CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

mutations: K94E (51% activity), driven by HLA-B*08; and H116N (80% activity), driven by HLA-B*57. Furthermore, NL4-3 viruses encoding Nef K94E and/or H116N displayed reduced infectivity and lower replication capacity, compared to WT virus (both p<0.0001). Conclusion: Our results demonstrate that Nef’s ability to counteract SERINC5 is modulated by natural sequence variation. Polymorphisms in two highly immunogenic CTL epitopes (restricted by B*08 and B*57) selectively impaired this Nef function, illustrating constraints on HIV-1 adaption and identifying potential targets for therapeutics that disrupt Nef/SERINC5 interactions. 203 HSV-1/HSV-2 INFECTION IN MACAQUES AND REACTIVATION AFTER EXPOSURE TO HETEROLOGOUS HSV Priya Srinivasan 1 , Jining Zhang 1 , Clare Burn 2 , Tyana Singletary 3 , Dawn Little 4 , Lara Pereira 1 , Pedro Mesquita 2 , Betsy Herold 2 , James M. Smith 1 1 CDC, Atlanta, GA, USA, 2 Albert Einstein College of Medicine, Bronx, NY, USA, 3 Anyar, Inc, Fort Walton Beach, CA, USA, 4 LifeSource Biomedical, LLC, Mountain View, CA, USA Background: HIV and herpes simplex virus 1 and 2 (HSV-1, HSV-2) are common coinfections and infection with one can increase the risk of infection with the other. The risk of HIV acquisition has been reported to be increased up to five times in HSV- infected individuals. It is important to develop a relevant animal model to evaluate the efficacy of preexposure prophylaxis (PrEP) modalities in the context of HSV/HIV coinfection. We have developed a macaque model for vaginal HSV infection using HSV-1 Bx 1.1, a primary isolate from Bronx, New York, and HSV-2 SD90, a low-passage clinical isolate from South Africa. Methods: Four SHIV162p3-positive female rhesus macaques received 30 mg of depot medroxyprogesterone acetate every six weeks, starting three weeks prior to the first HSV exposure. A crossover study was conducted in two phases. In phase 1 two animals received HSV-1 and two received HSV-2 (10^8-10^9 PFU) once weekly intravaginally for four weeks followed by an eleven-week rest period. In phase 2 the groups were switched and the same schedule was followed with the addition of cytobrush sampling of the vaginal wall just prior to each inoculation. We monitored for vaginal HSV shedding (strain specific RT-PCR, gB region) throughout the study. Flow cytometry was used to analyze changes in mucosal T cells. Results: HSV shedding was detected in all phase 1 macaques one week post challenge, with one HSV-1 animal positive at two weeks and one HSV-2 animal positive at three weeks post challenge. After the crossover, the HSV-2 infected animals from phase 1 showed a stronger and more consistent reactivation of HSV-2 after infection with HSV-1 than the reactivation of HSV-1 in the other group, with HSV-2 shedding detectable starting two days after the first HSV-1 inoculation and continuing for ten days after the last HSV-1 exposure. Mucosal CD4+ and CD8+ T cells following HSV infection expressed high levels of CD69 consistent with what is observed in humans. Conclusion: Successful infection of macaques with primary clinical isolates of HSV-1 and HSV-2 results in an infection that can be reactivated upon exposure to heterologous HSV strains. This model can help us better understand the mechanisms behind the increased risk and will be used to assess the effect of HSV infection on HIV PrEP efficacy and to also identify antiviral drugs that can prevent both HIV/HSV acquisition. 204 ASSESSING BIOLOGIC RISK FOR HIV TRANSMISSION IN TRANSGENDER WOMEN Alexandra Schuetz 1 , Carlo Sacdalan 2 , Nisakorn Ratnaratorn 2 , Yuwadee Phuang- Ngern 3 , Eugène Kroon 2 , Rungsun Rerknimitr 4 , Suthat Chottanapund 2 , Denise C. Hsu 1 , Tanyaporn Wansom 1 , Nelson L. Michael 5 , Merlin L. Robb 6 , Robert J. O’Connell 1 , Jintanat Ananworanich 6 , Sandhya Vasan 1 1 US Military HIV Research Program in Thailand, Bangkok, Thailand, 2 Thai Red Cross AIDS Research Center, Bangkok, Thailand, 3 Armed Forces Research Institute of Medical Sciences in Bangkok, Bangkok, Thailand, 4 Chulalongkorn University, Bangkok, Thailand, 5 US Military HIV Research Program, Silver Spring, MD, USA, 6 US Military HIV Research Program, Bethesda, MD, USA Background: High HIV infection rates in transgender women (TGW) are largely attributed to increased behavioral risk factors. However, effects of exogenous hormones on the immune system and injectable fillers or sex reassignment surgery (SRS) on immune activation may alter HIV risk. Methods: A cross-sectional study of HIV negative volunteers including 10 MSM, 10 natal or cis-women (CW) and 8 TGW post SRS was conducted. Peripheral blood mononuclear cells (PBMC) and mucosal mononuclear cells

