CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

192 PERMANENT CONTROL OF HIV-1 PATHOGENESIS IN EXCEPTIONAL ELITE CONTROLLERS Cristina Gálvez 1 , Concepcion Casado 2 , Maria Pernas 2 , Laura Tarancon-Diez 3 , Carmen Rodriguez 4 , Victor Sánchez-Merino 2 , Mar Vera 4 , Rebeca S De Pablo- Bernal 3 , Alberto Merino-Mansilla 2 , Jorge Del Romero 4 , Ramon Lorenzo- Redondo 5 , Ezequiel Ruiz-Mateos 3 , Maria Salgado 1 , Javier Martinez-Picado 1 , Cecilio Lopez-Galindez 2 1 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 2 Institute of Health Carlos III, Madrid, Spain, 3 Institute of Biomedicine of Seville, Sevilla, Spain, 4 Centro Sandoval, Madrid, Spain, 5 Northwestern University, Chicago, IL, USA Background: Elite controllers (EC) represent a small subset of HIV-1-infected people able to spontaneously control viral replication. However, natural virological suppression and absence of immune dysfunction are not always long-term sustained. Exceptional EC (EEC) are HIV-1 subjects who maintain the EC characteristics without disease progression for more than 10 years. Methods: We analyzed three EEC from the Sandoval Health Center in Madrid, diagnosed between 1988 and 1992, who without antiretroviral treatment have never shown signs of clinical progression. A comprehensive clinical, virological, and immunological study has been performed. Results: The three EEC studied, diagnosed for more than 25 years, simultaneously exhibited previously described EC characteristics as ≥3 host protective alleles, low levels of total HIV-1 DNA (<20 copies/10 6 CD4+ T-cells), absence of viral transcription, without evidence of replication-competent viruses (<0.025 Infectious Units Per Million). This was consistent with high levels of defective genomes, and strong cellular HIV-1-specific immune response with a high poly-functionality index (>0.50). Inflammation levels of EEC (measured as plasma levels of hsPCR, β2-microglobulin, D-Dimer, IL-6 and sCD163) were similar to HIV-1 negative donors. Remarkably, they showed 8-fold lower genetic diversity (<0.01 s/n) in env gene than transient EC, and an exceptional lack of viral evolution. Conclusion: We postulate that these EEC should be considered unique cases of spontaneous functional HIV-1 cure. Low genetic diversity and lack of viral evolution distinguish these individuals from other EC. The combined non- functional HIV-1 reservoir, extremely low viral diversity and an HIV-1-specific immune response seems to be key to mimic these cases of spontaneous functional cure in future eradication strategies. 193 LACK OF DONOR-DERIVED SUPERINFECTION IN HIV+ TO HIV+ KIDNEY & LIVER TRANSPLANTATION Tania S. Bonny 1 , Charles Kirby 1 , Craig Martens 2 , Christine Durand 1 , Niraj Desai 1 , Sander S. Florman 3 , Diane M. Brown 1 , Dorry Segev 1 , Aaron Tobian 1 , Andrew D. Redd 1 Background: HIV+ to HIV+ organ transplantation offers HIV-infected patients a unique treatment option for end-stage kidney and liver disease. One of the primary concerns for these surgeries, however is the risk of HIV superinfection (HIV-SI), which occurs when an HIV+ individual becomes infected with a new distinct HIV strain. Methods: HIV+ to HIV+ kidney and liver transplant recipients were followed in a prospective observational study (NCT02602262). Peripheral blood mononuclear cells (PBMCs) were collected from recipients (14=kidney and 8=liver) and their respective donors (n=14) at the time of transplant (week 0) and followed post-transplant (spanning fromweeks 13 to 104 post-transplant). Serum taken during a viremic episode from one recipient due to antiretroviral therapy (ART) non-adherence three years post-transplant was also evaluated. HIV proviral DNA from PBMC and viral RNA from the serum sample were extracted, amplified, and sequenced using a site-directed next generation sequencing (NGS) assay for both the reverse transcriptase region of pol and the gp41 portion of envelope with a sensitivity to detect minor variants at ≥1%. Neighbor-joining trees were constructed to examine for the presence of HIV-SI. Results: Sequence data was obtained for 18 of the 22 recipients and 12 of the 14 matched donors (median amplicons analyzed: recipient gp41=54582, pol=74369; donor gp41=89304, pol=51715). Phylogenetic analyses of recipient HIV sequences from one or more time points post-transplant and/or with their corresponding donor sequences revealed the donor and recipient pol and gp41 sequences clustered separately, thereby indicating no evidence of HIV-SI in all patients examined (n=18). In the serum taken during the viremic episode (viral load=2,080,000), only recipient virus sequences could be detected (total 1 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 NIAID, Baltimore, MD, USA, 3 Mt Sinai School of Medicine, New York, NY, USA

