CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Methods: We retrospectively evaluated the gut microbiome from 47 HIV+male adults enrolled the HIV Neurobehavioral Research Program cohort. HAND was diagnosed using standardized criteria, including activities of daily living as follow: HIV Associated Dementia (HAD, n=4), asymptomatic NC impairment (ANI, n=16), mild NC disorder (MND, n=7), and NC unimpaired (NC-U, n=20). Stool, sociodemographic, and clinical data were collected for each participant. Stool DNA was extracted and the V3-V4 hypervariable region of the 16S ribosomal RNA gene was amplified by PCR and sequenced. Microbiome and statistical analyses were performed using Qiime and R statistical software. Results: There were no significant group differences on age or clinical characteristics (see Table). Analysis of variance followed by a Tukey post-hoc adjustment identified that participants with HAD showed significantly higher levels of Bacteroidetes (median=0.59) compared to ANI (median=0.39, p=0.02), MND (median=0.47, p=0.03), and NC-U (median=0.42, p=0.08). Conversely, participants with HAD showed significantly lower levels of Firmicutes (median=0.28) compared to ANI (median=0.56, p<0.01), MND (median=0.48, p<0.01), and NC-U (median=0.47, p=0.06). While older age was associated with higher levels of Firmicutes (rho=0.35, p=0.01) and trending to lower levels of Bacteroidetes (rho=-0.25, p=0.08), in a multivariate analysis the associations of both Bacteroidetes (p<0.01) and Firmicutes (p<0.01) remained significant after adjusting for age. Conclusion: The gut microbiome, particularly Bacteroidetes and Firmicutes, is associated with the most severe form of HAND, HAD. While this sample was relatively small, these microbial signatures may be important for identifying individuals with increased risk of developing HAND and may lead to new therapeutic options for individuals with HAND after successful ART.

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HIV ANTIBODIES IN CSF AND SERUM IN UNTREATED AND TREATED INFECTION Magnus Gisslén 1 , Richard W. Price 2 , Serena Spudich 3 , Lars Hagberg 1 , Steven G. Deeks 2 , Peter Burbelo 4

