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HIV Antibodies Block Infection by Reservoir-Derived Virus in Laboratory Study
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NIH-Led Team Finds Strategy to Achieve Sustained HIV Remission Promising
Tae-Wook Chun, Ph.D., staff scientist in the NIAID Laboratory of Immunoregulation and first author of the study.
Credit: NIAID
WHAT:
A laboratory study led by scientists from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH), lends further weight to the potential effectiveness of passive immunotherapy to suppress HIV in the absence of drug treatment. Passive immunotherapy for HIV is an experimental strategy that involves periodically administering broadly neutralizing HIV-specific antibodies (bNAbs) to control the virus. It would be advantageous to control HIV without antiretroviral drugs because of their cost, the potential for cumulative toxicities from lifelong therapy, and the difficulties some patients have adhering to drug regimens and tolerating certain drugs.
Although bNAbs have proven effective at blocking infection by various strains of HIV in the laboratory, their effect on HIV in humans, and particularly on the virus particles that hide in immune cells (called latent viral reservoirs), has been unknown.
In this study, NIH scientists obtained HIV from the latent reservoirs of 29 infected people in whom antiretroviral therapy fully inhibited viral replication. In the laboratory, the researchers found that several bNAbs-particularly PGT121, VRC01 and VRC03-effectively blocked HIV from entering the CD4+ T cells obtained from uninfected healthy donors. In addition, the scientists demonstrated in the laboratory that these antibodies could completely block HIV replication in CD4+ T cells obtained from infected individuals receiving antiretroviral therapy.
The researchers conclude that passive immunotherapy involving bNAbs individually or in combination may control HIV in the absence of antiretroviral therapy. A number of clinical trials are already underway or planned to test this hypothesis.
ARTICLE:
T-W Chun, et al. Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir. PNAS DOI: 10.1073/pnas.1414148111 (2014).
WHO:
NIAID Director Anthony S. Fauci, M.D., and Tae-Wook Chun, Ph.D., staff scientist in the NIAID Laboratory of Immunoregulation, are available for comment.
CONTACT:
To schedule interviews, please contact Laura S. Leifman, (301) 402-1663, niaidnews@niaid.nih.gov.
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Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir
PNAS 2014 ; published ahead of print August 25, 2014
Tae-Wook Chuna,1, Danielle Murraya, Jesse S. Justementa, Jana Blazkovaa, Claire W. Hallahanb, Olivia Fankuchena,
Kathleen Gittensc, Erika Benkod, Colin Kovacsd,e, Susan Moira, and Anthony S. Faucia,1
aLaboratory of Immunoregulation and bBiostatistics Research Branch, National Institute of Allergy and Infectious Diseases, and cCritical Care Medicine
Department, National Institutes of Health, Bethesda, MD 20892; dMaple Leaf Medical Clinic, Toronto, ON, Canada M5G 1K2; and eDepartment of Medicine,
University of Toronto, Toronto, ON, Canada M5G 2C4
"We demonstrated that certain HIV-specific monoclonal antibodies (some better than others) can efficiently bind virions that have been induced from the latent reservoir of HIV-infected individuals whose plasma viremia has been successfully controlled on ART. In addition, several of these antibodies block entry of HIV isolated from the latent pool into CD4+ T cells derived from HIV-uninfected individuals. Furthermore, we demonstrated that these same antibodies could completely block HIV replication in mitogen-stimulated autologous CD4+ T cells of infected individuals. Of note, despite the fact that PG9 and PG16 are closely related somatically, PG16 showed a greater capacity to bind to virions isolated from the latent viral reservoir of HIV-infected individuals receiving ART"
Significance
A number of highly potent and broadly neutralizing HIV-specific monoclonal antibodies have recently been isolated from B cells of infected individuals. However, the effects of these antibodies on the persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We demonstrate that a select number of HIV-specific monoclonal antibodies potently suppressed entry into CD4+ T cells of HIV isolated from the latent viral reservoir as well as replication of reservoir virus in autologous CD4+ T cells derived from infected individuals receiving ART. These findings provide new opportunities for passive immunotherapy to prevent plasma viral rebound following discontinuation of antiretroviral drugs.
Abstract
Several highly potent and broadly neutralizing monoclonal antibodies against HIV have recently been isolated from B cells of infected individuals. However, the effects of these antibodies on the persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We show that several HIV-specific monoclonal antibodies-in particular, PGT121, VRC01, and VRC03-potently inhibited entry into CD4+ T cells of HIV isolated from the latent viral reservoir of infected individuals whose plasma viremia was well controlled by ART. In addition, we demonstrate that HIV replication in autologous CD4+ T cells derived from infected individuals receiving ART was profoundly suppressed by three aforementioned and other HIV-specific monoclonal antibodies. These findings have implications for passive immunotherapy as an approach toward controlling plasma viral rebound in patients whose ART is withdrawn.
