CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

Background: Studies of “elite controllers” (ECs) might lead to novel approaches for HIV cure. We characterized the clinical, immunologic and virologic characteristics of ECs with very low reservoirs (“exceptional controllers”). Such individuals may prove to be models for a functional cure. Methods: We systematically applied a clinical case definition to identify ECs within the SCOPE cohort. A related ART-treated cohort (n=80) was used for comparison. We measured CD4 T cell-associated (CA) HIV DNA and RNA using PCR frommedian 9M PBMCs, HIV-specific antibody responses using luciferase immunoprecipitation systems (LIPS), and T cell responses using flow cytometry. We stratified the sample by reservoir size and compared clinical outcomes, antibody response, and T cell immunophenotypes. Exceptional controllers were defined as ECs with no detectable HIV DNA. Clinical progression was defined as loss of virus control or CD4 decline requiring ART. Results: 96 individuals met our case definition. Median CA DNA and CA RNA was 1.5 (0-7.6) and 99 (4.8-317) copies/10 6 cells, respectively. These levels were significantly lower than those on ART (CA DNA 10.8 and CA RNA 2138 copies/10 6 cells, p<0.001 for both). CA DNA levels highly correlated with CA RNA levels (0.74, p<0.001). CA DNA levels were associated with antibody levels targeting matrix (r=0.30, p=0.008), integrase (r=0.26, p=0.03), and protease (r=0.27, p=0.02), but not envelope, or measures of T cell activation. 22 (23%) met our virologic definition of exceptional control. Exceptional controllers were more likely to have a protective HLA allele (B27 or 57; p=0.002) and less likely to progress clinically (18% vs 49%, p=0.02). Compared with the rest of the EC cohort, exceptional controllers had lower antibody levels to matrix (p=0.007), integrase (p=0.007), and protease (p=0.02), but comparable levels of T cell activation. In a logistic regression model, exceptional control was associated with presence of protective HLA alleles (6.8 fold effect, p=0.002). Conclusion: We identified a subset of controllers with very low HIV DNA and RNA levels, low HIV antibody levels, and lower risk of clinical progression. These individuals are enriched for certain HLA alleles, arguing that CD8+ T responses mediate control. Such individuals may not need ART and might prove to be a model for a “functional cure” or remission.