1 Sahlgenska Academy at the Univ of Gothenburg, Gothenburg, Sweden, 2 Univ of California San Francisco, San Fransisco, CA, USA, 3 Yale Univ, New Haven, CT, USA, 4 NIDCR, Bethesda, MD, USA Background: HIV likely persists in the CNS during antiretroviral therapy (ART) and may be important in continued neurocognitive impairment. Given that the reservoir in the CNS is small and difficult to access, host-responses to any residual HIV may prove to be a useful biomarker for studies aimed at studying or eradicating the virus. Here we quantitatively analyzed anti-HIV antibodies in matched CSF and serum samples from a diverse cohort of infected adults including long-term treated patients using luciferase immunoprecipitation systems (LIPS). Methods: Using LIPS, antibody responses against 7 HIV proteins were quantitatively analyzed in paired CSF and serum samples from uninfected controls (n=12), hyperacute HIV infection (n=2), early untreated HIV infection (n=4), elite controllers (n=6), treated acute infection (n=2) and before and after treatment of chronic infection (n=11). Results: HIV antibodies during early HIV infection emerged in the serum compartment before the CSF, with levels increasing over time in both bodily fluids. Antibodies to HIV were absent during hyperacute infection and low during primary/early infection. Anti-HIV antibodies were detected in CSF of all 11 participants with chronic infection prior to ART. Treatment of chronic infection resulted in significant decreases in CSF antibody levels against many HIV proteins including integrase, protease and gp120. Antibody levels in CSF and serum in the long-term treated were highly associated, with correlation coefficients (R) for integrase, protease, p24, matrix, reverse transcriptase, gp120, and gp41 of 0.87, 0.84, 0.82, 0.69, 0.60, 0.58, and 0.43, respectively. Comparison amongst the heterogeneous group of elite controllers revealed discordant antibody levels against p24 and reverse transcriptase between CSF and serum. Conclusion: Monitoring antibody response to HIV proteins in the CSF may provide a useful tool to longitudinally monitor the viral reservoir in the CNS before and during treatment. The discordant CSF and serum antibody responses seen in elite controllers and perhaps other groups suggest that the levels of HIV replication in these two compartments may be different. Although our sample size is small, early treatment of acute infection markedly blocked the presence of anti-HIV antibodies in serum and CSF. 392 NUCLEAR-MITOCHONDRIAL INTERACTIONS AND NEUROCOGNITIVE IMPAIRMENT IN HIV+ ADULTS Sandra P. Smieszek 1 , Asha R. Kallianpur 2 , David C. Samuels 3 , Donald Franklin 4 , Robert K. Heaton 5 , Scott Letendre 4 , Ronald J. Ellis 4 , Todd Hulgan 3 , William S. Bush 1 1 Case Western Reserve Univ, Cleveland, OH, USA, 2 Cleveland Clinic Lerner Coll of Med, Cleveland, OH, USA, 3 Vanderbilt Univ, Nashville, TN, USA, 4 Univ of California San Diego, San Diego, CA, USA, 5 Univ of California San Diego, La Jolla, CA, USA Background: HIV-Associated Neurocognitive Disorder (HAND) is a term that captures a wide spectrum of neurocognitive deficits, ranging frommild to severe, in HIV-infected persons. The genetic underpinnings of this complex phenotype are incompletely understood. Abnormalities of mitochondrial function and iron metabolism have long been implicated in neurodegeneration. In this analysis, we aimed to characterize the mitochondrial DNA (mtDNA) haplogroup interactions with nuclear genes found to be associated with HAND phenotypes. Methods: Genetic associations with HAND were investigated in the CHARTER cohort, encompassing 1025 individuals of African, European and admixed Hispanic ancestry. CHARTER is a US-based observational study of neuro-HIV outcomes in ambulatory, HIV+ adults who underwent standardized, comprehensive NC assessment (2003-7) and were assigned a Global Deficit Score (GDS) [normal (GDS<0.5) or impaired (GDS≥0.5)]. We employed a polygenic modeling approach to investigate the global effect of previously associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. Subsequently, we performed interaction analysis per SNP by mtDNA haplogroup combination, adjusting for population effects and known clinical covariates (comorbidity status, current CART use, plasma viral load, nadir CD4+ T-cell count). Results: We found evidence of interactions between nuclear genomic SNPs en masse and mtDNA haplogroups within European and African-ancestry individuals, as shown in Table 1. The analysis of each SNP by mtDNA haplogroup combination identified significant interactions between a region of chromosome 19 (two strongly correlated SNPs, rs17160128 and rs12460243) and European mtDNA haplogroups with continuous GDS after Bonferroni correction, with the SNPs showing a more dominant association in H and J haplogroups versus a more additive association in T and UK haplogroups. Conclusion: These associations highlight the potential role of FBN3, a nearby gene that belongs to the fibrillin gene family. Fibrillins assemble into microfibrils in many connective tissues and are important in regulating pathways of the immune response, inflammation and are involved in maintenance of blood-brain-barrier integrity. These findings were demonstrated using a novel analytic approach and indicate a new potential genetic mechanism in the pathogenesis of HAND, which may lead to greater understanding of the pathophysiology of this neurocognitive disorder. 393 GENETICALLY PREDICTED GENE EXPRESSION AND HIV-ASSOCIATED NEUROCOGNITIVE DISORDER Sandra Smieszek 1 , William S. Bush 1 , Todd Hulgan 2 , David C. Samuels 2 , Donald Franklin 3 , Robert K. Heaton 4 , Scott Letendre 3 , Ronald J. Ellis 3 , Asha R. Kallianpur 5

Poster and Themed Discussion Abstracts

CROI 2017 158