CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

Background: By infecting pigtailed macaques (PTMs) with SIVagmsab, we developed a newmodel of highly pathogenic SIV infection. This model is useful for HIV pathogenesis studies, as it faithfully reproduces classical features of HIV including a high degree of gut dysfunction, persistent immune activation and inflammation (IA/INFL) and high incidence of comorbidities. For model validation, it is critical to determine if available antiretroviral (ARV) therapies control virus replication at levels comparable to those in HIV-infected patients. While SIV is notoriously difficult to control with ARVs, a coformulated combination of three ARVs (reverse transcriptase inhibitors Emtricitabine [FTC] and tenofovir disoproxil fumarate [PMPA] and integrase inhibitor Dolutegravir [DTG]) induces robust virus control in SIVmac239-infected rhesus macaques. Methods: To assess the coformulated therapy efficacy, six SIVagmsab-infected PTMs received the coformulated regimen starting from 48 days post-infection (dpi) and lasting for 11 months. Plasma viral loads were determined by qRT-PCR assay (detection limit: 30 copy/ml). CD4+ T cells in blood, intestine and lymph node, immune activation and inflammation markers were frequently monitored. Results: SIVagmsab infection peaked at 108-109 copies/ml by 10 dpi and reached a set point of 105-107 copies/ml by 42 dpi. ARV administration resulted in a rapid decline (approx. 2 log) of plasma viremia within 48 hours, with a slower decline occurring over the next 30 days. VLs eventually became undetectable by conventional QRT-PCR between 16 and 164 days post- treatment (dpt), being then relatively well controlled, with only rare blips occurring during the follow-up. ART resulted in a robust restoration of the CD4+ T cells in both intestine and lymph node. Residual immune activation and inflammation were detected in ARV-treated PTMs. Conclusion: Our results demonstrate that the coformulated ARV regimen administered long-term to an SIV model with extremely high viral loads and severe gut damage is effective in controlling virus replication and results in robust CD4+ T cell restoration. Similar to ARV-treated HIV-infected patients, the PTMs experience residual immune activation and inflammation. Our results thus validate the SIVagmsab model and open large avenues for its use for pathogenesis and treatment studies involving ART. 211 EFFECTS OF SUBCLINICAL CMV REPLICATION ON T-CELL ACTIVATION DURING EARLY ART Aaron Christensen-Quick 1 , Marta Massanella 2 , Andrew Frick 1 , Celsa A. Spina 1 , Milenka Vargas 1 , Masato Nakazawa 1 , Christy M. Anderson 1 , Sara Gianella 1 1 University of California San Diego, San Diego, CA, USA, 2 Centre de Research du Centre Hospitalier de l’Université de Montreal, Montreal, QC, Canada Background: We previously showed that subclinical Cytomegalovirus (CMV) replication was associated with increased activation of CD4+ T cells during chronic HIV-infection and with a slower decay of HIV DNA in people starting antiretroviral therapy (ART) during early HIV infection. Here, we investigate changes in T cell activation that associate with CMV replication in the setting of early ART. Methods: We investigated 246 peripheral blood mononuclear cell (PBMC) samples from 64 individuals starting ART during early HIV infection with subsequent virologic suppression up to 90 months (<50cp/ml, no viral blips, median 4 time-points/participant). In each PBMC sample, levels of CMV DNA were measured by ddPCR. Expression of immunological markers of activation (HLA-DR+CD38+) on five T-cell memory subsets [Naïve (Tn, CD27+CD45RA+), Stem Cell Memory (Tscm, CD27+CD45RA+CD95+), Central Memory (Tcm, CD27+CD45RA-), Effector Memory (Tem, CD27-, CD45RA-), and Terminally Differentiated (Ttd, CD27-, CD45RA+)] were measured in CD4+ and CD8+ T cells by flow cytometry. Significant differences in % of activated lymphocyte markers by CMV shedding status were identified using Generalized Linear Mixed Effects models. Models were checked for the effects of relevant covariates (Nadir CD4+, Time to ART, Race, Age, and Peak HIV RNA). Results: Participants started ART within a median of 3 months of estimated date of HIV infection (IQR: 1.5-8.5), and were followed for a median of 33 months (IQR: 19-50) while on suppressive ART. During follow-up, CMV was detected in 60/246 time points. Individuals with detectable CMV had significantly higher % of activated CD8+ Tem and Ttd subsets at the time of ART initiation, but no differences in CD8+ Tn or Tcm (Table 1). We did not detect differences in CD4+ T cell activation at ART start. Over time, detectable CMV was associated with faster decay of activated CD8+ T cells (Tem and Ttd). Interestingly, during CMV replication, activated CD4+ Tscm presented a

