CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

Background: Recent studies in adults indicate early potent antiretrovirals (ARV) in acute HIV infection may reduce viral reservoir size, and potentially result in better long- term viral control. There is limited data, however, on the large population of HIV-infected high-risk youth. We hypothesize that the decay of HIV reservoirs and accompanying immune responses are different in youth who have an active thymus and are treated early with potent ARV. As part of a clinical trial, ATN 147, which identified acutely or recently HIV- infected youth (12-24 years), we assessed HIV viral load by HIV RNA PCR, viral reservoirs by DNA ddPCR and HIV antibody at baseline and sequentially for 12-24 months. Methods: ATN CARES enrolled 75 high risk youth in Los Angeles and New Orleans with newly diagnosed HIV infection; i.e., Fiebig 1-V, acute ( 34 %);, VI, recent (66%). Samples were collected at baseline, 1 & 2 weeks, 1, 2, 4, 8, 12, 18 and 24 months for plasma HIV RNA <20cp/ml (UD), HIV DNA measured by ddPCR on PBMC with primers SR1/661/ZXF. HIV antibody by Western blot (BioRad) was done at baseline for Fiebig staging and 12, and 24 mos. post treatment. Youth were considered complete responders (CR) if plasma HIV RNA became undetectable and sustained at <20cp/ml (UD), partial responders (PR) if HIV RNA became UD with minor blips and non-responder (NR) if HIV RNA never reached UD. Results: 14 male MSM (mean age 21) reached > 12 mos. of follow-up to date. Eight were CR, 5 PR and 1 NR. Median HIV DNA ddPCR at baseline (N=14) was 457 (SD 852) and decreased to 186 (SD 304) copies/10e6 at 52 weeks (p=0.02). HIV DNA levels remained constant or increased in 3/14; 11 had a decrease and 1 of these had very low levels <4 cp/10e6 at 52 wks. HIV AB measured by Western blot showed a significant decrease in HIV bands resulting in a negative or indeterminate results in 6/14 (43%) at 12 months post ARV Two of these participants were Fiebig stage 5 at entry. The median time to UD plasma HIV RNA was 14 wks. (range 3-34) in 13/14 participants. An example of biomarkers in a CR is shown in the figure. Conclusion: Identification, recruitment, treatment and follow up of high risk U.S. youth with acute/recent HIV is feasible. Early ARV can reduce HIV DNA levels and HIV antibodies in a subset with persistent virus suppression. Youth with lower levels of HIV viral reservoirs are a key target for future evaluation of CURE/ remission strategies including therapeutic vaccination.

