CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

118 CROSS-SPECIES CMV VACCINATION REVEALS DETERMINANTS OF NON- CLASSICAL T CELLS Justin Greene , Daniel Malouli, Scott Hansen, Travis Whitmer, Abigail Ventura, Roxanne Gilbride, Luke Uebelhoer, Jennie Womack, Matthew McArdle, Junwei Gao, Alfred Legasse, Michael K. Axthelm, Louis J. Picker, Klaus Fruh, Jonah Sacha Oregon Health and Sciences University, Portland, OR, USA Background: Rhesus macaques (RM) vaccinated with strain 68-1 rhesus CMV (RhCMV) vaccine vectors expressing SIV antigens demonstrate unprecedented protection against highly virulent SIVmac239 replication, with protected RM eventually clearing the virus. This protection is associated with unconventional CD8+ T cell responses that are either MHC-II or MHC-E restricted. These unconventional CD8+ T cell responses may be the result of the unique MHC complexity present in RM, or the result of conserved immunoregulatory mechanisms utilized by CMV. Methods: In order to parse out the importance of host immunogenetics from strain-specific CMV mechanisms, additional nonhuman primate models of CMV infection are needed. Mauritian-origin cynomolgus macaques (MCM) are a particularly attractive nonhuman primate model due to a significant population bottleneck 400 years ago that resulted in highly limited immunogenetics. We captured MCM CMV (CyCMV) as a BAC and subsequently developed an SIV Gag- expressing vector with deletions corresponding to those found in RhCMV 68-1. Results: Vaccination of MCM with “strain 68-1 like” CyCMV induced unconventional CD8+ T cell responses including MHC-E and MHC-II restricted responses, including “supertope” responses that are present in every RhCMV strain 68-1 vaccinated RM. Interestingly, both RhCMV vaccinated RM and CyCMV vaccinated MCM target identical supertope peptides that are restricted by MHC-E. Conclusion: These results demonstrate that species-specific CMV is required for non-classical T cell generation. Furthermore, as CMV-vectors advance toward human clinical trials, these results suggest a similarly designed human CMV may induce unconventional CD8+ T cell responses in humans. 119 HIV-1 PERSISTS IN CSF CELLS IN HALF OF INDIVIDUALS ON LONG-TERM ART Serena S. Spudich 1 , Rajesh T. Gandhi 2 , Joshua C. Cyktor 3 , Christina Lalama 4 , Ronald Bosch 4 , Bernard J. Macatangay 3 , Charles Rinaldo 3 , Kevin Robertson 5 , Ann Collier 6 , Catherine Godfrey 7 , Evelyn Hogg 8 , Joseph J. Eron 5 , Deborah McMahon 3 , John W. Mellors 3 1 Yale University, New Haven, CT, USA, 2 Massachusetts General Hospital, Boston, MA, USA, 3 University of Pittsburgh, Pittsburgh, PA, USA, 4 Harvard University, Boston, MA, USA, 5 University of North Carolina Chapel Hill, Chapel Hill, NC, USA, 6 University of Washington, Seattle, WA, USA, 7 NIAID, Bethesda, MD, USA, 8 Social &Scientific Systems, Silver Spring, MD, USA Background: The frequency of HIV persistence in the cerebrospinal fluid (CSF) and the factors associated with persistence in individuals on long-term antiretroviral therapy (ART) are incompletely understood. Methods: Participants who initiated ART during chronic HIV infection with documented sustained long-term viral suppression in ACTG A5321 underwent paired lumbar puncture and blood collection. Cell-associated (CA) HIV DNA and RNA were measured by qPCR assays in PBMCs and cell pellets derived from~13 mls of CSF and normalized by amplifiable CCR5 cell equivalents. Cell-free HIV RNA was quantified by single copy assay (SCA) in 3-5 mls of CSF supernatant and blood plasma. Inflammatory biomarkers (IL-6, IP-10, neopterin, MCP-1, sCD14, sCD163) were measured in cell-free CSF and plasma. Results: 69 participants (97%male) had median age 50 years, current CD4 696 cells/mm 3 , pre-ART CD4 288 cells/mm 3 and 8.6 (range 5.4-16.4) years on ART. In CSF, cell-free RNA was detected in only 4% of participants (at 0.4, 0.7, and 1.2 cps/mL), while CA-RNA was detected in 9% (6/69) and CA-DNA in 48% (33/69) (Figure). Among those with detectable CA-DNA in CSF, median levels were 2.1 (0.12 -7.00) cps/103 cells. Participants with detectable cell-free HIV RNA in CSF had higher levels of plasma HIV RNA by SCA than those with undetectable CSF HIV RNA (median plasma VL, 5.9 vs < 0.4 cps/ml, p=0.007). By contrast, detection of CA-DNA in CSF was not associated with HIV DNA levels in PBMCs. CSF inflammatory biomarkers, especially indicators of myeloid cell activation, correlated within CSF and between CSF and plasma, but not with CSF CA-DNA, CA-RNA or cell-free HIV RNA. Higher CSF neopterin, IP-10, MCP-1, sCD14 and sCD163 correlated with older age (p≤0.016); higher CSF neopterin correlated with lower pre-ART CD4:CD8 ratio (r=−0.29, p=0.017). Plasma HIV RNA by SCA correlated with CSF sCD14 (r=0.34, p=0.004) and sCD163 (r=0.29, p=0.017).

