HTB

IAS 2023: Rapporteur summary track A – basic science

Simon Collins, HIV i-Base

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.

This issue of HTB includes summaries from Tracks A and C as Track B was included in the previous issue.

The Track A summary was presented by Professor Lishomwa Ndhlovu, from Weill Cornell Medicine in the US who included 12 key talks or studies, covering bNAbs, vaccine developments, potential cures and cure-related research, HIV and the microbiome and measuring and targeting the viral reservoir. [1]

  • bNAbs in vaccine and cure-related research.
  • A potential HIV cure from wild-type CCR5 donor.
  • Role of microbiome in HIV transmission.
  • Measuring antibody responses and viral escape.
  • Obatoclax selectively induces cells with intact but not defective HIV.
  • In vivo CCR5 gene-editing produces ART-free HIV control in mice.
  • HIV controllers.
  • New approaches to measuring the reservoir.

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

  • Goal: new therapies that promote selective killing of infected cells.
  • Screening in ex vivo PBMCs from up to nine ART-suppressed individuals.
  • Obatoclax induced selective depletion of cells with intact proviruses.
  • No reduction of total of defective HIV DNA.
  • Future studies should test combinations ex vivo and in animal of human trials.

In vivo CCR5 gene-editing produces ART-free HIV control in mice

In an oral abstract session on immune-based interventions towards an HIV cure, Priti Kumar from Yale School of Medicine presented results from in vivo genome editing of human T cells to edit CCR5 using CRISPR technology. [10]

This process used non-infectious virus-like particles (VLPs) coated with antibodies to human CD7, administered by IV injection. Direct gene-editing overcomes the need for stem-cell transplants to develop CCR5-delta 32 changes in immune function.

Although viral load rebounded several weeks after ART was stopped in this mouse study, with some loss of CD4 cells, immune responses quickly rebounded, also reducing and controlling HIV. Control animals all experienced rapid viral load rebound after stopping ART and dramatic CD4 loss. Upwards of 80% of T cells were edited for CCR5 which contained very little HIV DNA and the group were unable to generate outgrowth virus by the end of the study. The process was therefore highly effective in changing humanised cells and that produced ART-free HIV control in humanised mice.

The plenary on the final morning of the conference included two important talks – on the phenomenon of natural HIV controllers and on new ways to measure the viral reservoir.

HIV controllers

Asier Sáez-Cirión reviewed how a better understanding of the viral and genetic mechanisms that might contribute to the as-yet unexplained mechanism of natural viral control without ART could be used to inform cure strategies. [11]

This small group of people includes both elite and post-treatment controllers, some of whom have seroreverted after many years (decades) and may be candidates for remission or cure. However, HIV control can also be a transient state for controllers who maintain residual or intermittent viraemia, with CD4 declines that still need use of ART.

The talk also interestingly referred to a recent ANRS survey reporting that quality of life wasn’t necessarily better for controllers compared to non-controllers on ART. [12]

New approaches to measuring the reservoir

Ya-Chi Ho from Yale University reviewed the 25-year history of measuring the viral reservoir and what it contains and the problem of the one-in-a-million challenge to find a “needle in a needlestack”. [13]

Exciting new approaches to measure and map the heterogenetic cells in the reservoir are now using single cell and multiomic tools – instead of using bulk RNA sequencing that measures the >99% of uninfected cells. Early attempts, since 2016, still relied on activating cells in order to count them, which destroyed the latent profile.

However, over the last year, several platforms reported these new approaches to identify DNA containing sleeping cells (including FINDseq, PhePseq, ASAPseq, ECCITEseq and DOGMAseq). Barcoded cells can then show the development of the reservoir during the first year of ART and describe the development of the diverse range and behaviour of reservoir cells. These tools can now identify, at a single cell level, HIV-infected cells that are not actively expressing HIV RNA.

