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Current Opinion in HIV and AIDS Jan 2020Several anti-HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency, and targeting different HIV-1 envelope epitopes have entered clinical... (Review)
Review
PURPOSE OF REVIEW
Several anti-HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency, and targeting different HIV-1 envelope epitopes have entered clinical trials. bNAbs are being evaluated for their potential as long-acting alternatives to antiretrovirals in HIV-1 prevention and therapy, and for potential role in strategies aiming at long-term viral remission. Here, we discuss recent findings from bNAb clinical studies.
RECENT FINDINGS
bNAbs targeting distinct HIV-1 envelope epitopes have shown, in general, favorable safety profiles, and engineered bNAb variants have demonstrated improved pharmacokinetics. Single bNAb infusions transiently decreased viremia with subsequent selection of escape variants, while a combination of two bNAbs successfully maintained viral suppression in individuals harboring antibody-sensitive viruses after antiretroviral therapy (ART) was discontinued. Studies in animal models suggest that bNAbs can modulate immune responses and potentially interfere with the establishment or composition of the latent reservoir, and ongoing clinical studies aim to assess potential bNAb-mediated effects on HIV-1 persistence and host immune responses.
SUMMARY
Early clinical studies support additional evaluation of bNAbs. Antibodies may offer advantages over standard ART for HIV-1 prevention and therapy, and as components of immunologic strategies to achieve sustained virologic control. The evaluation of engineered bNAbs with multispecificity, extended half-lives and increased potency, as well as alternative bNAb-delivery systems are being pursued.
Topics: Animals; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Broadly Neutralizing Antibodies; Clinical Trials as Topic; HIV Antibodies; HIV Infections; HIV-1; Humans; Viremia; env Gene Products, Human Immunodeficiency Virus
PubMed: 31764199
DOI: 10.1097/COH.0000000000000600 -
Cell Reports Jul 2023Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency...
Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency of neutralization. We employ the OSPREY computational protein design software to engineer variants of two apex-directed bNAbs, PGT145 and PG9RSH, resulting in increases in potency of over 100-fold against some viruses. The top designed variants improve neutralization breadth from 39% to 54% at clinically relevant concentrations (IC < 1 μg/mL) and improve median potency (IC) by up to 4-fold over a cross-clade panel of 208 strains. To investigate the mechanisms of improvement, we determine cryoelectron microscopy structures of each variant in complex with the HIV envelope trimer. Surprisingly, we find the largest increases in breadth to be a result of optimizing side-chain interactions with highly variable epitope residues. These results provide insight into mechanisms of neutralization breadth and inform strategies for antibody design and improvement.
Topics: Humans; HIV Infections; HIV Antibodies; Antibodies, Neutralizing; HIV-1; Broadly Neutralizing Antibodies; Cryoelectron Microscopy; HIV Seropositivity; Neutralization Tests
PubMed: 37436900
DOI: 10.1016/j.celrep.2023.112711 -
Frontiers in Immunology 2020Prophylactic vaccines remain the best approach for controlling the human immunodeficiency virus-1 (HIV-1) transmission. Despite the limited efficacy of the RV144 trial... (Review)
Review
Prophylactic vaccines remain the best approach for controlling the human immunodeficiency virus-1 (HIV-1) transmission. Despite the limited efficacy of the RV144 trial in Thailand, there is still no vaccine candidate that has been proven successful. Consequently, great efforts have been made to improve HIV-1 antigens design and discover delivery platforms for optimal immune elicitation. Owing to immunogenic, structural, and functional diversity, virus-like particles (VLPs) could act as efficient vaccine carriers to display HIV-1 immunogens and provide a variety of HIV-1 vaccine development strategies as well as prime-boost regimes. Here, we describe VLP-based HIV-1 vaccine candidates that have been enrolled in HIV-1 clinical trials and summarize current advances and challenges according to preclinical results obtained from five distinct strategies. This mini-review provides multiple perspectives to help in developing new generations of VLP-based HIV-1 vaccine candidates with better capacity to elicit specific anti-HIV immune responses.
Topics: AIDS Vaccines; Animals; Drug Design; HIV Antibodies; HIV Antigens; HIV Infections; HIV-1; Humans; Immunogenicity, Vaccine; Vaccines, Virus-Like Particle
PubMed: 33117367
DOI: 10.3389/fimmu.2020.573157 -
HIV-1 neutralizing antibodies provide sterilizing immunity by blocking infection of the first cells.Cell Reports. Medicine Oct 2023Neutralizing antibodies targeting HIV-1 Env have been shown to protect from systemic infection. To explore whether these antibodies can inhibit infection of the first...
Neutralizing antibodies targeting HIV-1 Env have been shown to protect from systemic infection. To explore whether these antibodies can inhibit infection of the first cells, challenge viruses based on simian immunodeficiency virus (SIV) were developed that use HIV-1 Env for entry into target cells during the first replication cycle, but then switch to SIV Env usage. Antibodies binding to Env of HIV-1, but not SIV, block HIV-1 Env-mediated infection events after rectal exposure of non-human primates to the switching challenge virus. After natural exposure to HIV-1, such a reduction of the number of first infection events should be sufficient to provide sterilizing immunity in the strictest sense in most of the exposed individuals. Since blocking infection of the first cells avoids the formation of latently infected cells and reduces the risk of emergence of antibody-resistant mutants, it may be the best mode of protection.