The sustained suppression of HIV replication by antiretroviral therapy (ART) has dramatically improved the clinical outcome of infected individuals (1). In addition, research directed at potential pathways toward the development of an effective preventive HIV vaccine has provided insights into the nature of the immune response to HIV infection (2, 3). In this regard, recent advances in antibody-cloning technologies have led to the discovery of several highly potent and broadly neutralizing monoclonal antibodies against HIV from B cells of HIV-infected individuals (4-7). Of interest, several studies have demonstrated that certain broadly neutralizing HIV-specific monoclonal antibodies can prevent acquisition of the virus, suppress viral replication, delay and/or prevent plasma viral rebound following treatment interruption in infected animals (8-14), and block cellto-cell transmission of laboratory-adapted HIV in vitro (15). However, it is unclear what in vivo effects these antibodies might have on HIV in humans and, in particular, what effects they may have on the virus contained in the persistently infected CD4+ T cells of individuals whose plasma viremia is controlled by ART. These infected CD4+ T cells are considered to be the major obstacle to viral eradication (16-18) as well as a potential source of plasma viral rebound following discontinuation of ART in patients whose viremia had been well controlled in therapy (1). In this regard, considerable efforts in current HIV therapeutic research have been focused on developing strategies aimed at achieving sustained virologic remission in the absence of ART (1). This focus is especially important given that viral rebound and sustained HIV replication has been observed in almost all
infected individuals whose plasma viremia had been well controlled while receiving ART and whose ART was subsequently withdrawn (19). Therefore, it is important to determine which, if any, of the many recently characterized HIV-specific monoclonal antibodies can inhibit viral entry into CD4+ T cells of HIV isolated from the latent viral reservoir as well as replication of reservoir virus in autologous CD4+ T cells derived from infected individuals whose plasma viremia was well-controlled on ART. Such knowledge is critical to establishing novel opportunities for passive immunotherapy to prevent plasma viral rebound following discontinuation of antiretroviral drugs. We conducted the present study to address this issue.
Discussion
In the present study, we investigated the effects of recently identified potent and broadly neutralizing HIV-specific monoclonal antibodies on viral isolates induced from the latent viral reservoir of HIV-infected individuals whose plasma viremia had been controlled on ART. The latent HIV reservoir has long been recognized as one of the major obstacles to eradicating the virus in infected individuals whose plasma viremia is controlled on ART (16-18). Consequently, there is a growing interest in developing novel therapeutic strategies to either completely eliminate the infected cells and/or achieve sustained virology remission that is sustained by the natural host immune response and/or by immunotherapy following the discontinuation of ART (20). Given that there are significant challenges in achieving total eradication of replication-competent virus in a substantial proportion of infected individuals (21)*, therapeutic strategies designed to maintain sustained virologic remission in infected individuals without the requirement for indefinite ART may represent more realistic goals. In this regard, recently identified potent and broadly neutralizing HIV-specific monoclonal antibodies have been shown to suppress the virus in infected animals (11-14) and to inhibit cell-to-cell transmission of laboratory adapted HIV in vitro (15). Clinical trials have been planned and/or are underway to determine the ability of these well-characterized monoclonal antibodies to prevent the acquisition of HIV infection and suppress HIV in infected individuals in vivo. In this regard, it would be of considerable interest to determine whether these antibodies are capable of suppressing replication-competent HIV that is contained within the persistent viral reservoir, and thus could be used as a potential modality to blunt the plasma viral rebound following the deliberate cessation of ART. Recently characterized HIV-specific antibodies have been shown to be broadly neutralizing-albeit with wide variations-against diverse panels of pseudotyped HIV grouped into tiers based on neutralization susceptibility (22).
We demonstrated that certain HIV-specific monoclonal antibodies (some better than others) can efficiently bind virions that have been induced from the latent reservoir of HIV-infected individuals whose plasma viremia has been successfully controlled on ART. In addition, several of these antibodies block entry of HIV isolated from the latent pool into CD4+ T cells derived from HIV-uninfected individuals. Furthermore, we demonstrated that these same antibodies could completely block HIV replication in mitogen-stimulated autologous CD4+ T cells of infected individuals. Of note, despite the fact that PG9 and PG16 are closely related somatically, PG16 showed a greater capacity to bind to virions isolated from the latent viral reservoir of HIV-infected individuals receiving ART. It has been shown that the binding of PG9 and PG16 to V1-V2 of HIV Env is influenced by the composition of glycans in this region (23). Moreover, it has been shown that levels of glycosylation and the composition of glycans are influenced by the type of cells from which the HIV Env or virions is expressed or secreted (24). Given that the cell-free virions we used to perform the antibody-HIV binding assays were recovered from short-term stimulated autologous CD4+ T cells of the study subjects-a process that likely closely resembles HIV propagation in vivo-our findings underscore the importance of glycan composition of virions used to assess the therapeutic potential of glycan-dependent antibodies such as PG16. However, it is also noteworthy that PG16, the antibody that showed the highest degree of binding to the visions isolated from the latent viral reservoir, was not the most effective entry inhibitor of the viral isolates from a larger proportion of the study subjects. It is plausible that PG16 may bind to a region of V1-V2 of the HIV Env that is highly accessible but not necessarily critical for viral entry. It is also possible that a brief period of virus propagation, a necessary step for obtaining sufficient titers of infectious HIV to perform the viral entry assays, may have altered the viral envelope composition, such that virions used in the binding assay were different from virus propagated for the entry assay in ways that had a greater effect on glycan-dependent antibodies such as PG16. These observations underscore the potential importance of addressing the functional capabilities of HIV-specific antibodies that might be used in the context of immune-based therapy in physiologically relevant experimental systems.
Our findings have potentially important implications for the design of therapeutic strategies. A combination of HIV-neutralizing monoclonal antibodies, particularly PGT121, VRC01, and VRC03, may provide sustained virologic remission in infected individuals following the discontinuation of ART. The above approach is a realistic therapeutic strategy given the potent activities of these antibodies against HIV isolated from the persistent viral reservoir and their likely long-circulating half-lives (25). With the possibility
of biochemical modification allowing for a more prolonged plasma half-life (25), it is conceivable that HIV-infected individuals could potentially maintain very low or undetectable plasma viremia in the absence of ART following relatively infrequent administration of these antibodies. Finally, clinical trials involving passive immunization should include prescreening of HIV isolates from the persistent viral reservoirs of infected individuals with a panel of HIVspecific antibodies, to identify those that manifest the most potent suppressive activity against the patient viral isolates.
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