Conclusion: Almost half of individuals on long-term ART have HIV-infected mononuclear cells in CSF; transcribed HIV RNA is detectable in CSF cells in a small subset. Persistence of HIV-infected cells in CSF was not associated with higher levels of HIV DNA in blood or with levels of inflammation in blood or CSF, but the level of residual plasma viremia was associated with both cell-free HIV RNA and myeloid cell activation in CSF. These findings highlight the need to develop interventions in addition to ART to clear persistently infected cells from the CSF compartment.

Oral Abstracts

120 LONGITUDINAL TRAJECTORY OF BRAIN VOLUME AND CORTICAL THICKNESS IN PRIMARY INFECTION

Ryan Sanford 1 , Beau M. Ances 2 , Richard W. Price 3 , Dieter Meyerhoff 3 , Serena S. Spudich 4 , Louis Collins 1 1 Montreal Neurological Institute, Montreal, QC, Canada, 2 Washington University St Louis, St Louis, MO, USA, 3 University of California San Francisco, San Francisco, CA, USA, 4 Yale University, New Haven, CT, USA Background: HIV penetrates the brain early in infection. However, brain volume changes that occur during this period and the effect antiretroviral therapy (ART) has on these changes are unclear. To explore this issue, we used tensor-based morphometry (TBM) and cortical modeling to examine the longitudinal trajectory of regional brain volumes and cortical thickness in treated and untreated primary HIV-infected (PHI) participants. Methods: PHI participants (<1 year after exposure) in the PISCES cohort from San Francisco underwent longitudinal MRI. Several participants commenced ART during follow-up. TBM and cortical modeling estimated regional brain volumes and cortical thickness, respectively. A two-phase mixed-effect model assessed the trajectory of our MRI measures before and after ART. This involved fitting a linear model at time points before ART initiation and a different linear model at time points after ART. Both models were constrained to meet at the time of ART initiation. Additional mixed-effect models assessed correlations of regional MRI measures with CD4+ and CD8+ cell counts, CD4/CD8 ratio, and CSF and blood HIV RNA at time points before ART. Results: 65 male PHI participants enrolled ((mean±SD) age 36.8±9 year, education 15.4±2.3 year, duration of infection 4.2±2.5 month, MRI per participant 2.5±1.5). Prior to ART initiation, we observed that longer duration of infection was correlated with brain volume loss in the thalamus, caudate, temporal lobe and cerebellum as shown by TBM (see Fig 1 for voxel-wise statistics), and with cortical thinning in the frontal and temporal lobes, as well as middle cingulate cortex (p<.05) (Fig 1B). After ART initiation, no further significant brain volume changes were found by TBM (Fig 1A). However, small but statistically significant increases of cortical thickness in the right frontal and temporal lobes correlated with longer ART duration (p<.05) (Fig 1B). Before ART, increased CSF HIV RNA was related with volume reductions in the thalamus (p<0.1) (Fig 1C). CD4+ cell count and CD4/CD8 ratio were positively correlated with cortical thickness in the left frontal lobe (p<.05) (Fig 1D). Conclusion: Regional subcortical volume loss and cortical thinning occur before ART initiation. However, initiating ART can halt further structural deterioration. These findings support the hypothesis that brain injury due to HIV occurs during untreated infection and worsens in the absence of ART. This suggests that early initiation of ART preserves long-term brain health.

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CROI 2018