CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

820 HIV-Tuberculosis Coinfection Leads to Increased Turnover of Late-Senescent CD8 + T Cells Shankar Esaki Muthu 1 ; ChongYee Kien 1 ; Alireza Saeidi 1 ; Adeeba Kamarulzaman 1 ;VijayakumarVelu 2 ; Marie Larsson 3 1 University of Malaya, Kuala Lumpur, Malaysia; 2 Emory University, Atlanta, GA, US; 3 Linkoping University, Linkoping, Sweden Background: CD8+ T cells reportedly have compromised functions including degranulation in HIV/TB coinfection. The role of T-cell immunosenescence and functional CD8 + T-cell responses in HIV/TB co-infection has seldom been studied. Methods: We examined and correlated surrogate markers of HIV disease progression with immune activation, immunosenescence and differentiation using T-cell pools of 19 treatment naïve HIV seropositive individuals, 9 with confirmed active TB (HIV+/TB+) and 10 without active TB (HIV+/TB-), recruited together with 6 HIV-/TB- healthy controls without active TB. Results: Our investigations showed increased plasma viremia and reduced CD4/CD8 T-cell ratio in HIV/TB co-infected subjects, and also a closer association with changes in the expression of immune activation markers CD38 and CD57 that were consistently expressed on late-senescent CD8 + T cells. Up-regulation of CD57 and CD38 were tantamount to lack of co-stimulatory and homeostasis markers, CD27 and CD28 on CD8 + T cells, besides diminished expression of CD127, CD27 and CD28 on CD57 + CD4 + T cells. We also showed that elevation of CD57 and abrogation of CD27, CD127 and CD28 on CD8 + T cells that correlated with markers of HIV disease progression, including CD38. Next, T-cell activation experiments using recombinant HIV gag p24 revealed diminished intracellular synthesis of IFN- γ , perforin and granzyme B in HIV-specific CD8 + T cells of HIV-TB co-infected subjects. Conclusions: We suggest that involvement of TB in co-infected patients may play a role that contributing to accelerated HIV disease progression, concurrently accompanied by elevated proliferative senescence, chronic immune activation, and functional insufficiency of CD8 + T cells. Background: Tuberculosis (TB) is the first cause of death in HIV+ patients. Mtb infection elicits CD8 T cell (CD8Tc) responses that contribute to control latent TB (LTB). We previously showed that Dehydroepiandrosterone (DHEA) in vitro reduces FoxP3 expression while raises Mtb -induced IFN- γ release in HIV-TB patients. In this study we explored the anti-tubercular function and effector/memory phenotype of CD8Tc during HIV-TB co-infection and their modulation by DHEA. Methods: 47 HIV+ with active TB (HIV-TB), 12 HIV+/TST+ (HIV-LTB), 12 HIV+/TST- (HIV+) and 25 healthy (HD) individuals were studied. Memory subsets, determined by CD27 and CD45RA staining, and ex-vivo IFN- γ production and CD107a/b staining in CD8Tc were assessed by flow cytometry. DHEA plasma levels were measured and the expression of transcription factors involved in effector/memory setting was evaluated by RT-PCR. Data was analyzed by using non-parametric tests. Results: Bulk CD8Tc in HIV+, HIV-LTB and HIV-TB patients showed different memory subset distribution compared to HD (p<0.05 by partial permutation test), with lower naïve (CD27+CD45RA+, T N ) proportions in HIV-LTB and HIV-TB (p<0.05 by Kruskal-Wallis followed by Dunns -KWD-) and higher effector memory (CD27-CD45RA-, T EM , p<0.001 by KWD) and terminal effector (CD27-CD45RA+, T TE , p<0.05 by KWD) frequencies only in HIV-TB patients. Despite this increase, T TE cells from HIV-TB showed lower CD45RA levels (p<0.01 vs. HD by KWD) suggesting a not fully differentiated phenotype. These changes were not related to TB localization or BAAR status but HAART partially restored T N and T EM levels in CD8Tc from HIV-TB (p<0.05 by Wilcoxon matched-pairs signed rank test -Wmp-). Also, HIV-TB patients showed increased T EM and T TE frequencies in CD107a/b+ and IFN γ + Mtb -specific CD8Tc respectively (p<0.05 vs. HD by KWD). DHEA plasma levels positively correlated with the % of T TE in bulk CD8Tc (Spearman r=0.47, p=0.027) and DHEA in vitro enhanced Mtb -specific CD8Tc degranulation (p<0.05 vs. Mtb by Wmp) and T TE CD107a/b+ proportions (p<0.05 vs. media by KWD) in HIV-TB. DHEA also raised Tbet expression and Tbet/EOMES ratio (p<0.01 vs. media by KWD) in Mtb -stimulated CD8+ cells. Conclusions: These data indicate that DHEA can induce terminal differentiation in CD8Tc during HIV-TB co-infection. To date, this is the first in-depth study of CD8Tc effector/ memory phenotype in HIV-TB patients and its modulation by DHEA. We propose the use of DHEA as an adjunct therapy during Mtb infection in people living with HIV. 821 CD8 T-Cell Terminal Differentiation and Its Regulation by DHEA in HIV-TB Coinfection Guadalupe V. Suarez 1 ; MatiasT. Angerami 1 ; Maria B.Vecchione 1 ; Omar Sued 2 ; Horacio Salomon 1 ; Maria F. Quiroga 1 1 INBIRS (UBA-CONICET), Buenos Aires, Argentina; 2 Fundacion Huesped, Buenos Aires, Argentina