with a >50-fold higher likelihood than patients without HIV in platelets (OR: 56, 95%CI: 4.3-719.2, p=0.002). Conclusion: Altogether, our results reveal that platelets act as a neglected transient shelter for infectious HIV in the blood of HIV-infected cART- suppressed patient. Platelets carrying HIV establish an alternative pathway for HIV dissemination in correlation with immunological failure, thus opening new treatment strategies for immunological nonresponders, for whom no efficient treatment is available yet . Furthermore, HIV contained in platelets can potentially fuel the tissue-macrophage reservoir we recently described in cART-suppressed patients (Ganor, Real et al., Nat Microbiol, 2019) in a process inhibited by the therapeutical anti-platelet agents.

Poster Abstracts

191 FOLICLE MORPHOLOGY AND HIV RNA DISTRIBUTION IN SPLEEN OF HIV+ HUMANIZED DRAGA MICE Joy M. Folkvord 1 , Matthew T. Ollerton 1 , Kristina K. Peachman 2 , Soumya Shashikumar 2 , Elaine B. Morrison 2 , Linda Jagodzinski 2 , Richard D'Aquila 3 , Sofia Casares 2 , Mangala Rao 2 , Elizabeth Connick 1 1 University of Arizona, Tucson, AZ, USA, 2 Walter Reed Army Institute of Research, Silver Spring, MD, USA, 3 Northwestern University, Chicago, IL, USA Background: The humanized DRAGA mouse model of HIV infection generates high viral loads, HIV-specific antibodies, and B cell follicles. Knowledge of follicle (F) morphology and HIV RNA distribution within secondary lymphoid tissues (SLT) of these mice is lacking. We assessed whether HIV+ DRAGA mice develop germinal centers (GC), whether F harbor high concentrations of HIV RNA+ cells, and whether follicular dendritic cells (FDCs) are present and trap HIV particles. Methods: DRAGA (HLA-DR4.HLA-A2.Rag1KO.IL2RgcKO.NOD) mice (n=17) were infused with HLA-matched human hematopoietic stem cells (hHSCs) from cord blood and 7 were infected with HIV at 4-10 months post-hHSC infusion. Snap frozen spleens were stained with antibodies to human CD20, CD4, IgD, Ki67, FDC, and mouse FDC and analyzed by microscopy. HIV RNA was detected by RNAscope, %CD4 and %FDC by quantitative image analysis, plasma viral load by a modified Abbott RealTime HIV test and HIV-specific p24 and gp41 antibodies by ELISA. Non-parametric tests were used for analysis. Results: No GC (IgD-Ki67+ regions) were seen in DRAGA spleen; IgD+ and Ki67+ cells were dispersed throughout F (CD20+ area). Human FDCs were not detected in any mice. Mouse FDCs were found throughout the F in contrast to normal mouse where FDCs localize in GC. %FDC+ area tended to be higher in HIV+ vs HIV- spleens (median 6% vs 2.9%; p=0.06). Many CD4+ cells localized within F (median, 70% in HIV- and 50% in HIV+; p=0.07). In 4 mice sacrificed at 4 months post HIV infection, more HIV RNA+ cells were located in F than extrafollicular regions (median, 128 vs 14 cells/mm 2 ), but differences disappeared when adjusted for CD4. In these mice, first HIV-specific IgM and then IgG antibodies were detected in plasma over time. HIV RNA particles colocalized with FDC in these animals, but not in 3 acutely infected animals (<16 days). Conclusion: DRAGA mice lack canonical GC in spleen, possibly because of incompatible signaling between mouse FDCs and human lymphocytes. Despite this, they produce HIV-specific and class-switched antibody. In chronic infection, HIV RNA+ cells are concentrated in F (likely due to high numbers of CD4+ cells rather than heightened permissivity) and HIV RNA+ particles are associated with mouse FDC (likely bound via human antibody). Thus, the DRAGA model recapitulates some key aspects of HIV disease in SLT. This knowledge is important in the use of the DRAGA mouse model in HIV immunopathogenesis studies.

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CROI 2020