CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

251 ANTI-CD4 AUTOANTIBODIES ARE ASSOCIATED WITH DISCORDANT IMMUNOLOGICAL RESPONSES TO ART Andrea Lisco 1 , Charalampos Mystakelis 1 , Chun-Shu Wong 1 , Gregg Roby 1 , Virginia Sheikh 1 , Peter Burbelo 2 , Irini Sereti 1 1 NIAID, Bethesda, MD, USA, 2 NIH, Bethesda, MD, USA Background: A discordant immunological response to ART with poor CD4 T cells reconstitution is associated with increased inflammation, morbidity and mortality. We hypothesized that anti-CD4 autoantibodies could limit CD4 T cell recovery despite suppressed HIV-1 replication. Methods: 204 HIV+ART naïve patients with CD4<100 at baseline were included in this prospective study and followed longitudinally for 192 weeks after ART initiation. Demographic, virologic and clinical data were analyzed. Luciferase Immunoprecipitation Systems (LIPS) was used for detection of autoantibodies against CD4, CD8α, CD8β, CD3γ, CD3ε, IFNGR1, CD127, CD25, CTLA4, CCR5, Ro52. IgG deposition and natural killer (NK) antibody-dependent cell mediated cytotoxicity (ADCC) assays in PBMCs were developed to assess the binding of anti-lymphocyte antibodies and their possible biological effects. Mann-Whitney U test and Wilcoxon matched pair tests were used to compare groups. Results: Out of the 204 patients tested with LIPS, 36 had (17.6%) CD4 autoantibodies (aCD4-Ab) and no other immunoreactive protein was detected. Patients with aCD4-Ab had significantly lower CD4 reconstitution at week 48 compared to those without with median CD4 of 162 CD4/μl vs 199 CD4/μl in (p=0.02). Median Δ for CD4 reconstitution for the aCD4-Ab group was 117.5 vs 162 in the group without (p=0.0037). After excluding patients who received immunomodulant treatment that could have affected CD4 T cells reconstitution (i.e. corticosteroids, rituximab, chemotherapy), patients with aCD4-Ab, had lower CD4 reconstitution at all timepoints (weeks 48, 96 and 192) with median CD4 at 192 weeks 278 CD4/μl for the aCD4-Ab group vs 364 CD4/μl for the anti-CD4 negative group (p=0.03) with median Δ of 247 CD4/μl vs 338 CD4/μl (p=0.057). The aCD4-Ab binding site was mapped to the D3-D4 domain of CD4 by mutation analysis. No evidence of IgG deposition or ADCC was identified in any of the tested subjects with aCD4-Ab. Conclusion: aCD4-Ab are associated with discordant immunological response to ART in patients with advanced HIV/AIDS. In this cohort, aCD4-Ab effects on CD4 T cell homeostasis was not explained by ADCC suggesting other potential mechanisms that may adversely affect T cell homeostasis.

252 SEX DIFFERENCES IN CMV REPLICATION AND HIV PERSISTENCE DURING SUPPRESSIVE ART Sara Gianella 1 , Sarah McDonald Tran 1 , Milenka Vargas 1 , Gemma Caballero 1 , Michelli Faria de Oliveira 1 , Steven Lada 1 , Mitchell Zhao 1 , Jyoti S. Mathad 2 , Timothy Wilkin 2 1 University of California San Diego, La Jolla, CA, USA, 2 Weill Cornell Medicine, New York, NY, USA Background: CMV replication is common in men living with HIV (MLWH), and is associated with increased immune activation, T cell proliferation and larger HIV reservoirs. The prevalence of CMV shedding and its relationship to HIV persistence have not been investigated in women (W)LWH. Methods: Fifty virologically suppressed WLWH were enrolled in New York City (between 07/2014 thru 09/ 2016). Participants provided oral, vaginal and urine samples with peripheral blood mononuclear cells (PBMCs, N=50) at one time- point. CMV DNA was quantified in each specimen by real-time PCR. Cellular HIV DNA and HIV RNA transcripts (unspliced and multiply spliced [ms] encoding tat-rev) were quantified by droplet digital (dd)PCR. Historical data generated from 49 CMV-seropositive MLWH (blood and semen) were used as controls (Gianella et al, PMID: 26842469). Results: Median age was 53 years for women and 46 years for men; 28 (56%) women were post-menopausal and 43 (86%) acquired HIV through heterosexual contact. All men reported sex with men as risk factor. Both groups were chronically infected with HIV and had undetectable HIV RNA in blood. Median CD4+ were 721 cells/ml (490-930) for women and 625 (538-744) for men. Levels of cellular HIV DNA and unpliced HIV RNA were not different between sexes, but women were less likely to have detectable msHIV RNA (54% versus 100% in men, Fisher <0.01). Of the 49 CMV-seropositive WLWH, 16/49 (33%) had detectable CMV DNA in at least one specimen type, compared to 26/49 (53%) men (P<0.01), Table 1. CMV DNA was most frequenty detected in vaginal swabs (16%) and PBMCs (14%) for women and in semen (40%) for men. Unlike previously shown in men, the presence of CMV DNA was not associated with increased HIV DNA in women. Among women, pre-menopausal status was associated with significantly lower HIV DNA compared to post-menopause, after adjusting for age and duration of HIV infection (42 versus 150 HIV DNA copies/106 cells, P<0.01. Men: 90 copies/106 cells). There was no difference in cellular HIV RNA transcription and CMV shedding between pre- and post- menopausal women. Conclusion: WLWH co-infected with CMV presented reduced cellular HIV transcription and less subclinical CMV replication compared to men, but similar HIV DNA levels. Interestingly, post-menopausal status was independently associated with increased HIV DNA reservoir, even after adjusting for age and duration of HIV infection. The exact mechanism is unclear and should be evaluated in future longitudinal studies.

Poster Abstracts

90

CROI 2019