Poster Abstracts

TUESDAY, FEBRUARY 24, 2015 Session P-R3 Poster Session

Poster Hall

2:30 pm– 4:00 pm TB Diagnostic Challenges 822 Unsuspected Prevalent TB among HIV-Infected Pregnant Women, South Africa Jennifer D. Hoffmann 1 ; Silvia E. Cohn 1 ; Fildah Mashabela 2 ; ZiyaadWaja 2 ; Christopher J. Hoffmann 1 ; Neil Martinson 2 ; Richard E. Chaisson 1 Tshepiso StudyTeam 1 Johns Hopkins University School of Medicine, Baltimore, MD, US; 2 Perinatal HIV Research Unit (PHRU), Johannesburg, South Africa

Background: HIV and tuberculosis (TB) are leading infectious causes of death among women of reproductive age worldwide. Nearly 30% of pregnant women presenting for prenatal care in South Africa are HIV-infected. In Soweto, 0.8-2.2% of pregnant women with HIV also have active TB. South African guidelines recommend symptom screening for TB (cough, fever, night sweats, weight loss or poor weight gain) at each prenatal visit with TB investigations if any symptom is present. Methods: Tshepiso is a prospective cohort study of HIV-infected pregnant women with active TB (cases) matched 1:2 by age, gestational age and antenatal clinic with HIV-infected pregnant women without TB (controls). Women are enrolled prenatally and followed peripartum and postpartum. Sputum culture for Mycobacterium tuberculosis is performed at enrollment using MGIT for all participants. We describe here cases of active TB (prevalent TB cases) in HIV-infected pregnant women selected as controls who were not considered to be TB suspects by antenatal clinic staff. Results: From January 2011 to June 2014, we enrolled 160 HIV-infected pregnant-women as controls, matched to 72 HIV-infected pregnant women with TB (cases). During screening 7/160 controls (4%) were found to have active TB (prevalent TB cases) with positive sputumMGIT culture for MTB with median (range) days to positivity 17 (10,31). None of the prevalent TB cases reported symptoms at baseline (cough, fever, night sweats, weight loss) while 14% of the remaining control subjects reported at least one symptom. None of the prevalent TB cases reported previous history of TB, while 18% of women in the cohort (28% of cases, 14% of controls) reported being treated for TB at least one time in the past (table 1). CD4 counts in prevalent TB controls were similar to other controls and higher than women recruited as TB cases.

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CROI 2015