Stemming the flow from HIV reservoirs with neutralising antibodies

1 October 2014. Related: Cure-related research, Basic science and immunology.

Richard Jefferys, TAG

Two recent papers address the potential of broadly neutralising 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 humanised mouse model with a “tri-mix” of three monoclonal bNAbs: 3BNC117, 10-1074, and PG16. [1]

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). [2]

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 humanised 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. [3]

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 HIV negative 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 positive individuals we studied were neutralised (>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-neutralising 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 immunisation 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. [4, 5]

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 immunisation with VRC01 in people with acute HIV infection were presented by Jintanat Ananworanich (the presentation is available on thr Forum’s website). [6]

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, sponsored by IAVI, is currently underway in the UK. [7]

Source:
TAG basic science blog (03 Sep 2014).
http://tagbasicscienceproject.typepad.com

References:

1. Halper-Stromberg et al. Broadly neutralising antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell. 2014 Aug 12. pii: S0092-8674(14)00993-3. doi: 10.1016/j.cell.2014.07.043. [Epub ahead of print] (open access)
   http://www.cell.com/cell/abstract/S0092-8674(14)00993-3
2. Jefferys R. Exploring the Therapeutic Potential of Neutralizing Antibodies. Tag Basic Science Blog (01 November 2013).
   http://tagbasicscienceproject.typepad.com
3. Chun T-W et al. Broadly neutralising antibodies suppress HIV in the persistent viral reservoir. PNAS Published online before print August 25, 2014, doi: 10.1073/pnas.1414148111.
   http://www.pnas.org/content/111/36/13151.abstract
4. http://clinicaltrials.gov/ct2/show/NCT02018510
5. http://clinicaltrials.gov/ct2/show/NCT01950325
6. Forum HIV Cure Project: Regulatory pathway for HIV cure research. Workshop 17 June 2014.
   http://www.hivforum.org/component/content/article/581/581
7. A phase 1, randomized, blinded, dose-escalation study of rAAV1-PG9DP recombinant AAV vector coding for PG9 antibody in HIV negative male adults.
   http://clinicaltrials.gov/ct2/show/NCT01937455