New data on identifying and targeting the latent HIV reservoir
23 February 2018. Related: Cure-related research.
Richard Jefferys, TAG
Several recently presented and published studies offer potentially important new data relevant to efforts to identify cells containing latent HIV and target them for elimination.
At the 8th International Workshop on HIV Persistence held in Miami last December, [multiple research groups reported on their attempts to confirm a newly published – and widely publicised – claim that the cell surface molecule CD32a is preferentially expressed on latently infected cells. [1, 2]
The results indicate that the picture is considerably more complicated: the original findings could not be verified and instead it appears that expression of CD32a may be driven by other factors, including cell activation and active HIV transcription. Summaries of these studies can be found in the published abstracts from the workshop (see abstract numbers OP 1.5, OP 2.4, OP 2.6 and OP 4.2). [3]
While disappointing, this work does not end hopes that markers of latently infected cells can be identified – other candidates that are being examined are CCR5, when expressed by resting memory CD4 T cells (see the study from the laboratory of Robert Siliciano published late last year [4]), and CD30, a cell surface molecule better known for its association with lymphoma that is being investigated by Tim Henrich and colleagues. [5]
One of the reasons why markers of latently infected cells would be a boon to the cure research field is that they might facilitate elimination strategies akin to those now being used successfully against cancers. A number of effective cancer immunotherapies involve equipping T cells with receptors that target cell surface molecules on malignant cells, such as CD19, CD22, and CD30. It is conceivable that this “chimeric antigen receptor” (CAR) T cell approach could be adapted to target latently infected cells if appropriate markers could be identified.
CAR T cells are also being developed that target HIV antigens, with a recent paper in PLoS Pathogens from Scott Kitchen colleagues reporting some encouraging results obtained with stem cell-derived CAR T cells in macaques. [6] However, in order for the approach to work against latently infected cells, it would be necessary to activate the latent HIV first to trigger production of viral antigens.
An article in STAT News by Sharon Begley provides an accurate and nuanced perspective on Kitchen’s paper, offering the appropriately cautious headline: “Preliminary study hints that genetically modified T cells might fight HIV.” [7] In contrast, coverage in The Daily Beast unfortunately opts for misleading hype, with their piece titled: “This doctor’s revolutionary stem cell treatments could eradicate HIV.” [8]
The research group of Jonathan Angel in Canada is pursuing a novel method for targeting latently infected cells: an oncolytic rhabdovirus named MG1, which is primarily being developed for its ability to preferentially infect and destroy cancer cells. Angel and colleagues have published a study in the Journal of Infectious Diseases demonstrating that MG1 also appears capable of targeting cells latently infected with HIV, while sparing uninfected cells (the paper is open access). [9]
In an analysis of the effects of MG1 on memory CD4 T cells isolated from 14 HIV positive individuals on ART, both total and integrated HIV DNA levels declined in 12 out of the 14 samples. The mechanism for MG1’s preferential targeting is unclear, but may relate to changes in latently infected cells that affect their response to the cytokine interferon. The authors note that clinical trials are already underway in cancer [10], which should help discern if the approach can be safely studied in HIV infection. In an interview with MD Magazine, Angel notes MG1 that can cause fever and malaise, and adverse events may be dose-dependent. [11]
Another paper in PLoS Pathogens comes from Christina Gavegnano and colleagues, who show that a class of drugs called Jak inhibitors can inhibit the maintenance of latently infected cells, and prevent them spreading infection when latent HIV is reactivated. [12] Jak inhibitors target a pathway involved in the survival and proliferation of memory CD4 T cells, and have been found safe in the treatment of certain inflammatory diseases and myelofibrosis. The authors note that an ongoing clinical trial is evaluating the effects of the Jak inhibitor ruxolitinib in HIV positive people on ART. [13]
Source
Jefferys R. TAG Basic Science Blog (17 January 2018)
http://tagbasicscienceproject.typepad.com
References
- 8th International Workshop on HIV Persistence
http://www.hiv-persistence.com - Jefferys R. Flagging the HIV reservoir. TAG basic science blog. (16 March 2017).
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2017/03/flagging-the-hiv-reservoir.html - Abstracts from the 8th International Workshop on HIV Persistence.
http://viruseradication.com/supplement-details/Abstracts_of_the_Eighth_International_Workshop_on_HIV_Persistence_during_Therapy - Jefferys R. HIV latency: tapped in transition, lurking in Treg. TAG basic science blog. (16 November 2017).
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2017/11/hiv-latency-trapped-in-transition-lurking-in-treg.html - NIH grant listings. Henrich TJ et al. Targeting latent HIV-1 reservoirs with the antibody-drug conjugate, brentuximab vedotin
http://grantome.com/grant/NIH/R33-AI116205-04 - Zhen A et al. Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS. PLoS Pathogens (28 December 2017).
https://doi.org/10.1371/journal.ppat.1006753 - Begley S. Preliminary study hints that genetically modified T cells might fight HIV. (02 January 2018).
https://www.statnews.com/2018/01/02/car-t-cells-hiv-treatment - Schultz KJ. This Doctor’s Revolutionary Stem Cell Treatments Could Eradicate HIV. Daily Beast, (15 January 2018).
https://www.thedailybeast.com/this-doctors-revolutionary-stem-cell-treatments-could-eradicate-hiv - Ranganath N et al. The oncolytic virus MG1 targets and eliminates cells latently infected with HIV-1: implications for an HIV cure. JID, 217(5);721–730. https://doi.org/10.1093/infdis/jix639. (14 February 2018)
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jix639/4706282 - Ottawa hospital news release. Cancer patients treated in world-first clinical trial of Canadian viral therapy. (10 July 2015)
http://www.ohri.ca/newsroom/newsstory.asp?ID=649 - Kaltwasser J. Virus seems able to destroy latent HIV-infected cells. MD mag. (04 January 2018).
http://www.mdmag.com/medical-news/virus-seems-able-to-destroy-latent-hivinfected-cells - Gavegnano C et al. Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. PLoS Pathogens. https://doi.org/10.1371/journal.ppat.1006740. (21 December 2017).
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006740 - Clinicaltrials.gov. Evaluating the safety and tolerability of ruxolitinib in antiretroviral-treated HIV-infected adults.
https://clinicaltrials.gov/ct2/show/NCT02475655