CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

373

Mycobacterium tuberculosis Infection Dampens the HIV-1 Antibody Response Marius Zeeb 1 , Chloé Pasin 1 , Irene A. Abela 1 , Katharina Kusejko 1 , Sonja Hartnack 2 , Julia Notter 3 , Hansjakob Furrer 4 , Matthias Hoffmann 5 , Hans Hirsch 6 , Alexandra Calmy 7 , Enos Bernasconi 8 , Huldrych F. Günthard 1 , Roger Kouyos 1 , Alexandra Trkola 2 , Johannes Nemeth 1 1 University Hospital Zurich, Zurich, Switzerland, 2 University of Zurich, Zurich, Switzerland, 3 St Gallen Cantonal Hospital, St Gallen, Switzerland, 4 University Hospital of Bern, Bern, Switzerland, 5 Olten Cantonal Hospital, Olten, Switzerland, 6 University Hospital Basel, Basel, Switzerland, 7 University Hospitals of Geneva, Geneva, Switzerland, 8 Ospedale Regionale di Lugano, Lugano, Switzerland Background: In prior investigations, we uncovered the impact of Mycobacterium tuberculosis (MTB) infection on the innate immune system in people with HIV (PWH). We showed an improved ability to control HIV and less susceptibility to opportunistic infections in untreated PWH. Intriguingly, it also heightened the risk of non- communicable diseases such as diabetes mellitus. Our exploration of the transcriptome in PWH, with and without MTB infection, unveiled gene alterations associated with innate immunity and B cell upregulation. Additionally, another group showed that active TB enhances immune responses. Here we extend these investigations and determine the effects of MTB infection on the anti-HIV-1 antibody (Ab) response. Methods: Using data from the Swiss HIV Cohort Study and the Swiss 4.5K neutralization Screen (Rusert, Nat Med, 2016), we assessed immune responses in PWH dependent on MTB status (excluding active TB and preventively treated). We examined two aspects: (i) plasma neutralization against eight HIV strains (activity/breadth score 0 to 24), and (ii) relative plasma Ab (IgG1/2/3) binding (score 0 to 1) to 20 HIV antigens. We determined the impact of MTB status by tobit and linear regression adjusting for ethnicity, age, sex, CD4, HIV viral load, viral diversity, and infection duration. We employed bayesian networks to elucidate interplays between factors, particularly disentangle direct and indirect effects. Results: Our analysis included 2,823 PWH (211 MTB infected). MTB infection was associated with a -0.74 (-1.44,-0.05) neutralization reduction in multivariable tobit regression. Moreover, MTB infection was associated with a -0.04 (-0.07,-0.01) binding decrease of epitopes/IgG classes (IgG2 trimer, IgG1 gp140, IgG1 V3), previously shown to be predictive of high neutralization. Bayesian network analysis (Figure) showed MTB infection was associated with a -0.36 (-0.63,-0.08) log 10 viral load decrease. In turn, one log 10 viral load increase, was associated with a 0.11 (0.03,0.19) neutralization increase. Conclusion: Consistent with our previous findings, our results underscore the immediate impact of MTB infection in reducing HIV-1 viral load. The resulting decreased exposure to HIV-1 antigen is likely the cause of the observed attenuated HIV-1 antibody response. While a modest decrease in binding Abs may be of limited consequence, a reduced ability to induce neutralizing Abs in untreated HIV and MTB co-infection may potentially counteract the gains in HIV-1 control induced by MTB.

374

Temsavir Treatment Enhances bNAb Recognition and Subsequent Clearance of HIV-1– Infected Cells Robert Ferris, Cristin Galardi, James Schawalder, Richard Dunham, Heather Madsen, Hangfei Qi ViiV Healthcare, Durham, NC, USA Background: HIV-1 gp120 is a viral envelope glycoprotein (Env) expressed on the surface of infected cells which renders it an attractive target for the clearance of the infected cells. However, Env is metastable and presents in multiple conformations, making it challenging for antibody-mediated clearance. Temsavir (TMR), the active form of the HIV-1 attachment inhibitor fostemsavir, binds to and stabilizes Env in a 'closed' conformation that may allow better targeting by broadly neutralizing antibodies (bnAbs). Methods: To understand whether TMR can modulate bnAb binding to Env on the infected cells, we conducted experiments with primary CD4+T cells isolated from HIV negative donors infected with a broad panel of viruses that includes 26 clinical HIV isolates. Antibody binding to Env on the infected cell surface was determined after 24h treatment with a serial titration of TMR ranging from 0 to 25μM. Results: We found that TMR treatment significantly enhances binding of bnAbs, including N6, to HIV-1 infected cells and leads to increased clearance of infected cells through antibody dependent cellular cytotoxicity (ADCC). This synergistic effect of N6 and TMR is most prominently observed on infected cells that maintain CD4 expression, the cells that are otherwise difficult to target by N6 and other bnAbs alone. The enhanced bnAb binding is diminished when tested against strains with reduced TMR sensitivity (clade AE), suggesting that it is an on-target MOA. We observed decreased bnAb binding to CD4 downregulated infected cells with some viruses. However, this effect only occurs at much higher TMR concentrations than required for neutralization and is not consistent across the panel. Alternatively, we saw significantly increased bnAb binding to the CD4 downregulated cells in 1/3 of isolates that are tested. Further analysis of HIV Env from infected cells demonstrated that the altered bnAb binding is not attributed to the modified gp160/gp120 processing by TMR. Conclusion: We have demonstrated for the majority of viruses tested that TMR treatment leads to enhanced bnAb binding to the infected cells that maintain CD4 expression, and the reduced bnAb binding to the CD4 downregulated infected cells occurs at much higher concentrations than neutralization. These results suggest that combination of bnAb and TMR can expand the population of HIV-1 infected cells susceptible to bnAb mediated clearance and may increase the likelihood of reservoir reduction in the clinical setting. AAV-1, -8, and -9 Seroprevalence in Healthy Donors and People Living With HIV in Sub- Saharan Africa Giselle Lopez Fernandez 1 , Daniel O'Hagan 1 , Siddhartha Shandilya 1 , Dorinda Mukura 2 , Tinashe Chidemo 2 , Alfred Kateta 2 , Rodney Goreraza 2 , Mookho Malahleha 3 , Zoe Moodie 4 , Mauricio A. Martins 5 1 The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA, 2 University of Zimbabwe, Harare, Zimbabwe, 3 Synergy Biomed Research Institute, London, United Kingdom, 4 Fred Hutchinson Cancer Center, Seattle, WA, USA, 5 The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Gainesville, FL, USA Background: Adeno-associated virus (AAV)-vectored delivery of monoclonal (m) HIV-specific broadly (b) neutralizing (n) antibodies (Abs) holds promise for treating HIV infection. Because AAV is non-pathogenic and its genome persists in host cells, successful AAV/bnAb transduction of long-lived cells, such as myocytes, can result in continuous bnAb expression for years, possibly

Poster Abstracts

375

87

CROI 2024