CROI 2022: Genomic entrapment of HIV in people on long-term ART, chimeric antigen receptor T cells and more on bNAbs

Richard Jefferys, TAG

Genomic entrapment of HIV in people on Long-Term ART

Kyra Seiger from the Ragon Institute of MGH, MIT and Harvard described results demonstrating that the makeup of the HIV reservoir shifts over time in people on long-term antiretroviral therapy (ART). [1]

The key finding is that a substantial proportion of the intact HIV that persists after long-term ART appears to be entrapped in the genetic code of remaining infected cells, and likely unable to emerge and replicate.

The finding relates to how HIV integrates its genetic code—in the form of HIV DNA—into the human DNA (known as the genome) of the cells that it infects.  

As a loose analogy, if you think of a cell’s genome as a factory for producing all the proteins the cell needs to go about its daily business, HIV DNA tends to integrate in machinery that gets switched on regularly. This gives the virus opportunities to hijack that machinery to make more HIV proteins (and potentially more copies of infectious HIV).

But HIV DNA can also land in the genomic equivalent of a darkened factory storage room nobody goes into (sometimes referred to as a “gene desert”)—in that case, the virus can become trapped and unable to reactivate.

The importance of where HIV DNA integrates into a cell’s genome was first highlighted by studies of elite controllers, which provided evidence that their immune responses can clear cells containing more active HIV, leaving behind only those cells containing HIV integrated in places in the genome from which it can’t reactivate. Essentially, the intact HIV that remains in their bodies appears entrapped, and unable to replicate or cause harm. [2]

In two widely publicised cases involving elite controllers – Loreen Willenberg and the Esperanza Patient – this phenomenon may have resulted in a natural cure of HIV.

More recently, a small study published by the laboratory of Xu Yu at the Ragon Institute has offered a hint that something similar may be occurring in people on long-term ART. [5]

Seiger’s CROI presentation built on this work, analyzing the location of integrated HIV in eight people who’ve been on ART for an average of around 20 years (the range was 17-23 years). In this group, approximately 84% of the intact HIV that could be detected was in locations in the genome that are unfavorable to reactivation. In contrast, only 31% of intact HIV in a cohort of 43 people on ART for a shorter duration (1-13 years) was in similar locations.

Seiger noted that this offers evidence that cells containing HIV capable of reactivating are preferentially eliminated over time in people on long-term ART—likely because the activity of HIV can generate viral proteins that flag the cells for destruction by the immune system.

Additional evidence supporting this scenario is that non-intact, defective integrated HIV DNA doesn’t show a similar pattern. When Seiger analyzed defective integrated HIV DNA in the group on long-term ART, there was no evidence for preferential elimination of defective HIV DNA located in more active regions of the genome.

The results are encouraging because they suggest that, over time, HIV-specific immune responses in people on ART can contribute to reducing the reservoir of intact HIV.

As reported by Jon Cohen for Science Magazine in January, the next step for this research is to conduct careful analytical treatment interruptions (ATIs) in people who’ve been on long-term ART and whose remaining intact HIV DNA is integrated into apparent gene deserts. [6]

The hope is that the only intact HIV left in their bodies may be inert and incapable of causing viral load rebound. The researchers stress, however, that only individuals with a particular HIV reservoir profile will be eligible for these studies, and people on long-term ART shouldn’t attempt ATIs on their own.

The evidence that HIV-specific immune responses can reduce the intact viral reservoir in people on ART also provides a fillip for efforts to bolster these responses with immune-based therapies, such as CAR T cells, broadly neutralising antibodies and therapeutic vaccines.

Chimeric antigen receptor (CAR) T cells

During an interactive session on chimeric antigen receptor (CAR) T cells, Jim Riley from the University of Pennsylvania revealed preliminary results from an ongoing clinical trial in people with HIV. [7, 8]

The CAR approach involves genetic modification of T cells to equip them with receptors that enable better recognition and killing of specific targets. CAR T cell candidates designed to recognize and kill cancerous cells have shown efficacy in clinical trials and several are now licensed as cancer treatments.