significantly slower decay rate, compared with samples with no detectable CMV. These results persisted when relevant covariates were included in the models. Conclusion: Unlike chronic ART, no effect of subclinical CMV replication was observed on CD4+ T cell activation in the setting of early ART start. While CD8+ T cell activation was initially elevated in the setting of CMV replication, it normalized rapidly during early ART. The effect of CMV on Tscm activation merits further evaluation, as it might be relevant to HIV persistence.

Poster Abstracts

212 SPECT/CT IMAGING OF CD4-POOL SUGGESTS A NOVEL CORRELATE OF BENIGN DISEASE PROGRESSION Sharat Srinivasula 1 , Jorge Carrasquillo 2 , Insook Kim 1 , Chang Paik 3 , H. Clifford Lane 3 , Michele Di Mascio 4 1 Leidos Biomedical Research, Inc, Frederick, MD, USA, 2 Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3 NIH, Bethesda, MD, USA, 4 NIH, Rockville, MD, USA Background: Global changes in the amount of lymphoid tissue have not been studied in the settings of acute, chronic progressive (CP) or long-term non-progressive (LTNP) SIV infection. A better understanding of changes in the total body immune system, especially in those organs capable of expanding or contracting in size, e.g. lymph nodes, may advance our knowledge of SIV pathogenesis. Methods: Uninfected (U, n=10) or SIV (mac251 or mac239)-infected (n=10) rhesus macaques were studied with in vivo CD4 pool SPECT imaging using 99mTc- F(ab΄)2-CD4R1, and volumetric imaging with Computed-Tomography (CT). Only animals with no evidence of immunogenicity to the radiotracer were included. In the cross-sectional analyses, the first scan after 5 months of untreated infection was used. 3 animals were also imaged longitudinally in acute and chronic phase. CD4 pool in the clusters of axillary lymph-nodes (AxLns) was quantified as maximum Standardized-Uptake-Value (SUVmax) of the anti-CD4 probe. The volume of these AxLn (LN-size-Max) were determined from the co-registered CT images. Results: Five of the SIV infected animals showed features of LTNPs with CD4 T cell count >600 during the entire period of untreated infection (median nadir:743 cells/µl; median SIV RNA set-point:3,760 copies/ml. 4/5 had a protective haplotype). The remaining five showed features of CP with CD4 T counts <500 (median nadir:177 cells/µl; median SIV-RNA of 140,000 copies/ ml, 1/5 had a protective haplotype). The SUVmax of the AxLns and the spleen was positively correlated with the peripheral blood CD4 T cell count (r, AxLn = 0.51 (P=0.01); Spleen = 0.74 (P<0.001)). In addition, a positive correlation was observed between the SUVmax and the LN-size-Max (r=0.42, P=0.03). AxLns were larger in the LTNP group compared to the U (P<0.001) or CP groups (P<0.05). No statistically significant differences were noted between the U and CP groups. In the longitudinal study, splenic CD4-pools decreased in all 3 animals in acute phase concomitant with paradoxical increases in the AxLn CD4 pool as well as increases in the volume of AxLns. During the chronic phase of infection, the size of AxLns was reduced in 2 animals (with CP features) but not in the third animal (with LTNP features, B017+). Conclusion: SPECT/CT imaging during acute and chronic SIV infection

highlighted an unexpected association between the size of lymph nodes and the CD4 pool, that may suggest a novel correlate of non-progressive SIV infection.

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CROI 2018