IAS 2023: Rapporteur summary Track A – basic science

1 September 2023. Related: Conference reports, Cure-related research, Basic science and immunology, Vaccines and microbicides, IAS 2023 Brisbane.

The following report is based on an edited transcription of the rapporteur summary at the end of the conference, with additional original content added for some of the selected studies.

bNAbs in vaccine and cure-related research

An early plenary session included two talks looking at how monoclonal antibodies (bNAbs) are being used in vaccines and cure research. [2]

In the first talk, Wilton Williams, from Duke University School of Medicine gave an overview of HIV vaccine research that aims to induce bNAbs that target HIV surface proteins to block infection.

This included new data from the exciting HTVN133 vaccine study that induced HIV-1 neutralising B cell lineages in humans, showing late, intermediate and early bNAbs that were maturing and showed progressive neutralisation capacity. [3]

The second plenary, from Katharine Bar, University of Pennsylvania, reviewed use of bNAbs in cure-related research, and as a component of combination immunotherapy, including at ART initiation and as therapeutic vaccination.

Exciting data demonstrated that on ART the neutralisation capacities of bNAbs can increase, providing optimism for vaccine approaches that could enhance autologous neutralisation antibodies. This included a phenomenal overview of this field that also gives us optimism for vaccines. [4]

A potential HIV cure from wild-type CCR5 donor

Asier Sáez-Cirión from the Pasteur Institute in France presented results of another case of potential cure following autologous stem-cell transplant. [5]

This case is a man in his 50s, diagnosed in 1990, now referred to as the Geneva patient (number 34 in the ICISTEM register). He had continuous viral suppression on ART since 2005 and was diagnosed with biphenotypic sarcoma (extramedullary myeloid tumour) in 2018. The treatment also included total body irradiation (4×2 Grays) + chemotherapy.

This case is ICISTEM patient number 34, named as the Geneva patient, who notably had a stem cell transplantation with a wild-type CCR5 donor. This person has now shown undetectable viral load off-ART for over 20 months. This case had several regions of graft vs host disease (GVHD) across his therapy. Although he also used PrEP, this was only twice and using on-demand (2:1:1) dosing at months 2 and 12 after stopping ART.

Role of microbiome in HIV transmission

In back-to-back sessions on the same day J Victor Garcia from the University of North Carolina, presented results on the importance of the gut microbiota in HIV transmission. [6]

Working with the germ-free BLT humanised mouse model, these animals were unable to be initially infected, after both oral and rectal HIV exposure. After subsequent doses, a few animals did show viraemia, suggesting an important role for the microbiota enhancing HIV acquisition. This model can now be used to better understand the role of the microbiome in HIV pathogenesis and cure.

Targetting cells in the viral reservoir

The following day, Karsten Eichholz from the Fred Hutchinson Cancer Center presented results showing that anti-PD-1 CAR-T cells can efficiently target SIV-infected CD4 cells in rhesus macaques showing complete removal of these cells. There seemed to be SIV replication, the T cells suggesting potentially an impact on immune responses. An important caution however, is that a couple of the animals developed lymphoma, showing the importance of finding better ways to develop these CAR T cells targeting the receptor in combination with others to improve the efficiency of these approaches. [7]

Following ART interruption, there was a higher viral rebound in CAR T-treated animals and also accelerated disease progression, associated with the acute depletion of CD8+ memory T cells after CAR T infusion in SIV+ animals on ART.

• 10-100 higher viral set-point in CAR-expanded animals.
• Viral set-point comparable to historical controls in animals treated with anti-CD8 antibodies (Okoye et al, 2021, JCI).
• Additional signs of immunodeficiency included opportunistic infections (lymphocryptovirus; LCV), LCV-associated lymphomas and loss of germinal centre Ki67+ B cells, due to absence of TFH cells.

Measuring antibody responses and viral escape

Alejandro Balazs from the Ragon Institute, talked about using a recombinant AAV vector to deliver immunotherapy using several different bNAbs and he expanded on the mechanisms for viral escape. [8]

Earlier animal studies previously showed that a single shot can generate antibody expression for many years in both immunocompetent and immunocompromised animals. Human studies conducted using an HIV-constructed vector using VRC603 showed that a single shot produced bNAb for over three years. However, levels are not as high in animals and occasionally result in anti-drug antibodies.

New data were presented on how vectored antibody delivery is being used for functional cure research in humanised BLT mice that have been infected with HIV and then given VRC07 and compared to controls. About half the treated animals continued to suppress viraemia and half initially suppressed but later rebounded.

However, repeating the experiment using two different bNAbs – PGM1400 and N6 – produced high drug levels and antibody expression but without any impact on reducing viral load. The different responses within the VRC07 groups were explained by different patterns of resistance, mainly requiring multiple mutation before viral load rebounded.

In contrast, the lack of viral effect with PGM1400 and N6 occurred due to a single mutation that generated complete resistance. The group then developed an escapability index to categorise and score responses across different antibodies under different viral selective pressure, which might be more appropriate than comparing in vitro potency.

Obatoclax selectively induces cells with intact but not defective HIV

An oral abstract session on viral persistence included a presentation from Steven Yukl from UCSF on differential susceptibility of cells infected with intact or defective HIV when presented within small molecule therapies. [9]

This group identified Obatoclax, a Bcl-2 inhibitor, which was able to reduce HIV DNA in this in vitro ex vivo assay of PBMCs from ART-suppressed individuals.

It was exciting that this particular drug was able to selectively deplete cells with intact proviruses but not those with defective DNA. Further studies will test combinations with Obatoclax in animal and human models.

Obatoclax (Bcl-2 inhibitor) reduces intact HIV DNA