiers in Immunology 2022Strategies to reduce the human immunodeficiency virus (HIV) reservoir are urgently required. The antibody-dependent cellular cytotoxicity (ADCC)-mediating anti-HIV...
Strategies to reduce the human immunodeficiency virus (HIV) reservoir are urgently required. The antibody-dependent cellular cytotoxicity (ADCC)-mediating anti-HIV antibodies have shown an association with HIV control. We assessed if such antibodies can be generated and whether the generated antibodies can facilitate the reduction of reactivated HIV reservoir. We isolated HIV-1-gp140-specific memory B cells from HIV-1-infected long-term non-progressors (LTNPs) with or without plasma ADCC and cultured them to generate anti-HIV antibodies. The ability of the generated antibodies to mediate ADCC and facilitate NK cell-mediated lysis of reactivated HIV reservoir was assessed by the rapid fluorometric antibody-dependent cellular cytotoxicity assay and a flow-based novel latency reduction assay, respectively. All LTNPs showed the presence of gp140-specific memory B cells [median: 0.79% (0.54%-1.225%)], which were successfully differentiated into plasma cells [median 72.0% (68.7-82.2%)] in an culture and secreted antibodies [median OD: 0.253 (0.205-0.274)]. The HIV-gp140-specific antibodies were generated from 11/13 LTNPs irrespective of their plasma ADCC status. The generated antibodies from LTNPs with plasma ADCC showed higher ADCC potency (median: 37.6%, IQR: 32.95%-51%) and higher reduction in reactivated HIV reservoir (median: 62.5%, IQR: 58.71%-64.92%) as compared with the antibodies generated from LTNPs without plasma ADCC (ADCC: median: 8.85%, IQR: 8%-9.7%; and % p24 reduction median: 13.84, IQR: 9.863%-17.81%). The potency of these antibodies to reduce latent reservoir was two-fold higher than the respective plasma ADCC. The study showed that the potent ADCC-mediating antibodies could be generated from memory B cells of the LTNPs with plasma ADCC activity. These antibodies also showed potent ability to facilitate NK cell-mediated lysis of reactivated HIV reservoirs. It also indicated that memory B cells from individuals with plasma ADCC activity should be preferentially used for such antibody generation. The important role of these antibodies in the reduction of latent reservoirs needs to be further evaluated as a useful strategy to obtain a functional cure for HIV infection.
Topics: Antibody-Dependent Cell Cytotoxicity; Elite Controllers; HIV Antibodies; HIV Infections; HIV-1; Humans; env Gene Products, Human Immunodeficiency Virus
PubMed: 35309295
DOI: 10.3389/fimmu.2022.844610 -
PLoS Pathogens Apr 2022A key challenge for the development of a cure to HIV-1 infection is the persistent viral reservoir established during early infection. Previous studies using Toll-like...
A key challenge for the development of a cure to HIV-1 infection is the persistent viral reservoir established during early infection. Previous studies using Toll-like receptor 7 (TLR7) agonists and broadly neutralizing antibodies (bNAbs) have shown delay or prevention of viral rebound following antiretroviral therapy (ART) discontinuation in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques. In these prior studies, ART was initiated early during acute infection, which limited the size and diversity of the viral reservoir. Here we evaluated in SHIV-infected rhesus macaques that did not initiate ART until 1 year into chronic infection whether the TLR7 agonist vesatolimod in combination with the bNAb PGT121, formatted either as a human IgG1, an effector enhanced IgG1, or an anti-CD3 bispecific antibody, would delay or prevent viral rebound following ART discontinuation. We found that all 3 antibody formats in combination with vesatolimod were able to prevent viral rebound following ART discontinuation in a subset of animals. These data indicate that a TLR7 agonist combined with antibodies may be a promising strategy to achieve long-term ART-free HIV remission in humans.
Topics: Animals; Anti-Retroviral Agents; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Immunoglobulin G; Macaca mulatta; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Toll-Like Receptor 7; Viral Load
PubMed: 35452496
DOI: 10.1371/journal.ppat.1010467 -
Current Opinion in HIV and AIDS Sep 2020Recent work defining Fc-mediated effector functions for both viral control and protection against infection is summarized and considered along with new strategies to... (Review)
Review
PURPOSE OF REVIEW
Recent work defining Fc-mediated effector functions for both viral control and protection against infection is summarized and considered along with new strategies to drive robust Fc-mediated responses.
RECENT FINDINGS
In new human and nonhuman primate (NHP) vaccine trials as well as studies of natural infection, Fc-mediated effector responses have sometimes been observed to correlate with decreased risk of infection or with better clinical outcomes, suggesting a potential role for these responses in HIV-1 prevention and therapy. Recent highlights include use of antibody-dependent cellular cytotoxicity-sensitizing CD4-induced mimetic compounds, novel V1V2 immunogens, passive transfer studies, and vaccine regimens that successfully elicited Fc-mediated responses and were reported to decrease risk of infection in challenge studies in NHPs. Lastly, detailed studies of IgG3 forms of HIV-specific antibodies have reported that both neutralizing and Fc-mediated responses can be increased relative to the more prevalent IgG1 subclass.