Riley’s study administered CAR T cells designed to target HIV-infected cells, in combination with CD4 T cells that have been genetically modified to block expression of the CCR5 receptor (which HIV uses to enter cells). The latter strategy was developed by Sangamo Therapeutics. Each study participant had their cells sampled, expanded and modified in the laboratory, and then reinfused.

Riley was able to share data from eight participants. Four started an ATI the day after receiving the cell infusions and four waited eight weeks after the infusion before undergoing ATI. All participants in the first group experienced viral load rebounds over 100,000 copies/ml, which necessitated restarting ART before the end of the planned 16-week ATI. In contrast, the second group were able to complete the ATI with viral loads mostly in the low thousands.

One participant maintained a very low viral load and didn’t restart ART after 16 weeks. This individual has now been followed for around 16 months off ART and the most recent viral load was 37 copies/ml.

Riley noted that this person had participated in previous Sangamo trials and had received two infusions of CD4 T cells genetically modified to block expression of the CCR5 receptor. While this single case of extended viral load control off ART is an outlier in the context of the trial, the outcome suggests that strategies aiming to bolster the number of gene-modified cells are worth pursuing.

Riley’s research group already has a potentially enhanced CAR T cell design that they intend to move into trials. This newer CAR T cell includes the co-stimulatory molecules 4-1BB and CD28 and, in animal models, showed increased proliferative potential and activity.

More on broadly neutralising antibodies (bNAbs)

Rosás-Umbert explained that bNAbs can bind to HIV and chaperone the virus into cell pathways that promote antigen presentation (in other words, help make HIV visible to other components of the immune system, including T cells). Evidence for bNAbs boosting virus-specific CD8 T cell responses has been previously reported in both macaque and human studies. [11, 12]

Among eCLEAR study participants with HIV that was sensitive to 3BNC117, Rosás-Umbert found that CD8 T cell responses targeting HIV Gag and Pol proteins were significantly higher at months three and 12 of follow up compared to other participants.

The ability of T cells to produce the cytokine interferon gamma in response to HIV Gag was also significantly greater in participants with HIV that was sensitive to 3BNC117, and this capacity was associated with maintenance of viral load below 5,000 copies/mL during an ATI (in one case, HIV viral load has remained undetectable for 3.7 years off ART). [13]

A poster presentation by Christian Gaebler from Rockefeller University debuted results from a trial combining two bNAbs, 3BNC117 and 10-1074, in people with HIV on ART. [14]

As in previously published studies from the same group, the bNAbs showed strong anti-HIV activity. [15]

The most intriguing finding was that two participants were able to maintain HIV viral load suppression without ART for an extended period after bNAb administration. One of the individuals has since been lost to follow up, but the other is approaching three years off ART with no viral load rebound. Similarly prolonged post-treatment control of viral load was observed for two participants in a prior trial of this bNAb combination. [16]

Taken together, these results strongly support the idea that bNAbs can have a vaccine-like effect that improves the immune response to HIV. The challenge now is to increase the proportion of people able to control viral load after an ATI. Multiple trials of bNAb combinations are ongoing (see TAG’s Research Toward a Cure Trials listing) and many more are planned. [17]

Source

Jefferys R. Genomic entrapment of HIV in people on long-term antiretroviral therapy, chimeric antigen receptor T cells and more on bNAbs. TAG Basics Science Blog. (21 March 2022).
https://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2022/03/croi-2022-genomic-entrapment-of-hiv-in-people-on-long-term-antiretroviral-therapy-chimeric-antigen-r.html

References

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   https://www.croiconference.org/abstract/selection-of-intact-hiv-1-proviruses-in-deep-latency-during-long-term-art
2. Jiang C et al. Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Nature. 2020;585(7824):261-267. doi:10.1038/s41586-020-2651-8.
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837306
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   https://www.treatmentactiongroup.org/cure/media-monitor/story-the-esperanza-patient-argentinian-womans-immune-system-may-have-cleared-all-intact-hiv
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