CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Results: Higher baseline levels of sCD14 were not associated with progression to HAART eligibility when adjusted for treatment arm, baseline CD4, and viral load. Higher CRP levels were also not predictive of disease progression. Levels of CRP increased in both arms, and were not significantly different (p=0.25). Levels of sCD14 decreased slightly in both arms, but at a significantly increased rate in the treated women (-0.003 log 10 sCD14/month, 95% CI=-0.005- -0.002) compared to the placebo group (-0.001 log 10 sCD14/month, 95% CI=- 0.002-0.001; p=0.02), which was independent of HIV viral load and CD4 count (p=0.039). However, the decrease in sCD14 in the treatment group was small with a total change in levels of 0.072 log 10 (290 ng/mL) over the two-year period, which is 15% of the mean sCD14 levels at baseline in the treatment group. Conclusions: sCD14 levels decreased faster in the acyclovir treated arm than in the placebo arm independent of CD4 count and viral load. These data support the hypothesis that decreased monocyte activation may contribute in part to the slower HIV disease progression observed during daily acyclovir treatment. 322 Atorvastatin Reduced T-Cell Activation and Exhaustion Among Suboptimal Immune Responders: A Randomized Crossover Placebo Controlled Trial Damalie Nakanjako Makerere University Infectious Diseases Institute, Kampala, Uganda Background: T-cell activation independently predicts mortality, poor immune recovery and non-AIDS illnesses during combination antiretroviral therapy (cART). Atorvastatin showed anti-immune activation effects among HIV-infected cART-naïve individuals. We hypothesized that adjunct atorvastatin therapy would reduce T-cell activation among cART-treated adults with suboptimal immune recovery. Methods: A randomized double-blind placebo controlled cross-over trial, of atorvastatin 80 mg daily versus placebo for 12 weeks, among individuals with CD4 increase <295cells/ m l after seven years of suppressive cART. Change in CD4 T-cell-activation (CD3+CD4+/CD8+ CD38+HLADR+) and CD8 T-cell-activation and in T-cell-exhaustion (CD3+CD4+/ CD8+PD1+) were measured using flow cytometry. Results: Thirty patients were randomized, 15 to each arm. Atorvastatin resulted in a 28% greater reduction in CD4 T-cell-activation (60% reduction) than placebo (32% reduction); p=0.001. Atorvastatin also resulted in a 35% greater reduction in CD8-T-cell-activation than placebo (49% versus 14%, p=0.0009), CD4 T-cell exhaustion (27% versus 17% in placebo), p=0.001, and CD8 T-exhaustion (27% versus 16%), p=0.004. There was no carry-over/period effect. Expected adverse events were comparable in both groups and no serious adverse events were reported. Conclusions: Atorvastatin reduced T-cell immune activation and exhaustion among cART-treated adults in a Ugandan cohort. Atorvastatin adjuvant therapy should be explored as a strategy to improve immune recovery during antiretroviral therapy. 323 P2X Type Purinergic Antagonists Can Block HIV-1 Infection and Associated Inflammation Talia Swartz ; Meagan O’Brien; Anthony Esposito; Nina Bhardwaj; Benjamin Chen Icahn School of Medicine at Mount Sinai, New York, NY, US Background: HIV-1 causes a chronic, incurable infection that is associated with chronic inflammation. Even in the face of virologic suppression with antiretroviral therapy this inflammation can persist. The mechanism of this inflammation is not clearly understood. Purinergic receptors are known to be mediators of inflammatory responses and can contribute to pro-inflammatory cytokine production and lymphocyte cell death. Purinergic receptor signaling has been found to be important for HIV-1 infection and we have recently found that inhibition of the P2X subtype purinergic receptors potently blocks HIV-1 productive infection at the level of membrane fusion. This study examines whether virus-induced purinergic signaling is responsible for inflammatory cytokine release during HIV-1 infection. Methods: Our laboratory has developed methods using fluorescent constructs of HIV-1 to evaluate productive infection by flow cytometry and confocal microscopy. Infected supernatants can be subjected to multiplex bead capture assays to test for an array of human cytokines including IL-12, IL-10, IL-8, IL-6, TNF, and IL-1 β . We have tested the effect of HIV-1 infection on peripheral blood mononuclear cells and observed levels of pro-inflammatory cytokine production. Results: We observe that HIV-1 productive infection in CD4 T lymphocytes is potently blocked by P2X selective inhibitors. We further observed that exposure of peripheral blood mononuclear cells to HIV-1 results in induction of pro-inflammatory cytokines including IL-1 β and IL-6 and that these levels are reduced with P2X inhibition. This suggests that P2X inhibitors can block both HIV-1 productive infection and associated inflammation. Conclusions: Our findings distinguish P2X receptors as key signaling mediators of HIV-1 infection and inflammation. Studies in progress will examine the mechanism of P2X signaling in HIV-1 entry and will test whether purinergic antagonists can block HIV and reduce inflammatory sequelae of HIV-infection in humanized mouse models. We are exploring whether these drugs could be used as adjunctive antiretroviral therapy that could serve to reduce the morbidity and mortality associated with HIV-1 chronic inflammation.

Poster Abstracts

THURSDAY, FEBRUARY 26, 2015 Session P-C12 Poster Session

Poster Hall

2:30 pm– 4:00 pm Pathogenesis in Lymph Nodes 324 CD4 + T cell death mediated by pyroptosis in early SIV infected lymphatic tissues Wuxun Lu 1 ; Guobin Kang 1 ; Fangrui Ma 1 ;YanminWan 2 ;Yue Li 1 ; Mark Lewis 3 ; Qingsheng Li 1

1 University of Nebraska-Lincoln, Lincoln, NE, US; 2 Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; 3 BIOQUAL, Inc., Rockville, MD, US Background: Lymphatic tissues are the principle sites for HIV-1 replication, host-virus interaction and CD4 + T cell loss. However, the current understanding of the virus-host molecular interaction in lymphatic tissues, especially in early infection, is limited. We thus investigated virus-host interaction in the lymph nodes (LNs) of rhesus macaques during early simian immunodeficiency virus (SIV) infection. Methods: Sixteen adult male macaques were intra-rectally inoculated with SIVmac251 (3.1 x 10 4 TCID 50 ) and were euthanized at 3, 6, 10, 14 or 28 days post-inoculation (dpi); another 3 macaques were used as uninfected controls. Total RNA was isolated from rectal draining LNs of macaques and whole genome transcriptome was profiled using Illumina GAIIx, and genes with altered expression were identified and analyzed. SIV RNA in rectal draining LNs was quantified by using qRT-PCR and in situ hybridization (ISH). CD4 + and caspase-1 + cells in LNs were quantified using flowcytometry.

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CROI 2015