Harnessing ADCC responses in HIV vaccines

The final study highlighted was a plenary talk given by Guido Ferrari from Duke University, who looked at using antibody-dependent cellular cytotoxicity (ADCC) responses to increase vaccine protection against HIV infection. [14]

This involved using the traditional ALVAC vaccine backbone and adding additional envelope sequences to this prime boosting strategy. Results from human studies showed that we may need to improve the maturation responses by using multiple dosing and delayed boosting, but also that the antigenic diversity of these vaccine immunogens will allow for broad ADCC responses. 

Thanks to Richard Jefferys for additional editorial comments.

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 12th IAS conference (IAS 2023), 23–26 July 2023, Brisbane, Australia.

  1. Ndhlovu L. Rapporteur report back session. Track A. IAS 2023.
    https://conference.ias2023.org/media-1123-rapporteur-report-back-session
  2. Vaccines and cure research: spotlight on antibodies. IAS 2023. Plenary session PL01.
    https://programme.ias2023.org/Programme/Session/4365
  3. Williams W. Vaccines and cure: Spotlight on antibodies: Engineered HIV-1 immunogens to induce bNab responses. IAS 2023, plenary session PL01.
    https://programme.ias2023.org/Programme/Session/4365
  4. Bar K. Vaccines and cure: Spotlight on antibodies: Strategies for using antibodies for HIV cure. IAS 2023, plenary session PL01.
    https://programme.ias2023.org/Programme/Session/4365
  5. Sáez-Cirión A et al. Absence of viral rebound for 18 months without antiretrovirals after allogeneic hematopoietic stem cell transplantation with wild-type CCR5 donor cells to treat a biphenotypic sarcoma. IAS 2023, oral abstract OALBA0504.
    https://programme.ias2023.org/Abstract/Abstract/?abstractid=5819
  6. Garcia JV et al. Resident microbiota enhance HIV acquisition, replication, and pathogenesis in vivo. IAS 2023, oral abstract OAA0102.
    https://programme.ias2023.org/Abstract/Abstract/?abstractid=5101
  7. Eichholz K et al. Anti-PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers of rhesus macaques. IAS 2023, oral abstract OAA0205.
    https://programme.ias2023.org/Abstract/Abstract/?abstractid=1718
  8. Balazs A. Advances in gene delivery and engineering of T and B cells: Implications for prevention, therapy and cure: HIV broadly neutralizing antibody escapability drives therapeutic efficacy of vectored immunotherapy. IAS 2023, symposium SY12.
    https://programme.ias2023.org/Programme/Session/4362
  9. Yukl S et al. Differential susceptibility of cells infected with defective and intact proviruses to HIV-selective cell killing by small molecule therapies. IAS 2023, oral abstract OAA0302.
    https://programme.ias2023.org/Abstract/Abstract/?abstractid=1717
  10. Kumar P et al. In vivo genome engineering of human T cells results in ART-free control of HIV-1 in humanized mice. IAS 2023, oral abstract OAA0203.
    https://programme.ias2023.org/Abstract/Abstract/?abstractid=591
  11. Sáez-Cirión A. Understanding the HIV reservoir: New technologies and specific populations: Understanding elite control to inform cure strategies. IAS 2023, plenary session PL07.
    https://programme.ias2023.org/Programme/Session/4366
  12. Préau M et al. Does quality of life and sexual quality of life in HIV patients differ between non-treated HIV controllers and treated patients in the French ANRS VESPA 2 national survey? AIDS Behav. 2019 Jan;23(1):132-139. doi: 10.1007/s10461-018-2237-8.
    https://pubmed.ncbi.nlm.nih.gov/30073634/
  13. Ho Y-C. Understanding the HIV reservoir: New technologies and specific populations: New approaches to measuring the reservoir. IAS 2023, plenary session PL07.
    https://programme.ias2023.org/Programme/Session/4366
  14. Ferrari G. Immune responses critical for viral control and approaches to harness them in vivo: Requirements to harness ADCC responses for protection from HIV infection. IAS 2023, symposium SY20.
    https://programme.ias2023.org/Programme/Session/4437

This report was first published on 15 August 2023.

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