Neutralizing Monoclonal Antibodies to Fight HIV-1: On the Threshold of Success

Jaworski, Juan Pablo; Vendrell, Alejandrina; Chiavenna, Sebastián

doi:10.3389/fimmu.2016.00661

Cited by 12 publications

(15 citation statements)

References 147 publications

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“…Attempts to use anti-HIV-1 bnAbs alone, in combination, or as components of chimeric antigen receptors (CARs), bispecific T cell engagers (BiTEs), and other bispecific proteins have shown promising in vitro and in vivo results (36)(37)(38)(39). However, resistance has been reported for various bnAbs targeting multiple sites, including V1/V2, V3, and the CD4 binding site.…”

Section: Discussionmentioning

confidence: 99%

Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

Xue

Wang

et al. 2019

J Virol

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Early human immunodeficiency virus type 1 (HIV-1) treatment during the acute period of infection can significantly limit the seeding of viral reservoirs and modify the course of disease. However, while a number of HIV-1 broadly neutralizing antibodies (bnAbs) have demonstrated remarkable efficacy as prophylaxis in macaques chronically infected with simian-human immunodeficiency virus (SHIV), intriguingly, their inhibitory effects were largely attenuated in the acute period of SHIV infection. To investigate the mechanism for the disparate performance of bnAbs in different periods of SHIV infection, we used LSEVh-LS-F, a bispecific bnAb targeting the CD4 binding site and CD4-induced epitopes, as a representative bnAb and assessed its potential therapeutic benefit in controlling virus replication in acutely or chronically SHIV-infected macaques. We found that a single infusion of LSEVh-LS-F resulted in rapid decline of plasma viral loads to undetectable levels without emergence of viral resistance in the chronically infected macaques. In contrast, the inhibitory effect was robust but transient in the acutely infected macaques, despite the fact that all macaques had comparable plasma viral loads initially. Infusing multiple doses of LSEVh-LS-F did not extend its inhibitory duration. Furthermore, the pharmacokinetics of the infused LSEVh-LS-F in the acutely SHIV-infected macaques significantly differed from that in the uninfected or chronically infected macaques. Host SHIV-specific immune responses may play a role in the viremia-dependent pharmacokinetics. Our results highlight the correlation between the fast clearance of infused bnAbs and the treatment failure in the acute period of SHIV infection and may have important implications for the therapeutic use of bnAbs to treat acute HIV infections. IMPORTANCE Currently, there is no bnAb-based monotherapy that has been reported to clear the virus in the acute SHIV infection period. Since early HIV treatment is considered critical to restricting the establishment of viral reservoirs, investigation into the mechanism for treatment failure in acutely infected macaques would be important for the therapeutic use of bnAbs and eventually towards the functional cure of HIV/AIDS. Here we report the comparative study of the therapeutic efficacy of a bnAb in acutely and chronically SHIV-infected macaques. This study revealed the correlation between the fast clearance of infused bnAbs and treatment failure during the acute period of infection.

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Section: Discussionmentioning

confidence: 99%

Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

Xue

Wang

et al. 2019

J Virol

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“…Several methods, including single B cell culture coupled to high throughput neutralization screening, are currently used to identify new broadly neutralizing antibodies from large cohort of HIV infected patients [150]. Several new anti-HIV-1 neutralizing monoclonal antibodies have been isolated and shown to block HIV-1 and SHIV infection in animal models [151]. Indeed, they efficiently cured SHIVs infected macaque monkeys and HIV-1 infected humanized mice.…”

Section: Humoral-mediated Immune Responsementioning

confidence: 99%

On the way to find a cure: Purging latent HIV-1 reservoirs

Schwartz

Bouchat

Marban

et al. 2017

Biochemical Pharmacology

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Introduction of cART in 1996 has drastically increased the life expectancy of people living with HIV-1. However, this treatment has not allowed cure as cessation of cART is associated with a rapid viral rebound. The main barrier to the eradication of the virus is related to the persistence of latent HIV reservoirs. Evidence is now accumulating that purging the HIV-1 reservoir might lead to a cure or a remission. The most studied strategy is the so called "shock and kill" therapy. This strategy is based on reactivation of dormant viruses from the latently-infected reservoirs (the shock) followed by the eradication of the reservoirs (the kill). This review focuses mainly on the recent advances made in the "shock and kill" therapy. We believe that a cure or a remission will come from combinatorial approaches i.e. combination of drugs to reactivate the dormant virus from all the reservoirs including the one located in sanctuaries, and combination of strategies boosting the immune system. Alternative strategies based on cell and gene therapy or based in inducing deep latency, which are evoked in this review reinforce the idea that at least a remission is attainable.

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“…Screening for important mAbs is therefore technically challenging and although proof of principle has been achieved with viruses, it remains to be seen whether or not this strategy will work against more complex organisms. For instance, in HIV, none of the immunogens targeted by broadly neutralizing mAbs have elicited antibodies of similar breadth or potency following immunization in humans . The design of immunogens that mimic the native epitopes identified by functional antibodies or those that activate the germline B‐cell precursors are currently being explored .…”

Section: Functional Antibody‐guided Vaccine Candidate Discoverymentioning

confidence: 99%

“…For instance, in HIV, none of the immunogens targeted by broadly neutralizing mAbs have elicited antibodies of similar breadth or potency following immunization in humans. 83,84 The design of immunogens that mimic the native epitopes identified by functional antibodies or those that activate the germline B-cell precursors are currently being explored. 83 We postulate that for complex pathogens like Plasmodium, what may be required are combinations of antibodies that target multiple epitopes or those that act in synergy to achieve a protective response.…”

Section: Functional Antibody-guided Vaccine Candidate Discoverymentioning

confidence: 99%

Vaccine candidate discovery for the next generation of malaria vaccines

et al. 2017

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SummaryAlthough epidemiological observations, IgG passive transfer studies and experimental infections in humans all support the feasibility of developing highly effective malaria vaccines, the precise antigens that induce protective immunity remain uncertain. Here, we review the methodologies applied to vaccine candidate discovery for Plasmodium falciparum malaria from the pre‐ to post‐genomic era. Probing of genomic and cDNA libraries with antibodies of defined specificities or functional activity predominated the former, whereas reverse vaccinology encompassing high throughput in silico analyses of genomic, transcriptomic or proteomic parasite data sets is the mainstay of the latter. Antibody‐guided vaccine design spanned both eras but currently benefits from technological advances facilitating high‐throughput screening and downstream applications. We make the case that although we have exponentially increased our ability to identify numerous potential vaccine candidates in a relatively short space of time, a significant bottleneck remains in their validation and prioritization for evaluation in clinical trials. Longitudinal cohort studies provide supportive evidence but results are often conflicting between studies. Demonstration of antigen‐specific antibody function is valuable but the relative importance of one mechanism over another with regards to protection remains undetermined. Animal models offer useful insights but may not accurately reflect human disease. Challenge studies in humans are preferable but prohibitively expensive. In the absence of reliable correlates of protection, suitable animal models or a better understanding of the mechanisms underlying protective immunity in humans, vaccine candidate discovery per se may not be sufficient to provide the paradigm shift necessary to develop the next generation of highly effective subunit malaria vaccines.

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Neutralizing Monoclonal Antibodies to Fight HIV-1: On the Threshold of Success

Cited by 12 publications

References 147 publications

Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

On the way to find a cure: Purging latent HIV-1 reservoirs

Vaccine candidate discovery for the next generation of malaria vaccines

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