The 2019 HIV and Hepatitis B Cure Forum took place on 20-21st July immediately before the 10th International AIDS Society Conference on HIV Science (IAS 2019) in Mexico City this week.

The forum this year included research into curing chronic hepatitis B
infection as well as HIV, as the two viruses share similarities, the
chief one being that they mainly cause disease by generating a damaging
immune response to their viruses rather than, as other viruses do,
killing cells directly.

In HIV the problem that prevents a cure has always been that a
minority of HIV-infected cells are long-lived, quiescent so-called
‘reservoir cells’ that the immune system fails to recognise and
eliminate.

The forum heard of some exciting new genetically-engineered molecules
that have the potential to seek out and kill these cells, even without
using a chemical ‘kick’ to flush them out of hiding.

One of the most promising was IMMTAV. This high-tech drug, already used
in cancer research, involves remodelling T-cells taken from participants so
that the receptor proteins they have on their surface, which normally
do the job of detecting all kinds of viruses, are altered so
that their response becomes exquisitely HIV-specific and potent. 

Lucy Dorrell of Oxford University told the forum that IMMTAV is
developed by a process of repeatedly refining and retuning the
sensitivity of T-cell receptors, and the genes that generate these
proteins. The first version of IMMTAV was developed from T-cells taken
from an elite controller with a strong anti-HIV CD8 T-cell response. Their CD8 cells recognised a specific string of amino acids – a
peptide – that is a highly-conserved portion of HIV, i.e. one that the
virus cannot easily mutate away from. Infected cells display such
epitopes on their surface as ‘distress signals’ to alerts the immune
system that they are infected.

IMMTAV cells are similar to CAR T-cells (Chimeric Antigen Receptors), a type of cell with genetically altered receptors that
have been used to detect and kill cancer cells. However, they can only
detect the 10% of so of viral proteins that infected cells have on their
surfaces, chiefly proteins from the HIV envelope. Part of the problem
with reservoir cells is that they often do not display many of these
envelope proteins.

IMMTAV cells can recognise the signals of viral proteins buried deep within the cell.

Part of the problem with such technologies in the past is that the
molecular complexes that recognise the foreign proteins from infected
cells are extremely short-lived – they only last as complete entities
for a matter of seconds. The process of maturation and selection that
generates IMMTAV receptors also greatly extends their persistence, to
the extent that the IMMTAV T-cell receptors developed now have a
half-life of nearly two days.

Dorrell showed a video of IMMTAV T-cells attaching themselves to and
destroying infected cells, taken from people with HIV, in the test tube.

At present, the IMMTAVs developed only recognise components from the
HIV gag structural protein, and their core component is HLA-A2, which is
only one of the many HLA (human leukocyte antigen) proteins that
distinguish between self and non-self substances in the body. This means
they are rather too specific at present but other varieties of IMMTAV
are in development.

The most exciting aspect of IMMTAV cells is that they have been shown
to kill reservoir cells without being used alongside an
immune-stimulating drug that activates the cells so they can be ‘seen’
by cell-killing therapies. One disadvantage of this strategy is that the
activated cells start producing HIV again, with the risk of seeding a
new wave of HIV infection. But IMMTAV cells were able to kill reservoir
cells without any activation or viral production – a ‘kill’ without the
‘kick’. Control experiments also showed that non-infected cells were not
attacked by the therapy.

This technology needs more development before it can be used in human
trials, mainly by broadening the number of viral epitopes it is
responsive too, but may offer the best hope yet of a therapy that
detects and kills reservoir cells.