Manipulating the immune system to tackle HIV
Positively Aware Richard Jeffreys
By Richard Jefferys @TAGHIVscience

The immune system can be a potent weapon against disease, and a major avenue of cure research involves attempting to enhance the immune response against HIV. The task is challenging, not least because one of the properties of the virus is that it infects and compromises CD4 T cells, the component of the immune system normally responsible for coordinating anti-viral immunity.

Multiple clinical trials are investigating whether immune-based approaches can deliver the “kill” in “kick & kill.” This strategy combines latency-reversing agents (the “kick”) with interventions designed to enhance the ability of the immune system to recognize and destroy the latently infected cells that are stimulated to produce HIV. Researchers are also studying whether immune-based therapies can promote control of viral load after ART is interrupted. (See chart)

CURRENT CANDIDATE IMMUNE-BASED THERAPIES
APPROACH DESCRIPTION EXAMPLES STATUS
Broadly neutralizing antibodies (bNAbs)

Antibodies capable of potently inhibiting the replication of diverse HIV variants

There is evidence that some bNAbs can promote clearance of HIV-infected cells via mechanisms called antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP)—the antibodies bind to HIV proteins expressed on the outside of cells that have been induced to produce virus, flagging them for destruction by the immune system

VRC01

3BNC117

10-1074

PGT121

In early phase trials, including in dual combinations

Two trials are investigating a “kick & kill” combination of 3BNC117 with the HDAC inhibitor romidepsin, a latency-reversing agent

Therapeutic vaccines

Designed to induce more effective immune responses against HIV than those seen in natural infection

Particular emphasis on promoting CD8 T cell (killer T cell) responses capable of recognizing and killing virus-infected cells

MVA.HIVconsv

ChAdV63.HIVconsv

Ad26.Mos.HIV

MVA-Mosaic

iHIVARNA-01

GTU-MultiHIV B-clade

MVA HIV-B

Many different clinical trials, including in combinations with the latency reversing agents romidepsin and vorinostat

Plans to combine therapeutic vaccination with the TLR-7 agonist vesatolimod

Adoptive immunity The extraction and expansion of anti-HIV CD8 T cells from HIV-positive individuals, followed by reinfusion HIV 1 antigen expanded specific T cell therapy (HXTC) In trials both alone and in combination with the latency-reversing agent vorinostat
Immune checkpoint inhibitors

Antibodies targeting molecules known to be expressed by dysfunctional “exhausted” T cells

Goal is to revive the activity of these T cells against their targets (e.g. virus-infected cells or cancerous cells)

Several are FDA approved as cancer therapies, but carry some risk of life-threatening side effects due to induction of autoimmunity

Studies suggest some immune checkpoint inhibitors may also have latency-reversing activity

durvalumab
(anti-PD-L1 antibody)

nivolumab
(anti-PD-1 antibody)

ipilimumab
(anti-CTLA-4 antibody)

pembrolizumab
(anti-PD-1 antibody)

Almost exclusively being studied in HIV-positive individuals requiring treatment for cancers due to potential risks

One trial is studying a single dose of pembrolizumab in
HIV-positive people without cancer

Toll-like receptor (TLR) agonists

Toll-like receptors (TLRs) are elements of the immune system capable of recognizing certain structural features shared by many different pathogens

TLRs play a role in generating immune responses to infections, and can be stimulated with products known as TLR agonists

There are indications that certain TLR agonists can both stimulate latent HIV and bolster immune responses to the virus

vesatolimod
(TLR7 agonist)

MGN1703
(TLR9 agonist)

Gilead Sciences is testing the effects of a TLR7 agonist in HIV-positive individuals, having seen promising results in animal studies

Researchers at Arhus University in Denmark are studying a TLR9 agonist

Cytokines

Signaling proteins produced by immune system cells with a multiplicity of potential effects

Certain cytokines may be able to bolster anti-HIV immune responses

Interest in interleukin-15 due to evidence it can also have latency-reversing effects

ALT-803
(recombinant human super agonist IL-15 complex)

IL-2

Alpha-interferon

Multiple ongoing trials
Anti-α4β7 integrin antibodies

Antibodies designed to target anti-α4β7 integrin, a molecule involved in the trafficking of CD4 T cells to the gut

Studies in animal models suggest administration may contribute to enhanced control of viral replication after an ART interruption

vedolizumab Initial trial underway
at the National Institutes of Health (NIH)
Chimeric antigen receptor (CAR) T cells

T cells genetically modified to better recognize and kill HIV-infected cells (see “Gene Therapy in HIV Cure Research”)

May need to be delivered in combination with CD4 T cells genetically modified to resist HIV entry

  Preclinical
(not yet in trials)