CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Results of study assays. PHI = primary HIV infection; CHI = chronic HIV infection; ART = antiretroviral therapy; IQR = interquartile range; G1/G2/G3 = Groups 1/2/3; NS = non significant Conclusions: Initiation of ART during primary HIV-1 infection correlated with normalization of markers of immune senescence. Timing of ART initiation did not appear to correlate with any difference in select markers of inflammation or immune activation. These improvements in senescence markers may further support early treatment in patients with HIV. 306 Chronic HIV Infection Exacerbates Cellular Aging Markers in Isolated T-Cell Subsets Anthony Hsieh ; Beheroze Sattha; Hélène Côté CIHRTeam in Cellular Aging and HIV Comorbidities inWomen and Children (CARMA cohort) University of British Columbia, Vancouver, Canada Background: Shorter telomere in the expanded senescent CD8 + T cell compartment is an age-related immunologic abnormality reported in a small cohort study of people living with HIV. This immune defect, along with imbalance in CD4 + and CD8 + T cell distributions may link chronic HIV infection with premature age-related comorbidities, even in people treated with combination ART (cART). Little is known about markers such as telomere length (TL) and mitochondrial DNA apparent oxidative damage (mtDNA AOD) in isolated immune compartments during HIV infection. Our objective was to characterize these aging markers in CD4 + and CD8 + T cell subsets, and explore the possible role of HIV/cART on modulating immune aging. We hypothesized that HIV infection and factors such as viral load or time since diagnosis would be associated with skewed immune aging markers. Methods: In this pilot study, live PBMCs were obtained from 33 HIV + subjects and 10 HIV - controls enrolled in the CARMA cohort study. FACS was used to isolate CD4 + , proliferative CD8 + CD28 + , and senescent CD8 + CD28 - T cells, as well as CD19 + B cells. Relative TL and mtDNA AOD were measured in all cell subsets with sufficient cell count using qPCR. Results were compared using Spearman’s correlation, two-tailed Mann-Whitney tests, and ANCOVA. Results: As expected, a decreased CD4 + /CD8 + T cell ratio (n=43, median 0.24 vs. 1.75, p<0.001) and an expanded senescent CD8 + CD28 - T cell subset (n=43, 39 vs 17% of total T cells, p=0.02) were observed in the HIV + group compared to the HIV - group. HIV infection was associated with shorter TL in proliferative CD8 + CD28 + T cells (n=27, 3.35 vs. 3.73, p=0.02), but not in CD8 + CD28 - or CD4 + T cells after adjusting for age. Within the entire cohort, older age was associated with shorter TL in CD4 + (n=26, R=-0.45, p=0.02), and proliferative CD8 + CD28 + (n=27, R=-0.47, p=0.01) but not senescent CD8 + CD28 - cells (R=-0.06). MtDNA AOD correlated with lifetime cART duration in both CD8 + CD28 - and CD8 + CD28 + T cells (n=22, R=0.53, p=0.01, and n=22, R=0.45, p=0.04). No relationship was seen between current HIV viral load, CD4 current or nadir, or time since diagnosis, and the aging markers assayed here. Conclusions: Taken together, these results suggest a potential relationship between HIV infection and shorter TL in proliferative CD8 + T cells. In contrast, cART duration was related to mtDNA oxidative damage in CD8 + T cells, suggesting that cumulative exposure may play a role in mitochondrial aging in this immune compartment. 307 Age Associated Increases in Markers of Microbial Translocation and Inflammation in HIV-1 Infection Eileen Scully 1 ; Ainsley Lockhart 1 ; Lisa Huang 2 ; Marisol Romero-Tejeda 1 ; Mary Albrecht 4 ; Chrstine D. Palmer 1 ; Ronald Bosch 3 ; Marcus Altfeld 1 ; Daniel Kuritzkes 2 ; Nina Lin 5 1 Ragon Institute of MGH, MIT and Harvard, Jamaica Plain, MA, US; 2 Brigham and Women’s Hospital, Boston, MA, Boston, MA, US; 3 Harvard School of Public Health, Center for Biostatistics in AIDS Research, Boston, MA, US; 4 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, US; 5 Boston University School of Medicine, Boston, MA, US Background: The aging of the HIV-1 infected population obligates a focus on the interaction of the virus with aging and comorbid conditions. Enhancing the survival and quality of life of infected individuals requires identification of the etiologic drivers of these pathologies in order to disrupt pathways leading to non-AIDS morbidity and mortality. Methods: We recruited a cohort of HIV-1 infected men aged ≤ 35 years (n=22) or ≥ 50 years (n=23) on fully suppressive antiretroviral therapy (ART). Cryopreserved PBMCs were analyzed for T cell activation, exhaustion, proliferation, and innate cellular subsets. Functional capacity of the innate compartment was assessed by intracellular cytokine staining after stimulation with a panel of Toll-like receptor (TLR) agonists. Plasma markers of inflammation were measured, and selected analytes compared to an age-matched cohort of 46 uninfected men. Results: No differences in T cell activation, exhaustion, proliferation or CD4/CD8 ratio were observed between age groups. Distributions of monocyte subsets (classical, nonclassical and intermediate), and myeloid and plasmacytoid dendritic cells were comparable. Innate functional capacity as measured by TNFa, IL-1b and IP-10 production by the relevant cell populations was not significantly different in response to TLR2, TLR3, TLR4, and TLR7/8 agonists. Analysis of plasma levels of cytokines identified elevated expression of the chemokine MCP-1 in the older age stratum (p<0.05, Mann-Whitney), which was confirmed by increased levels of mRNA expression (p<0.05). The ≥ 50 age group also showed higher levels of LPS as measured by the LAL assay (p<0.05). When compared to a group of uninfected control subjects, older HIV-1 infected adults were more frequently in the upper quartile of sCD14 expression (OR 4.12, 95% CI 1.06-16.0, p<0.05, chi square) compared to the age ≤ 35 HIV-infected and uninfected groups. Conclusions: In a cohort of HIV-infected individuals well-matched on virologic parameters and separated into age strata, there was a significant difference in levels of plasma MCP-1 and markers of microbial translocation in the absence of significant differences in adaptive or innate cellular markers of immunosenescence, or in the functional assessment of innate immune capacity. Together, the data suggest that exploration of MCP-1 and LPS as a potential early signature of risk for age-related comorbidities is warranted.

Poster Abstracts

249

CROI 2015