CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

726 MYCOBACTERIUM TUBERCULOSIS COINFECTION INCREASES HIV RESERVOIR SIZE Jingna Xun, Hongzhou Lu, Jun Chen , Tangkai Qi, Yongjia Ji, Renfang Zhang, Li Liu, Yinzhong Shen, Wei Song, Yang Tang, Qi Tang, Zhenyan Wang Shanghai Public Health Clinical Center, Shanghai, China Background: Tuberculosis (TB) is the most frequent opportunistic infection among people living with HIV. The contribution of Mycobacterium tuberculosis (Mtb) co-infection in HIV reservoir establishment and maintain is not clear, hindering HIV/TB co-infected persons benefit from HIV cure strategy. Methods: We prospectively enrolled 38 HIV-infected participants with culture-confirmed TB and 35 participants with HIV mono-infection naïve to therapy. Participants received antituberculosis and/or antiretroviral therapy (ART) accordingly. Blood samples were collected from all the participants prior to therapy and after a median of 12 months of ART. Total HIV-DNA in peripheral blood mononuclear cells (PBMC) were quantified by real-time PCR. Plasma levels of interleukin-7 (IL-7), the key cytokine in the development and hemostasis of T cells, were measured by ELISA. Results: Levels of total HIV-DNA among participants with HIV/TB co-infection was significantly higher than that in HIV mono-infected participants at pre-ART (3.34 ± 0.42 log10/106 PBMC vs 2.70 ± 0.45 log10/106 PBMC, P<0.001). M.tb co-infection was identified as the only predictor of high HIV DNA level (Table). After 12 months of ART, the HIV reservoir size decreased significantly, which was positively correlated with their pre-ART level. HIV/TB co-infected participants, who had already been cured for TB, maintained a larger reservoir size compared to HIV mono-infection participants (2.86± 0.36 log10/106 PBMC vs 2.09 ± 0.60 log10/106 PBMC, P< 0.001). Multiple linear regression analysis showed that M.tb co-infection contribute to HIV-DNA independent of pre-ART HIV DNA level (P=0.033). Mechanically, plasma levels of IL-7 was significantly higher in HIV/TB co-infected participants than that in HIV mono-infection participants at both pre-ART (20.94±10.13 pg/ml vs 9.10±7.05 pg/ml, P<0.001) and on-ART(16.26±9.54 pg/ml vs 7.35± 5.36 pg/ml, P=0.004). Level of IL-7 was positively correlated with HIV-DNA level (R= 0.33, P< 0.01). Conclusion: M.tb co-infection contributes to a larger size of HIV reservoir in HIV infection. Interventions targeting IL-7 may reducing HIV reservoir size in this population and warrant further investigations.