we analyzed tissues obtained from individuals who underwent autopsy after expiring with comorbid neoplasms. Methods: Participants (N=2) underwent autopsy after therapy for primary effusion lymphoma (PEL) or metastatic adenocarcinoma; both were on effective ART with HIV RNA < 50 c/ml. Tissue samples (lung, mediastinal lymph node, spleen, testes, liver, and neoplastic tissue, including individual metastases) were obtained during autopsy; nucleic acid was extracted and levels of HIV and total cellular DNA were quantified by qPCR as previously described. HIV integration sites were determined for one individual with PEL [for whom single genome sequencing (SGS) have been reported]. For the individual with adenocarcinoma, HIV pro-pol SGS were obtained. Results: Levels of HIV DNA were diverse (range 30-700 copies/10 6 cells), highest in lymphoid tissue. In the individual with PEL, 391 integration sites were obtained from lymph node, lung, spleen, and testes; 72 sites (18.4%) were from cell clones. Clones were detected within individual tissues, but were also present across tissues, in both local (lung and draining lymph node), and distant tissues (lung, spleen, testes); infected cells were present in the effusion. HIV was integrated in many host genes, including STAT5B, which has been associated with clonal expansion and persistence of infected cells. In the individual with adenocarcinoma, 183 SGS were recovered; HIV was genetically highly diverse, but identical sequences were present, these were possible cell clones. Identical sequences were present within and across tissues. Individual metastases all contained HIV infected cells. Conclusion: Populations of clonally expanded HIV infected cells are widely, but not uniformly, distributed in individuals with neoplasms, showing that cells from some of the largest infected clones are widely distributed in different tissues. Tumors contain infected cells and analyzing neoplasms contributes to understanding their role in the immune response during ART. 381 LOW FREQUENCY OF CTL ESCAPE MUTATIONS IN INTACT PROVIRUSES FROM ELITE CONTROLLERS Xiaodong Lian 1 , Chenyang Jiang 1 , Ce Gao 1 , Joshua Chevalier 1 , Ben S. Rhee 1 , Jane Blackmer 1 , Kevin Einkauf 1 , Xiaoming Sun 1 , Mary Carrington 2 , Bruce D. Walker 1 , Mathias Lichterfeld 3 , Xu G. Yu 1 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 National Cancer Institute, Frederick, MD, USA, 3 Brigham and Women's Hospital, Boston, MA, USA Background: Elite controlles (ECs), maintain undetectable plasma virus levels in the absence of antiretroviral therapy, and serve as a model for cure of HIV-1 infection. Cytotoxic T lymphocytes (CTL) are widely recognized as the immune correlate most closely associated with an elite controller phenotype, but the frequency of CTL-driven mutations in intact proviral sequences from such individuals is unknown. Methods: Single-genome near full-length proviral sequencing was used to analyze the proviral reservoir in 49 untreated ECs with undetectable viral loads for 1-20 years and in 28 HIV-1 patients treated with ART for 2-19 years. Optimal epitopes and escape mutations associated each person’s HLA-A, -B, and -C alleles were obtained from the Los Alamos HIV Immunology Database. Integration sites of intact proviruses were analyzed by Matched Integration Site and Proviral Sequencing (MIP-Seq) assays. Results: We obtained 199 and 89 near full-length intact proviral genomes from ECs and ART-treated individuals. A median of 47 optimal epitopes corresponding to expressed HLA Class I alleles were analyzed in ECs, compared to 49 in ART- treated individuals. Frequencies of CTL epitopes matching the clade B consensus sequence were higher in ECs relative to ART-treated patients (47.4% vs 37.9%, p=0.0005). Moreover, the proportion of CTL epitopes displaying known escape mutations was lower in ECs than in ART-treated individuals but did not reach statistical significance (5.67% vs 7.32%, p=0.2818). Among individuals carrying the protective HLA-B*27 and B*57 alleles, optimal epitopes from EC were more likely to show wild-type sequences (43.5% vs 30.4%, p=0.0013), and less likely to encompass previously defined CTL escape mutations (5.84% vs 17.4%, p=0.0043). Notably, among ECs, intact proviral sequences integrated in centromeric satellite DNA and non-genic DNA tended to exhibit lower frequencies of defined CTL escape mutations, compared to the intact proviral sequences integrated in non-centromeric DNA (p=0.0245) or genic regions (p=0.0254). Conclusion: EC exhibit low frequencies of CTL escape-associated mutations in intact proviruses, despite the absence of antiretroviral therapy, suggesting either lack of viral replication or effective targeting of mutationally intolerant epitopes. The low proportion of CTL escape mutations in intact proviruses

Poster Abstracts


Monica A. Gouzoulis 1 , Daria W. Wells 2 , James Q. Virga 1 , Camille M. Lange 1 , Kristi Huik 1 , Shawn Hill 1 , Stephen M. Hewitt 3 , Rob Gorelick 2 , Thomas S. Uldrick 4 , Joseph A. Kovacs 3 , Robert Yarchoan 3 , Xiaolin Wu 2 , Stephen H. Hughes 1 , Frank Maldarelli 1 1 NIH, Frederick, MD, USA, 2 Leidos Biomedical Research, Inc, Frederick, MD, USA, 3 NIH, Bethesda, MD, USA, 4 Fred Hutchinson Cancer Research Center, Seattle, WA, USA Background: HIV persistence during combination antiretroviral therapy (ART) is the principal challenge preventing viral eradication. We and others reported that HIV infected cells undergo clonal expansion during ART, and we reported that clones of infected cells are present in tissues and in a neoplasm. The tissue distribution of infected cells and their roles in HIV persistence are not well understood. To determine the distribution of clones of infected cells during ART,

CROI 2020 131

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