CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: Cytotoxic CD8 + T cells that dominate the inflammatory response in patients with PML-IRIS highly express CCR5. By inhibiting migration and/or activation of effector cells expressing CCR5, maraviroc might be beneficial to prevent and/or treat the deleterious inflammatory reaction that occurs during immune recovery in HIV-infected PML patients. This possibility deserves further studies. 815 Monocyte Immune Responses in Cryptococcal Immune Reconstitution Inflammatory Syndrome David B. Meya 1 ; Godfrey Zziwa 2 ; Samuel Okurut 2 ; Stephen Cose 3 ; Paul Bohjanen 4 ; SharonWahl 5 ; David R. Boulware 4 ;Yuka Manabe 6 ; Edward N. Janoff 7 1 Makerere University College of Health Sciences, Kampala, Uganda; 2 Makerere University Walter Reed Project, Kampala, Uganda; 3 Medical Research Council, Kampala, Uganda; 4 University of Minnesota, Minneapolis, MN, US; 5 National Institute for Dental and Craniofacial Research, Bethesda, MD, US; 6 Johns Hopkins University School of Medicine, Baltimore, MD, US; 7 University of Colorado, Denver, CO, US Background: Immune Reconstitution Inflammatory Syndrome (IRIS) occurs in up to 30% of HIV-infected patients with Cryptococcal Meningitis (CM), resulting from exaggerated immune responses upon initiation of antiretroviral therapy (ART). The role of monocyte immune responses in the immunopathogenesis of cryptococcal IRIS is not well understood. Methods: We isolated peripheral blood mononuclear cells from 11 subjects in Kampala, Uganda at CM diagnosis and at the time of CM-IRIS (CM-IRIS) and 6 subjects with CM without IRIS matched for ART duration (Controls). Upon in vitro stimulation with IFN- γ , a proxy for CD4 + T cell help, frequencies of monocytes expressing IL-6 and TNF- α were quantified by intracellular flow cytometry. We defined monocytes as CD4 lo CD11c + CD14 + CD16 +/- and classical monocytes (CD14 ++ CD16 - ); intermediate monocytes (CD14 ++ CD16 + ) and non-classical monocytes (CD14 + CD16 ++ ). Results: Non-classical monocytes at CM diagnosis were less frequent in persons with future IRIS vs CM controls, median 0% (IQR, 0,0) vs 4% (IQR, 3, 5), P <0.001. Similarly, activated (PD-L1 + CD25 + ) non-classical monocytes at CM diagnosis were less frequent in CM-IRIS vs Controls; median 0% (IQR, 0, 0) vs 11% (IQR, 6, 16), P <0.001. There were no differences in the frequencies of classical and intermediate monocytes between CM-IRIS vs Controls at baseline. TNF- α expression by activated classical monocytes was more frequent in CM-IRIS vs. Controls, whereas TNF- α - and IL-6-producing non-classical monocytes were higher among Controls. During CM-IRIS, the frequencies of IL-6 + classical and intermediate monocytes were increased compared with baseline pre-ART among 10 subjects with paired samples. Moreover, subjects with CM-IRIS showed a higher frequency of activated monocytes and increased frequencies of IL-6 + , TNF- α + classical monocytes and IL-6 + intermediate monocytes vs. Controls. These results were seen in both unstimulated and IFN- γ stimulated monocytes, with greater magnitude in IFN- γ stimulated cells. Conclusions: At CM diagnosis, persons who later developed CM-IRIS had increased activation and TNF- α responses compared with those who did not develop CM-IRIS. At CM-IRIS, monocyte activation was high compared to matched controls while classical and intermediate monocytes were the predominant source of cytokines. Distinct proportions and activation profiles of monocytes at CM diagnosis may lead to poor cryptococcal clearance and possible involvement of the innate immune axis in CM IRIS. 816LB Does HIV Infection Reduce the Probability of Transmission of Pulmonary Tuberculosis? Judith R. Glynn 1 ; José Afonso Guerra-Assunção 1 ; Rein M. Houben 1 ;Themba Mzembe 2 ; Lifted Sichali 2 ; PalwashaY. Khan 1 ; Ruth McNerney 1 ; Julian Parkhill 3 ;Taane G. Clark 1 ; Amelia