Topics: Animals; Simian Acquired Immunodeficiency Syndrome; Antibodies, Viral; HIV-1; Macaca mulatta; Antibodies, Neutralizing; Simian Immunodeficiency Virus; HIV Infections; HIV Antibodies
PubMed: 37804829
DOI: 10.1016/j.xcrm.2023.101201 -
Frontiers in Immunology 2021Many broadly neutralizing antibodies (bnAbs) targeting the HIV-1 envelope glycoprotein are being assessed in clinical trials as strategies for HIV-1 prevention,... (Review)
Review
Many broadly neutralizing antibodies (bnAbs) targeting the HIV-1 envelope glycoprotein are being assessed in clinical trials as strategies for HIV-1 prevention, treatment, and antiretroviral-free remission. BnAbs can neutralize HIV-1 and target infected cells for elimination. Concerns about HIV-1 resistance to single bnAbs have led to studies of bnAb combinations with non-overlapping resistance profiles. This review focuses on the potential for bnAbs to induce HIV-1 remission, either alone or in combination with latency reversing agents, therapeutic vaccines or other novel therapeutics. Key topics include preliminary activity of bnAbs in preclinical models and in human studies of HIV-1 remission, clinical trial designs, and antibody design strategies to optimize pharmacokinetics, coverage of rebound-competent virus, and enhancement of cellular immune functions.
Topics: Anti-Retroviral Agents; Broadly Neutralizing Antibodies; Clinical Trials as Topic; HIV Antibodies; HIV Infections; Humans; Vaccination; Virus Replication
PubMed: 34322136
DOI: 10.3389/fimmu.2021.710044 -
Nature Jun 2022HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable...
HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable reservoir of latent proviruses integrated into the genome of CD4 T cells. Immunotherapy with anti-HIV-1 antibodies has the potential to suppress infection and increase the rate of clearance of infected cells. Here we report on a clinical study in which people living with HIV received seven doses of a combination of two broadly neutralizing antibodies over 20 weeks in the presence or absence of ART. Without pre-screening for antibody sensitivity, 76% (13 out of 17) of the volunteers maintained virologic suppression for at least 20 weeks off ART. Post hoc sensitivity analyses were not predictive of the time to viral rebound. Individuals in whom virus remained suppressed for more than 20 weeks showed rebound viraemia after one of the antibodies reached serum concentrations below 10 µg ml. Two of the individuals who received all seven antibody doses maintained suppression after one year. Reservoir analysis performed after six months of antibody therapy revealed changes in the size and composition of the intact proviral reservoir. By contrast, there was no measurable decrease in the defective reservoir in the same individuals. These data suggest that antibody administration affects the HIV-1 reservoir, but additional larger and longer studies will be required to define the precise effect of antibody immunotherapy on the reservoir.
Topics: Anti-Retroviral Agents; CD4-Positive T-Lymphocytes; HIV Antibodies; HIV Infections; HIV-1; Humans; Proviruses; Viral Load; Viremia; Virus Latency
PubMed: 35418681
DOI: 10.1038/s41586-022-04597-1 -
Frontiers in Immunology 2023Glycan masking is a novel technique in reverse vaccinology in which sugar chains (glycans) are added on the surface of immunogen candidates to hide regions of low... (Review)
Review
Glycan masking is a novel technique in reverse vaccinology in which sugar chains (glycans) are added on the surface of immunogen candidates to hide regions of low interest and thus focus the immune system on highly therapeutic epitopes. This shielding strategy is inspired by viruses such as influenza and HIV, which are able to escape the immune system by incorporating additional glycosylation and preventing the binding of therapeutic antibodies. Interestingly, the glycan masking technique is mainly used in vaccine design to fight the same viruses that naturally use glycans to evade the immune system. In this review we report the major successes obtained with the glycan masking technique in epitope-focused vaccine design. We focus on the choice of the target antigen, the strategy for immunogen design and the relevance of the carrier vector to induce a strong immune response. Moreover, we will elucidate the different applications that can be accomplished with glycan masking, such as shifting the immune response from hyper-variable epitopes to more conserved ones, focusing the response on known therapeutic epitopes, broadening the response to different viral strains/sub-types and altering the antigen immunogenicity to elicit higher or lower immune response, as desired.
Topics: HIV Antibodies; Antibodies, Neutralizing; Epitopes; Polysaccharides; HIV-1
PubMed: 37033915
DOI: 10.3389/fimmu.2023.1126034 -
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 -
Current Opinion in HIV and AIDS Jul 2019Broadly neutralizing antibodies (bnAbs) are considered a key component of an effective HIV-1 vaccine, but despite intensive efforts, induction of bnAbs by vaccination... (Review)
Review
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.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 31107283
DOI: 10.1097/COH.0000000000000552 -
Nature Medicine Oct 2023Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a,... (Randomized Controlled Trial)
Randomized Controlled Trial
Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .
Topics: Female; Humans; Male; Adjuvants, Immunologic; Antibodies, Neutralizing; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Toll-Like Receptor 9
PubMed: 37696935
DOI: 10.1038/s41591-023-02547-6