SUMMARY
Successful harmonization of neutralizing and Fc-mediated responses may make key contributions to the goal of reducing HIV-1 infection via active and passive vaccination. New studies continue to highlight the importance of Fc-mediated antibody responses as correlates of decreased risk of infection and suggest enhanced phagocytosis is a potential mechanism of reduced risk of infection associated with human IgG3 responses. Results from recent studies may help guide the rational design of therapies and vaccines that aim to specifically leverage antibody effector function.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunoglobulin Fc Fragments
PubMed: 32675573
DOI: 10.1097/COH.0000000000000638 -
Cell Host & Microbe Apr 2020Recombinant HIV-1 envelope (Env) glycoproteins of ever-increasing sophistication have been evaluated as vaccine candidates for over 30 years. Structurally defined mimics... (Review)
Review
Recombinant HIV-1 envelope (Env) glycoproteins of ever-increasing sophistication have been evaluated as vaccine candidates for over 30 years. Structurally defined mimics of native trimeric Env glycoproteins (e.g., SOSIP trimers) present multiple epitopes for broadly neutralizing antibodies (bNAbs) and their germline precursors, but elicitation of bNAbs remains elusive. Here, we argue that the interactions between Env and the immune system render it exceptional among viral vaccine antigens and hinder its immunogenicity in absolute and comparative terms. In other words, Env binds to CD4 on key immune cells and transduces signals that can compromise their function. Moreover, the extensive array of oligomannose glycans on Env shields peptidic B cell epitopes, impedes the presentation of T helper cell epitopes, and attracts mannose binding proteins, which could affect the antibody response. We suggest lines of research for assessing how to overcome obstacles that the exceptional features of Env impose on the creation of a successful HIV-1 vaccine.
Topics: AIDS Vaccines; Adaptive Immunity; Antibodies, Neutralizing; B-Lymphocytes; CD4 Antigens; Epitopes, B-Lymphocyte; HIV Antibodies; HIV-1; Immunity, Innate; Mannose; Membrane Glycoproteins; Molecular Mimicry; Protein Binding; Protein Multimerization; T-Lymphocytes; env Gene Products, Human Immunodeficiency Virus
PubMed: 32272076
DOI: 10.1016/j.chom.2020.03.018 -
Frontiers in Immunology 2021Despite the benefits achieved by the widespread availability of modern antiretroviral therapy (ART), HIV RNA integration into the host cell genome is responsible for the... (Review)
Review
Despite the benefits achieved by the widespread availability of modern antiretroviral therapy (ART), HIV RNA integration into the host cell genome is responsible for the creation of latent HIV reservoirs, and represents a significant impediment to completely eliminating HIV infection in a patient modern ART alone. Several methods to measure HIV reservoir size exist; however, simpler, cheaper, and faster tools are required in the quest for total HIV cure. Over the past few years, measurement of HIV-specific antibodies has evolved into a promising option for measuring HIV reservoir size, as they can be measured simple, well-known techniques such as the western blot and enzyme-linked immunosorbent assay (ELISA). In this article, we re-visit the dynamic evolution of HIV-1-specific antibodies and the factors that may influence their levels in the circulation of HIV-positive individuals. Then, we describe the currently-known relationship between HIV-1-specific antibodies and HIV reservoir size based on study of data from contemporary literature published during the past 5 years. We conclude by highlighting current trends, and discussing the individual HIV-specific antibody that is likely to be the most reliable antibody for potential future utilization for quantification of HIV reservoir size.
Topics: Biomarkers; Enzyme-Linked Immunosorbent Assay; Feasibility Studies; HIV Antibodies; HIV Seropositivity; HIV-1; Humans; RNA, Viral; Viral Load; Virus Latency; Virus Replication
PubMed: 34858439
DOI: 10.3389/fimmu.2021.786341 -
Frontiers in Immunology 2022A major barrier in the use of humanized mice as models of HIV-1 (HIV) infection is the inadequate generation of virus-specific antibody responses. Humanized DRAGA...
A major barrier in the use of humanized mice as models of HIV-1 (HIV) infection is the inadequate generation of virus-specific antibody responses. Humanized DRAGA (hDRAGA) mice generate antigen-specific class switched antibodies to several pathogens, but whether they do so in HIV infection and the extent to which their secondary lymphoid tissues (sLT) support germinal center responses is unknown. hDRAGA mice were evaluated for their ability to support HIV replication, generate virus-specific antibody responses, develop splenocyte subsets, and organize sLT architecture. hDRAGA mice supported persistent HIV replication and developed modest levels of gp41-specific human IgM and IgG. Spleens from uninfected and HIV infected hDRAGA mice contained differentiated B and CD4 T cell subsets including germinal center (GC) B cells and T follicular helper cells (TFH); relative expansions of TFH and CD8 T cells, but not GC B cells, occurred in HIV-infected hDRAGA mice compared to uninfected animals. Immunofluorescent staining of spleen and mesenteric lymph node sections demonstrated atypical morphology. Most CD4 and CD8 T cells resided within CD20 areas. CD20 areas lacked canonical germinal centers, as defined by staining for IgDKi67cells. No human follicular dendritic cells (FDC) were detected. Mouse FDC were distributed broadly throughout both CD20 and CD20 regions of sLT. HIV RNA particles were detected by hybridization within CD20 areas and some co-localized with mouse FDC. Viral RNA cells were more concentrated within CD20 compared to CD20 areas of sLT, but differences were diminished in spleen and eliminated in mesenteric lymph nodes when adjusted for CD4 cell frequency. Thus, hDRAGA mice recapitulated multiple aspects of HIV pathogenesis including HIV replication, relative expansions in TFH and CD8 T cells, and modest HIV-specific antibody production. Nevertheless, classical germinal center morphology in sLT was not observed, which may account for the inefficient expansion of GC B cells and generation of low titer human antibody responses to HIV-1 in this model.
Topics: Mice; Animals; HIV-1; HIV Infections; CD8-Positive T-Lymphocytes; Germinal Center; HIV Antibodies
PubMed: 36505432
DOI: 10.3389/fimmu.2022.1047277