C. Crampin 1 1 London School of Hygiene and Tropical Medicine, London, United Kingdom; 2 Karonga Prevention Study, Chilumba, Malawi; 3 Wellcome Trust Sanger Institute, Hinxton, United Kingdom Background: HIV positive patients with pulmonary tuberculosis (TB) are thought to be less likely to transmit M.tuberculosis , even accounting for sputum bacillary load, because they have a shorter duration of disease. Whole genome sequencing of M.tuberculosis can identify who transmits to whom, and provides a newmethod to test this hypothesis. Methods: In Karonga District Malawi all TB patients are identified and asked about prior contacts with patients with TB. Whole genome sequencing with ~100 fold coverage was carried out on all available cultures from 1996-2010. Transmission networks were constructed using SeqTrack, including links ≤ 10 mutations, and ensuring coherence of dates. The relative risk of transmitting and causing disease was estimated using ordered logistic regression, using the last 3 years of data only for assessing transmissions. In addition, the probability that a TB case acquired TB from their named contacts with smear-positive TB was calculated, by HIV status. Results: Overall 1687 high quality sequences were available: 72 % of all culture positive cases in the district over this period. After excluding cases from the last 3 years, 431/1346 patients with pulmonary TB were identified as a source of transmission, resulting in disease in ≥ 1 (and up to 12) further patients. 181/588 (30.8%) HIV positive patients and 91/318 (28.6%) HIV negative patients transmitted. (8% of HIV positive patients were on antiretrovirals before TB diagnosis.) Using ordered logistic regression there was little difference in transmission from HIV positive and HIV negative patients (odds ratio 1.1, 95%CI 0.81-1.5), and this hardly changed when adjusting for age, sex, lineage, sputum smear status and year. In the analysis of named contacts, among index case-prior contact pairs, transmission was confirmed from 27/71 (38.0%) HIV positive smear-positive prior contacts and 29/63 (46.0%) HIV negative smear-positive prior contacts (risk ratio 0.83, 0.55-1.2). This reduced slightly after adjusting for closeness of contact (adjusted risk ratio 0.78, 95%CI 0.54-1.1). In this population about 60% of smear-positive TB patients were HIV positive. If transmission from HIV positive patients was reduced by 22%, then they would still account for 47% of transmission. Conclusions: Contrary to what is sometimes stated, HIV positive patients appear to play an important role in onward transmission of M.tuberculosis . Where a high proportion of pulmonary TB patients are HIV positive they may be the main source of infection.

Poster Abstracts

TUESDAY, FEBRUARY 24, 2015 Session P-R2 Poster Session

Poster Hall

2:30 pm– 4:00 pm T-Cell Responses to Tuberculosis Infection 817 The Relationship Between T-Regulatory Cells and Latent Tuberculosis Infection in Household Contacts Exposed to Pulmonary Tuberculosis Infection in Kampala, Uganda Rhoda Namakula 1 ; Irene A. Odanga 2 ; Josephine Kasolo 2 ; Ekii A. Abuku 3 1 Makerere University–Johns Hopkins Research Collaboration, Kampala, Uganda; 2 Makerere University College of Health Sciences, Kampala, Uganda; 3 Medical Research Council (Uganda Virus Research Institute), Entebbe, Uganda Background: Tuberculosis remains a serious public health threat worldwide. It has been estimated that 2 billion people worldwide are latently infected with Mycobacterium tuberculosis . A vast pool of individuals with latent tuberculosis infection (LTBI) persists in developing countries, posing a major barrier to global TB control. Immunosuppressive regulatory T-cells (T-Regs) and CD4 + T-lymphocytes in general are important in the host immune response to LTBI. T-Regs down regulate the immune system to prevent excessive

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CROI 2015