Methods: Subjects with advanced HIV/AIDS were enrolled in a prospective study of IRIS. Plasma and peripheral blood lymphocytes were collected at pre-, early (2-14w) and prolonged (44-200w) ART from subjects with TB-IRIS (n=9), TB/no IRIS (n=8) and no TB/no IRIS (n=9). Cell-associated (CA) HIV DNA and RNA were assessed by qPCR. HIV populations were characterized by single genome sequence (SGS) analysis of HIV pro-pol from plasma RNA and CA DNA. SGSs were evaluated with phylogenetic and population genetic analyses; clonal prediction scores for identical HIV sequences were determined (Laskey et al. PLOS Path 2016). Population parameters were compared with Fisher-Exact and Mann-Whitney tests. Results: Study subjects had a median CD4 count of 34 cells/µl and significant declines in HIV CA RNA and DNA after starting ART (pre- vs on-ART p<0.0001). No differences in CA HIV RNA, DNA or RNA:DNA ratios were detected on ART between groups (for all p>0.05). TB-IRIS subjects had higher CA HIV DNA diversity than no TB/no IRIS subjects pre-ART (1.2% vs. 1.9% p=0.03) and during IRIS (1.1% vs 1.9% p=0.03). After prolonged ART, HIV population shifts (pre-ART RNA vs. CA DNA on ART) were detected in 6/9 TB-IRIS subjects but only in 3/17 subjects without IRIS (p=0.03) when identical sequences were collapsed. Identical HIV DNA SGSs emerged during ART in all groups and were probable clones (p<0.05). However after 144w ART, probable clones were less frequent in TB-IRIS than in non-IRIS groups (p=0.0001). Conclusion: Despite broad immune activation, TB-IRIS did not drive elevated levels of CA HIV RNA. Clonal expansion of HIV infected cells results in profound differences in HIV populations after prolonged ART between IRIS and non-IRIS groups. This data highlights the role of inflammation in reshaping HIV populations and the HIV reservoir. Pholo W. Maenetje 1 , Shruthi Ravimohan 2 , Itai T. Ncube 1 , Sara C. Auld 3 , Nelly Ratsela 1 , Mandla Mlotshwa 1 , Modulakgotla Sebe 1 , Jonathan Smith 3 , Mboyo-Di- Tamba Vangu 4 , Hardy Kornfeld 5 , DrewWeissman 2 , Gavin Churchyard 1 , Gregory Bisson 2 1 The Aurum Institute, Johannesburg, South Africa, 2 University of Pennsylvania, Philadelphia, PA, USA, 3 Emory University, Atlanta, GA, USA, 4 University of the Witwatersrand, Johannesburg, South Africa, 5 University of Massachusetts, Worcester, MA, USA Background: Initiation of antiretroviral therapy (ART) in HIV-infected patients with pulmonary tuberculosis (TB) is associated with rapid reconstitution of CD4+ T cells, which may lead to expansion of Th1-type responses and respiratory compromise via TB-immune reconstitution inflammatory syndrome (TB-IRIS). Mechanisms driving pulmonary inflammation in HIV/TB are unclear. We hypothesized that rapid recovery of antigen (Ag)-specific CD4+ T cell responses on ART are associated with worsening pulmonary inflammation and lung function. Methods: We enrolled a cohort of HIV-infected, ART-naïve adults with pulmonary TB in Tembisa, South Africa. Lung inflammation was assessed using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) at baseline (ART initiation) and four weeks following ART initiation to measure lung total glycolytic activity [TGA]. Changes in lung function were assessed using spirometry (% predicted forced expiratory volume in 1 second [FEV1%]) at both time points. Intracellular cytokine staining and flow cytometry were used to determine the frequency of CD4+ T cells expressing IFN-γ, IL-2 and/or TNF-α in response to PPD. Wilcoxon rank-sum test was used to compare functional responses at baseline, week 4, and change from baseline to week 4 among participants who had increase versus decrease in 1) lung TGA and 2) FEV1% on ART. P values were corrected for multiple comparisons. Results: Thirty subjects, with a mean age of 38 years (range 27-49), a median CD4 count of 112 (IQR 48-294), of whom 15 (50%) were females, completed both FDG PET-CT scans. Those with increases in lung TGA had similar baseline, but markedly greater increases from baseline to week 4 post-ART initiation in total IFN-γ+ and TNF-α+ (Figure 1A), as well as dual IFN-γ+/TNF-α+ and TNF-α+ monofunctional CD4+ T cells (Figure 1B) (all p< 0.01). Similarly, subjects with an incident FEV1% drop on ART (median drop of -9% (IQR -14 to -4) had similar baseline, but greater changes and week-4 levels of TNFα+monofunctional CD4+ T cells (all p<0.03) versus participants whose FEV1% did not drop. Conclusion: Rapid increases in TB-specific CD4+ T cells expressing IFN-γ and/ or TNFα soon after ART initiation in HIV/TB co-infected participants is associated with incident pulmonary inflammation and decreased lung function. New

728 TB-SPECIFIC CD4+ T CELLS ARE ASSOCIATED WITH PULMONARY INFLAMMATION ON ART IN HIV/TB

Poster Abstracts

727 FUNDAMENTAL SHIFTS IN HIV POPULATION STRUCTURE AFTER TB-IRIS Camille Lange 1 , Maura Manion 2 , Rob Gorelick 3 , Natalie Lindo 1 , Christian Gonsalves 1 , James Virga 1 , Virginia Sheikh 2 , Gregg Roby 2 , Joseph Adelsberger 4 , Frank Maldarelli 1 , Irini Sereti 2 1 National Cancer Institute, Frederick, MD, USA, 2 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 3 AIDS and Cancer Virus Program, Frederick, MD, USA, 4 Leidos Biomedical Research, Inc, Frederick, MD, USA Background: Tuberculosis (TB) is the most common coinfection in HIV-infected people. Those with advanced HIV/AIDS and TB who initiate antiretroviral therapy (ART) are at risk for potentially lethal immune reconstitution inflammatory syndrome (IRIS), characterized by exuberant expansions of TB-specific CD4+ T cells. HIV infected CD4+ T cells also undergo clonal expansion during ART, which has profound effects on HIV population structure. The effects of the combination of IRIS and ART on HIV population structure remain unknown. Thus we hypothesized that TB-IRIS drives fundamental changes in the size and structure of HIV populations.

CROI 2019 280