Can Broadly Neutralizing HIV-1 Antibodies Help Achieve an ART-Free Remission?

Hsu, Denise C.; Mellors, John W.; Vasan, Sandhya

doi:10.3389/fimmu.2021.710044

Cited by 22 publications

(21 citation statements)

References 79 publications

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“…Passive infusion with highly potent broadly neutralizing antibodies (bNAbs) against distinct HIV Env regions may represent an advantageous strategy due to the ability of bNAbs to neutralize free virions via the Fab domain and to engage cognate receptors on host innate and adaptive via the Fc domain. Passive infusion with single or combination bNAbs is actively evaluated as therapeutic strategy for HIV remission in the clinics by measuring the effects of antiviral activities of bNAbs on plasma viremia and viral suppression following ATI as well as impact on viral reservoir by delaying viral rebound ( 121 ). Most of these studies were conducted in adults with acute or chronic infections while on ART and similar studies in pediatric HIV population are lacking.…”

Section: Passive Immunization Strategiesmentioning

confidence: 99%

Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

et al. 2022

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Early initiation of antiretroviral therapy (ART) significantly improves clinical outcomes and reduces mortality of infants/children living with HIV. However, the ability of infected cells to establish latent viral reservoirs shortly after infection and to persist during long-term ART remains a major barrier to cure. In addition, while early ART treatment of infants living with HIV can limit the size of the virus reservoir, it can also blunt HIV-specific immune responses and does not mediate clearance of latently infected viral reservoirs. Thus, adjunctive immune-based therapies that are geared towards limiting the establishment of the virus reservoir and/or mediating the clearance of persistent reservoirs are of interest for their potential to achieve viral remission in the setting of pediatric HIV. Because of the differences between the early life and adult immune systems, these interventions may need to be tailored to the pediatric settings. Understanding the attributes and specificities of the early life immune milieu that are likely to impact the virus reservoir is important to guide the development of pediatric-specific immune-based interventions towards viral remission and cure. In this review, we compare the immune profiles of pediatric and adult HIV elite controllers, discuss the characteristics of cellular and anatomic HIV reservoirs in pediatric populations, and highlight the potential values of current cure strategies using immune-based therapies for long-term viral remission in the absence of ART in children living with HIV.

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Section: Passive Immunization Strategiesmentioning

confidence: 99%

Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

et al. 2022

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“…Consequently, these drugs require daily administration, with the possibility of drug resistance and adverse events. Therefore, alternative approaches for HIV-1 therapy or a functional cure are desirable ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

Anti-HIV-1 Nanobody-IgG1 Constructs With Improved Neutralization Potency and the Ability to Mediate Fc Effector Functions

et al. 2022

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The most effective treatment for HIV-1, antiretroviral therapy, suppresses viral replication and averts the disease from progression. Nonetheless, there is a need for alternative treatments as it requires daily administration with the possibility of side effects and occurrence of drug resistance. Broadly neutralizing antibodies or nanobodies targeting the HIV-1 envelope glycoprotein are explored as alternative treatment, since they mediate viral suppression and contribute to the elimination of virus-infected cells. Besides neutralization potency and breadth, Fc-mediated effector functions of bNAbs also contribute to the in vivo efficacy. In this study multivalent J3, 2E7 and 1F10 anti-HIV-1 broadly neutralizing nanobodies were generated to improve neutralization potency and IgG1 Fc fusion was utilized to gain Fc-mediated effector functions. Bivalent and trivalent nanobodies, coupled using long glycine-serine linkers, showed increased binding to the HIV-1 Env and enhanced neutralization potency compared to the monovalent variant. Fusion of an IgG1 Fc domain to J3 improved neutralization potency compared to the J3-bihead and restored Fc-mediated effector functions such as antibody-dependent cellular phagocytosis and trogocytosis, and natural killer cell activation. Due to their neutralization breadth and potency and their ability to induce effector functions these nanobody-IgG1 constructs may prove to be valuable towards alternative HIV-1 therapies.

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“…These relatively conserved and accessible regions become transiently exposed during cell attachment and viral entry, allowing bNAbs to bind to these regions [54]. Some bNAbs target epitopes in the V3 loop (10-1074) whereas others are directed against the highly conserved CD4 þ -binding site (VRC01 and 3BNC117) [21]. Additional antibodies targeting other epitopes, such as the V1/V2 loop and the membrane proximal external region (MPER) have also entered clinical trials, and recent studies have also evaluated the use of bi-specific and tri-specific antibodies [24,55].…”

Section: Broadly Neutralizing Antibodies As Therapies In Hiv Infectionmentioning

confidence: 99%

“…However, improvements in single cell antibody cloning techniques paved the way for isolation and characterization of newer generation bNAbs with a much higher breadth and neutralization activity [20]. Currently, numerous in-human clinical trials are underway to assess the safety, efficacy and immunogenicity of these bNAbs against HIV infection [21].…”

Section: Introductionmentioning

confidence: 99%

An exploration of how broadly neutralizing antibodies might induce HIV remission: the ‘vaccinal’ effect

Tipoe

Fidler

Frater

2022

Current Opinion in HIV and AIDS

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Purpose of reviewBroadly neutralizing antibodies (bNAbs) are a potential new therapeutic strategy to treat HIV infection. This review explores possible mechanisms of action of bNAbs and summarizes the current evidence supporting their immunomodulatory properties, which might lead to sustained virological remission --the 'vaccinal effect'. Recent findingsAntiretroviral therapy (ART) is required to confer lasting HIV suppression; stopping ART almost invariably leads to HIV recrudescence from a persistent pool of virally infected cells --the HIV reservoir. HIV-specific broadly neutralizing antibodies (bNAbs) may confer viral control after ART cessation predominantly through blockade of viral entry into uninfected target cells. In some human and animal studies, HIV bNAbs also conferred lasting viral suppression after therapeutic bNAb plasma levels had declined. Immune-modulatory mechanisms have been postulated to underlie this observation --the 'vaccinal effect'. Hypothesized mechanisms include the formation of immune complexes between bNAbs and HIV envelope protein, thereby enhancing antigen presentation and uptake by immune cells, with boosted adaptive immune responses subsequently controlling the HIV reservoir. SummaryThere is emerging evidence for potent antiviral efficacy of bNAb therapy. Whether bNAbs can induce sustained viral suppression after dropping below therapeutic levels remains controversial. Mechanistic data from on-going and future clinical trials will help answer these questions.

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Can Broadly Neutralizing HIV-1 Antibodies Help Achieve an ART-Free Remission?

Cited by 22 publications

References 79 publications

Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

Anti-HIV-1 Nanobody-IgG1 Constructs With Improved Neutralization Potency and the Ability to Mediate Fc Effector Functions

An exploration of how broadly neutralizing antibodies might induce HIV remission: the ‘vaccinal’ effect

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