CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

markers including choline (r=-0.63, p=0.02) and glutamate/glutamine (r=- 0.49, p=0.02) in frontal white matter. Conclusion: These data highlight the persistence of HIV-specific CD8 T cells over 2 years of suppressive ART started in AHI. The persistence of these cells after treatment suggests the presence of HIV antigen in the CNS during effective ART. Nonetheless, associations with CNS biomarkers indicate that they may play an effective role in resolving neuroinflammation after treatment.

417 CSF HIV-TAT AS A BIOMARKER OF NEUROCOGNITION AND AGING IN HIV- INFECTED PATIENTS Bryan Smith 1 , Lisa Henderson 1 , Alina Popescu 1 , Elizabeth F. Horne 1 , Ulisses Santamaria 1 , Eliezer Masliah 2 , Joseph Snow 2 , Avindra Nath 1 , Ankit Saxena 2 , John P. McCoy 2 , for the Neuro-HIV Research Consortium 1 National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA, 2 NIH, Bethesda, MD, USA Background: Virus-specific markers are limited when researching the neurologic complications of HIV infection, especially for participants on antiretroviral therapy. HIV-Tat protein can be released from infected cells despite antiviral therapy and experimental studies show that it can cause neuroglial dysfunction. Hence we investigated its presence in CSF, in an HIV-Tat/ amyloid protein transgenic animal model and in vitro to determine interactions between Tat and amyloid beta (Aβ) peptide. Methods: Tat was measured by ELISA in CSF of patients with HIV infection on antiretroviral therapy. Evaluations included neurocognitive tests, CSF cytokines, Aβ peptide, tau, and neurofilament-light chain by Quanterix SIMOA immunoassay. Tat levels were dichotomized: undetectable or detectable; or <1000 or ≥ 1000 pg/ml and associations with clinical outcomes (GDS, average T score), with neurocognitive impairment (NCI) defined by GDS ≥ 0.5. APP-PS1 transgenic mice were injected with Tat protein or crossed with Tat transgenic mice, and amyloid plaques were examined for Tat by immunohistochemistry. Aβ peptide-Tat complexes were studied by atomic force microscopy, circular dichroism and single fiber imaging by TIRF and molecular modeling. Results: All patients (n=48; mean age 53.2 yrs; 62.5% AA; 64.6%men) had a plasma viral load <40 c/ml. CSF VL was >40 c/ml in 5 (10.4%). Tat was detectable in CSF in 21 (43.8%) and >1000 pg/ml in 12 (25%). Tat was detectable in 4 (80%) with CSF escape and 17 (39.5%) without escape (p=0.08). Tat levels >1000 pg/ml associated with higher likelihood of NCI (41.7% vs. 11.10%). Detectable CSF Tat was associated with lower Aβ40 (p=0.03), lower Aβ42 (though not significantly at p=0.08), and higher total tau/Aβ42 ratio (p=0.03). Tat localized to the amyloid plaques in the brains of both animal models and in vitro studies showed that in the presence of Tat, uniform amyloid fibrils become double twisted fibrils and formed populations of thick unstructured filaments and aggregates. Tat binding to the exterior surfaces of the Aβ fibrils increased β-sheet formation and lateral aggregation into multifibrillar structures, producing fibers with increased rigidity and mechanical resistance. Conclusion: The presence of Tat in CSF is an indicator of restricted viral replication and may be associated with cognitive impairment. It also indicates the formation of Tat-amyloid complexes in the brain which may contribute to the pathophysiology of HAND. 418 NEUROCOGNITION, FRAILTY, AND MORTALITY AMONG PERSONS AGING WITH HIV AND SUBSTANCE USE Damani A. Piggott , Ola A. Selnes, Jason Creighton, Shruti H. Mehta, Ned Sacktor, Gregory D. Kirk Johns Hopkins University, Baltimore, MD, USA Background: With effective antiretroviral therapy (ART), HIV-infected persons are living longer. Yet, survival disparities remain, particularly for persons with a history of injecting drugs (PWID). Such disparities have been attributed to

Poster Abstracts

416 CSF HIV-SPECIFIC T CELLS PERSIST DURING ART AND ASSOCIATE WITH LOWER CNS INFLAMMATION Caroline Subra 1 , Faria Fatmi 1 , Supranee Buranapraditkun 2 , Phillip Chan 3 , Carlo Sacdalan 3 , Kamonkan Tangnaree 3 , Morgane Rolland 1 , Shelly J. Krebs 1 , Napapon Sailasuta 4 , Sodsai Tovanabutra 1 , Nelson L. Michael 5 , Jintanat Ananworanich 6 , Serena S. Spudich 7 , Lydie Trautmann 1 1 Henry M Jackson Foundation, Silver Spring, MD, USA, 2 Chulalongkorn University, Bangkok, Thailand, 3 SEARCH, Bangkok, Thailand, 4 University of Hawaii at Manoa, Honolulu, HI, USA, 5 Walter Reed Army Institute of Research, Silver Spring, MD, USA, 6 Henry M Jackson Foundation, Bethesda, MD, USA, 7 Yale University, New Haven, CT, USA Background: During acute HIV infection (AHI), CD8 T cells compose the majority of cells infiltrating the cerebrospinal fluid (CSF). They are highly activated and contain HIV-specific cells. It is unknown whether these HIV- specific CD8 T cells persist in the CSF during antiretroviral therapy (ART) and how their presence associates with markers of HIV neuropathogenesis. Their presence could serve as a surrogate marker of HIV persistence in the CNS. Methods: Twelve RV254 Thai participants treated in AHI underwent lumbar punctures and Magnetic Resonance Spectroscopy (MRS) scans at diagnosis and at 24 and 96 weeks post-ART. CD4 and CD8 T cells from the CSF samples were polyclonally expanded in vitro. CD8 T cells were cocultured with autologous B-EBV cells loaded with CRF01_AE HIV peptide pools and HIV-specific CD8 T cell responses were assessed by flow cytometry using intracellular staining for IFN-γ. HIV DNA was measure in CD4 T cells by ultrasensitive qPCR. Results: In AHI, HIV-specific CD8 T cells were detected in the CSF at low frequencies in Fiebig I-II (0.5%, n=4), and at higher frequencies in Fiebig III-V (8%, n=8, Fig 1A). As previously shown, HIV-specific CD8 T cell frequency was positively associated with CSF viral load and inflammation in AHI. After 24 weeks of ART, plasma and CSF HIV RNA were undetectable. However, HIV DNA was detected in CSF CD4 T cells from 1 participant at week 24, and from 2 participants at week 96. HIV-specific CD8 T cells were still detected in 9 donors at week 24 and in 8 donors at week 96 (Fig 1A). They targeted all HIV proteins (Fig 1B). After ART, the frequency of CSF HIV-specific CD8 T cells negatively associated with CSF inflammatory markers sCD14, IL-6Rα, sgp130 and TNFR1 (all r<-0.50, and p<0.04) and with the CSF neuronal injury marker S100b (r=-0.65, p=0.001; Fig. 1C). It was also positively associated with MRS neuronal integrity marker, N-acetylaspartate, in basal ganglia (r=0.4, p=0.04) and frontal gray matter (r=0.5, p=0.01) and negatively associated with MRS inflammatory

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