Two recent papers address the potential of broadly neutralizing antibodies (bNAbs) to decrease HIV rebound from persistent reservoirs. In the journal Cell, Ariel Halper-Stromberg and colleagues report the results of experiments conducted in the humanized mouse model with a “tri-mix” of three monoclonal bNAbs: 3BNC117, 10-1074, and PG16. When administered as post-exposure prophylaxis four days after the mice were challenged with HIV, the bNAb tri-mix did not prevent infection, but there was a significant delay in viral load rebound after the treatment was stopped (compared to a control group of mice given combination antiretroviral therapy on the same schedule). The researchers conclude that the bNAbs were more effective than ART at preventing the formation of the latent HIV reservoir in the mice, likely due to antibody-mediated effector mechanisms facilitating the clearance of infected cells (similar to recent findings in the macaque model).
Subsequent experiments investigated the effects of combining the bNAb tri-mix with potential latency-reversing agents including vorinostat (an HDAC inhibitor), I-BET151 (a BET protein inhibitor) and CTLA (a T cell inhibitory pathway blocker). In humanized mice with established HIV infection, the combination of the bNAb tri-mix and all three latency-reversing agents significantly reduced the number of mice experiencing viral load rebound after therapy cessation compared to bNAbs alone (10 of 23 mice rebounded in the combination group versus 22 of 25 in the bNAbs group). In contrast, bNAbs plus any single latency-reversing agent did not show significant effects.
The second paper—published in PNAS by Tae-Wook Chun and colleagues—explores the effects of bNAb combinations on HIV isolated from the latently infected CD4 T cells of individuals on ART. To try and model the spread of HIV from the latent reservoir that occurs when ART is interrupted, laboratory experiments were conducted in which CD4 T cells sampled from uninfected individuals were exposed to HIV from the latent reservoir in the presence or absence of various bNAbs. Results showed that the most potent suppression of the reservoir-derived HIV was achieved by the bNAbs PGT121 (mean 2.4 log), VRC01 (2.1 log), and VRC03 (1.8 log). The authors also note: “viral isolates from 72%, 52%, and 44% of HIV-infected individuals we studied were neutralized (>2 log suppression) by PGT121, VRC01, and VRC03, respectively;” this finding underscores that not all circulating HIV is susceptible to every bNAb.
In discussing their results, the researchers suggest: “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.” Because bNAbs may have the potential to be administered infrequently, they argue this could represent an alternative to continuous ART. The paper concludes by recommending that, due to the variation in HIV susceptibility to bNAbs, “clinical trials involving passive immunization should include prescreening of HIV isolates from the persistent viral reservoirs of infected individuals with a panel of HIV-specific antibodies, to identify those that manifest the most potent suppressive activity against the patient viral isolates.”
Currently there are two ongoing phase I, first-in-human clinical trials of the monoclonal bNAbs 3BNC117 and VRC01. A study of PGT121 is also in the works. At the recent Forum for Collaborative HIV Research workshop in Washington DC, plans for a trial involving passive immunization with VRC01 in people with acute HIV infection were presented by Jintanat Ananworanich (the presentation is available on the Forum’s website). The administration of bNAbs in these studies is via injection, but there may be alternative possibilities. As covered previously on the blog, two research groups are testing adeno-associated virus (AAV) as a possible means to generate a permanent supply of circulating bNAbs after a single injection; although the original impetus for this work was the goal of preventing HIV acquisition, there is also interest in exploring the therapeutic potential. A phase I study of the approach in HIV-negative individuals is currently underway in the UK.
Cell. 2014 Aug 12. pii: S0092-8674(14)00993-3. doi: 10.1016/j.cell.2014.07.043. [Epub ahead of print]
Halper-Stromberg A, Lu CL, Klein F, Horwitz JA, Bournazos S, Nogueira L, Eisenreich TR, Liu C, Gazumyan A, Schaefer U, Furze RC, Seaman MS, Prinjha R, Tarakhovsky A, Ravetch JV, Nussenzweig MC.
Abstract
Latent reservoirs of HIV-1-infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, immunologically invisible, and may undergo homeostatic proliferation, a "shock and kill" approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.
PNAS Published online before print August 25, 2014, doi: 10.1073/pnas.1414148111
Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir
Tae-Wook Chun, Danielle Murray, Jesse S. Justement, Jana Blazkova, Claire W. Hallahan, Olivia Fankuchen, Kathleen Gittens, Erika Benko, Colin Kovacs,e, Susan Moir, and Anthony S. Fauci
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.
This might be a naive question, but an immunologist friend of mine observed that the entire field of HIV latency reversal presupposes that antiretroviral therapy is shutting down active viral replication 100%.
If there is, as appears to be, on-going low level viral replication on even the most successful suppressive combination therapies, is it accurate to say that the only remaining virus is latent? It would seem that a cure would need to have at least 3 components: 1) treatment intensification (a tat inhibitor or even perhaps something that recruits a more effective innate immune response, such as NK cells) to actually stop ALL active replication; 2) a way to excise or inactivate integrated virus (or to destroy or render permanently dormant virus-infected cells) and 3a) fix a defective immune response that could clean up the mess and effectively survey for any subsequent emergent trouble— and/or 3b) genetically engineer HIV-resistant immune cells and preemptively repopulate the body with such cells.
If this is a fair portrayal, it would seem the HDAC/LRA field of research might be receiving an undue amount of attention. Thank you for all your great work.
Posted by: Joao Pauzinho | October 12, 2014 at 10:50 AM