none of the HIV-1 only infected individuals had a similar or higher BP score as that observed among 2nd generation bnAbs (BP score range 0.71-0.98, p= 0.04). Neutralization BP score correlated with the total plasma IgG (r = 0.51, p= 0.003), but not with baseline viral load, absolute CD4 count, IL-6, soluble CD163 or MCP-1 concentrations. After completing TB treatment and starting HIV-1 therapy, HIV-1/TB (0.68 ± 0.07, n= 6, range 0.28-0.88) as compared to HIV-1 only infected subjects (0.57 ± 0.07, n= 8, range 0.34-0.82) still had higher neutralizing capacity, but the difference was not statistically significant (p= 0.56). The plasma activity of the 4 HIV-1/TB individuals with high baseline BP score clustered with CD4 binding site and membrane-proximal external region targeting bnAbs. Conclusion: Our results suggest that active TB enhances anti-HIV-1 antibody response, possibly leading to the emergence of bnAbs that target conserved envelope domains. Dissecting mechanisms that account for the enhanced HIV-1 neutralization in HIV-1 cases with TB could be leveraged in the generation of a more effective humoral response in HIV-1 vaccination and treatment. 266 IMPACT OF IMMUNE CHECKPOINT INHIBITORS IN VACCINE-INDUCED ANTI-HIV RESPONSES Miguel A. Marin 1 , Alba Ruiz 1 , Esther Jimenez-Moyano 1 , Dan Ouchi 1 , Oscar Blanch-Lombarte 1 , Daniel Gorman 2 , Ruth Penya 1 , Richard Barnard 3 , Christian Manzardo 4 , Tomas Hanke 5 , Christian Brander 1 , Bonnie J. Howell 6 , Bonaventura Clotet 1 , Beatriz Mothe 1 , Julia G. Prado 1 1 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 2 Merck & Co, Inc, Kenilworth, NJ, USA, 3 Merck & Co, Inc, Upper Gwynedd, PA, USA, 4 IDIBAPS, Barcelona, Spain, 5 The Jenner Institute, Oxford, UK, 6 Merck & Co, Inc, West Point, PA, USA Background: To attain the control or elimination of HIV-1 infection it is critical to delineate immune interventions capable of boosting or reinvigorating HIV- 1-specific CD8+ T-cell responses. Immune interventions, including therapeutic vaccines or immune checkpoint inhibitors (ICIs), have been postulated to achieve this goal. However, the potency of combining both immune interventions has not yet been tested. Here, we assessed ex vivo the impact of ICIs on vaccine- induced HIV-1 CD8+ T cell responses in samples from a vaccine trial conducted in early-treated HIV-1 infected individuals. Methods: We selected PBMCs of individuals from the BCN01 (NCT01712425) trial receiving early treatment and a ChAdV63.HIVconsv/MVA.HIVconsv prime- boost regimen (Etvac; n=12). For comparison, we selected PBMCs from early treated not vaccinated individuals (Et; n=13) and chronically treated individuals (Chro; n=11). PBMCs were CFSE-stained and stimulated with an HIV-1 peptide pool in the presence of anti-PD-1, anti-TIM-3, anti-PD-1+TIM-3 or isotype antibodies. After seven days, we quantified the frequency of CFSE-, IFNg+ and HLA-DR+/CD38+ HIV-1-specific CD8+ T cells by polychromatic flow cytometry. Also, we measured a panel of 17 human cytokines in the culture supernatants by multiplex assay. Results: The blockade of PD-1 in Etvac boosted the frequency of vaccine- induced HIV-1-specific CD8+ T-cell responses in terms of proliferation (p=0.004), IFNγ production (p=0.04), and HLADR+/CD38+ expression (p=0.004). These results were consistent for anti-PD-1+TIM-3 in the absence of response to anti-TIM-3. In Et, ICI did not have any effect while Chro individuals showed an increase in the frequency of HIV-1-specific CD8+ responses upon PD-1 or PD-1+TIM-3 inhibition. The cytokine profiling in Etvac individuals revealed a specific signature of IFNg, sFasL, GM-CSF, sCD137, IL-5, IL-13, Granzyme A, Granzyme B, MIP-1b and Perforin secretion in response to anti-PD- 1 that differed in Chro by the lack of IL-5 and IL-13 and the presence of IL-4 and IL-10. Conclusion: Our data demonstrate a significant increase in the magnitude of vaccine-induced HIV-1-specific CD8+ T-cell responses by ICIs linked to a particular cytokine signature profile in Etvac. Thus, we propose the combined use of ICI and therapeutic vaccines to boost vaccine-induced anti-HIV CD8+ responses in vivo. In addition, the use of combined ICI as an anti-HIV immunotherapeutic strategy in Chro warrants further investigation. 267 CHARACTERIZING “EXCEPTIONAL” CONTROL AMONG HIV ELITE CONTROLLERS Michael J. Peluso 1 , Peter Burbelo 2 , Shreya Kumar 1 , Sadie Munter 1 , Rebecca Hoh 1 , Sulggi Lee 1 , Peter W. Hunt 1 , Rachel L. Rutishauser 1 , Timothy J. Henrich 1 , Steven G. Deeks 1 1 University of California San Francisco, San Francisco, CA, USA, 2 NIH, Bethesda, MD, USA

Poster Abstracts

268 HIV-SPECIFIC CD8+ T CELLS EXHIBIT POOR CYTOLYTIC POTENTIAL IN THE HUMAN AIRWAY Raphael Kamng'Ona 1 , Leonard Mvaya 1 , Joseph Phiri 1 , Elizabeth Chimbayo 1 , Rose Malamba 1 , Anstead Kankwatira 1 , Henry Mwandumba 1 , Kondwani C. Jambo 1 1 Malawi–Liverpool–Wellcome Trust Clinical Rsr Prog, Blantyre, Malawi Background: HIV mRNA and proteins are detectable in airway samples from individuals on long-term ART with undetectable plasma viral load. Effector CD8+T cells play a direct role in the control of HIV replication through direct

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CROI 2020