CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

271 No Impact of Early Intensified Antiretroviral Therapy on Gut Immune Reconstitution Connie J. Kim 1 ; Rodney Rousseau 2 ; Colin Kovacs 3 ; Sanja Huibner 2 ; Gabor Kandel 4 ; Erika Benko 3 ; Kamnoosh Shahabi 2 ;TaeWook Chun 5 ; Mario Ostrowski 2 ; Rupert Kaul 2 1 Toronto General Hospital, Toronto, Canada; 2 University of Toronto, Toronto, Canada; 3 Maple Leaf Medical Clinic, Toronto, Canada; 4 St. Michael’s Hospital, Toronto, Canada; 5 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, US Background: HIV infection is characterized by reduced mucosal Th22 and Th17 cell numbers and function, which contribute to microbial translocation and inflammation. Standard antiretroviral therapy (ART) is slow to reverse these mucosal defects, and the resulting persistent inflammation is linked to serious non-AIDS illnesses (SNAs). We examined whether ART intensification with maraviroc and raltegravir during very early HIV infection would accelerate the resolution of gut immune dysfunction, microbial translocation, and SNA biomarkers. Methods: ART-naïve men with early HIV infection were randomized 1:1 in a double-blind manner to receive standard ART (emtricitabine/tenofovir + lopinavir/ritonavir) with either raltegravir (400 mg/day) and maraviroc (150 mg/day), or placebo, for 48 weeks [NCT01154673]. In a predefined substudy, paired blood and sigmoid biopsies were collected from participants at baseline and week 48, and from HIV-uninfected controls. Mucosal CD4 T cell immunology (Th1, Th17 and Th22 cells), and blood markers of microbial translocation (LPS), immune activation (sCD14) and SNA (IL-6 and D-dimer) were assessed. Results: Twenty-two participants documented to have acquired HIV a median of 4 months ago were enrolled. Prior to ART initiation, gut Th22 cell numbers (P<0.001) and Th17 polyfunctionality (P=0.001) were reduced compared to controls, and plasma LPS (P=0.033) and D-dimer levels (P=0.020) were elevated. At 48 weeks after ART initiation, overall gut Th22 cell numbers were restored (P=1.00), but plasma LPS levels (P=0.226) and gut Th17 function (P=0.990) were unchanged, and blood D-dimer levels had actually increased (P=0.020). ART intensification had no impact on gut CD4 T cell immune subsets (Th1, Th17 and Th22 cells), microbial translocation (LPS), or SNA biomarkers (D-dimer and IL-6); there was a trend to reduced plasma sCD14 in the intensified arm (P=0.080). Conclusions: Early HIV infection was associated with substantial gut mucosal immune dysfunction, bacterial translocation and systemic inflammation. Regardless of intensification with raltegravir and maraviroc, one year of ART had a limited impact on mucosal immune reconstitution or blood markers of microbial translocation, inflammation, and SNAs. 272 Altered Properties of Mucosal NK Cell Subsets During Acute HIV-1 Infection Alexandra Schuetz 1 ;Yuwadee Phuang-Ngern 1 ; Eugene Kroon 1 ; Rungsun Rerknimitr 3 ; Nitiya Chomchey 2 ; Nittaya Phanuphak 2 ; Merlin L. Robb 4 ; Jerome H. Kim 4 ; Mark de Souza 2 ; Jintanat Ananworanich 4 RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups 1 Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; 2 Thai Red Cross AIDS Research Center, Bangkok, Thailand; 3 Chulalongkorn University, Bangkok, Thailand; 4 US Military HIV Research Program, Silver Spring, MD, US Background: The role of mucosal innate immunity during acute HIV infection (AHI) is poorly understood, however increasing evidence supports a beneficial role of natural killer (NK) cells. Here, we investigate the distribution and activation of mucosal NK cell subsets during early AHI. Methods: 27 subjects in Fiebig (F) I (n=11) and FIII (n=16) underwent sigmoid biopsy at the time of AHI diagnosis. Ten gender- and age-matched HIV-uninfected (HIV-) and 5 ART-naïve chronically HIV-infected (CHI) subjects served as controls. Mucosal mononuclear cells were isolated, and NK cell subsets were defined by the expression of CD56 (neg,dim, bright) and NKp44 using multi-parameter flow cytometry. Results: At the time of diagnosis, FI subjects had similar frequencies of total NK cells compared to HIV- and CHI, while FIII subjects showed a significant expansion (Table 1). In contrast surface expression of the activating natural cytotoxicity receptor, NKp44, was significantly increased on total NK cells at FI compared to FIII, HIV- and CHI. CD56 dim cytolytic NK cells were the dominant subset of NK cells and were significantly decreased in FI and FIII patients compared to HIV- and CHI. The expression of NKp44 on CD56 dim NK cells correlated inversely with plasma HIV RNA (r=-0.48, p=0.01). However, FI patients showed a significantly higher expression of NKp44 compared to FIII, HIV- and CHI. The frequency of immunoregulatory NK cells (CD56 bright ) also decreased in FI and FIII compared to HIV-, and did not recover during CHI. In contrast, a significant expansion of the CD56 neg NK cell subset, associated with chronic viral infection, was observed in FI and FIII compared to HIV- and CHI. Conclusions: Distribution of mucosal NK cells subsets is altered during early AHI characterized by the loss of cytolytic CD56 dim and immunoregulatory CD56 bright NK cells and the expansion of CD56 neg NK cells, a dysfunctional subset associated with impaired cytotoxicity. The reason for the early loss, without recovery, during CHI of the CD56 bright subset warrants further investigation in the pathogenesis of HIV infection. 273 Loss of Cervical Gamma Delta 1 T cells in HIV-InfectedWomen Natasa Strbo 1 ; Maria L. Alcaide 1 ; Laura Romero 1 ; Hector Bolivar 1 ; Deborah L. Jones 1 ; Eckhard R. Podack 1 ; Margaret A. Fischl 1 1 University of Miami, Miami, FL, US; 2 University of Miami, Miami, FL, US Background: Human gamma delta (GD) T cells are essential components of the adaptive and innate immune system and play a well-documented role in epithelial barrier protection and tumor surveillance. Two subsets of GD T cells, defined by the use of either the V delta 2 (D2) or V delta 1 (D1) TCR, predominate. The majority of the circulating GD T cells bear V D2 TCR while the majority of the tissue-associated GD T cells are D1. We hypothesized that, being the major component of intraepithelial mucosal compartment, endocervical GD T cells may have a decisive role in HIV infection and could help to control HIV replication. This study evaluates GD T cells in endocervical samples fromwomen with and without HIV infection. Methods: HIV infected (n=6) and HIV uninfected (n=7) pre-menopausal women participating in the WIHS cohort were recruited. Participants underwent vaginal examination with collection of endocervical cytobrushes and peripheral blood. Frequency and phenotype of CD3+ T lymphocytes and GD T cells were determined in cervical cytobrush samples and peripheral blood by multicolor flow cytometry. Results: We found GD2 T cells are predominant GD T subset in the blood of HIV uninfected women (GD2 vs GD1 ratio 2.37 ± 0.90), while we observed significant depletion of GD 2 T cells in the blood of HIV infected women (0.07 ± 0.027). In contrast, only GD1 T cells were readily detected in the endocervical samples in both, HIV infected (GD2 vs GD1 ratio 0.03 ± 0.01) and uninfected women (0.028 ± 0.01). In the HIV infected women, we found significant decrease in the frequency of cervical GD1 T cells compared to HIV uninfected

Poster Abstracts

234

CROI 2015