(MMC) isolated from sigmoid biopsies (TGW, MSM, CW), and cervical (CW) and neovaginal (TGW) swabs were analyzed. Lymph node (LN) biopsies underwent immunohistochemical staining. Results: Median lifetime sexual partners was higher in TGW (53) vs. CW (3, p=0.006) and MSM (25, p=NS). Among TGW, mean age of initial gender dysphoria was 7yrs, cross dressing 13yrs, hormone initiation 14yrs, and SRS 24yrs. Median duration of hormone use in TGWwas 7.6yrs, with 5/8 using estrogen/progesterone, and 3/8 estrogen only. Median time post SRS was 1.3yrs, all by penile inversion, with 7/8 still using dilators post SRS. All TGW reported anal sex; 7/8 reported neovaginal sex. No difference in frequency of CD4+ or CD8+ T cells in PBMC and sigmoid MMC among groups was found. Frequency of neovaginal CD4+ T cells was decreased (1.8%) and CD8+ T cells increased (77.7%) vs. sigmoid and cervical CD4+ (54.4% and 48.3%), and CD8+ (33.6% and 30.2%) T cells (p<0.001, all). Neovaginal CD4+CCR5+ T cell frequency was lower in than cervical MMC (1.2% vs 35%, p=0.02), but comparable to sigmoid MMC (31.1%, p=NS). MFI of CD4+CCR5+ T cells was higher in neovaginal MMC (1491) vs. sigmoid MMC (761, p=0.04), but similar to cervical MMC (578, p=NS). Increased activated CD4+ T cells (HLA-DR+/CD38+), were seen in cervical MMC (2.3%) vs. sigmoid (1.1%) and neovaginal MMC (1.0%, p=0.02 and p=0.05, respectively). Filler use was higher in TGW (63%) than MSM (10%) or CW (0%). One TGW using hip fillers had multiple inguinal siliconomas, corresponding with high frequency of peripheral Ki67+CD4+ expression (0.4% vs median 0.1% in TGW) and Ki67+CD4+ cells in her inguinal LN. Conclusion: CD4/CD8 T cell composition of neovaginal MMC differs from sigmoid and cervical MMC. There was no increase in frequency of neovaginal activated CD4+ or CD4+CCR5+ T cells. Higher use of fillers in TGWmay contribute to systemic immune activation, although studies are ongoing. Characterization of biologic HIV risk factors specific to TGWmay inform additional prevention strategies.

Poster Abstracts

205 RACIAL DIFFERENCES IN Α4Β7 EXPRESSION OF THE CCR6+ SUBSET OF CD4+ T CELLS Alyssa R. Martin 1 , Aida Sivro 2 , Zoe Packman 3 , Livia R. Goes 1 , Lyle McKinnon 2 , Jacquie Astemborski 3 , Gregory D. Kirk 3 , Shruti H. Mehta 3 , Claudia Cicala 1 , James Arthos 1 , Andrew D. Redd 1 , Anthony S. Fauci 1 , Thomas C. Quinn 1 1 NIH, Bethesda, MD, USA, 2 CAPRISA, Durban, South Africa, 3 Johns Hopkins University, Baltimore, MD, USA Background: The α4β7 heterodimer is important for CD4+ T cell trafficking to the gut. Cells that express high levels of α4β7, including the CCR6 expressing Th17 subset of CD4+ T cells, are highly susceptible to HIV infection. Previous research found that black men who have sex with men (MSM) have higher levels of CD4+ β7hi expressing cells than white MSM, suggesting that racial differences in α4β7 expression may be related to increased risk of HIV acquisition. This difference in α4β7 expression has not been studied in people who inject drugs (PWID), in men and women of multiple racial groups, or in terms of differences in CD4+ T cell subset expression of α4β7. Methods: PBMC samples from HIV seronegative PWID were stained and analyzed by flow cytometry for expression of β7 integrin (as a proxy of α4β7 heterodimer expression), CCR6 (to identify Th17 cells), and activation markers. 100 subjects (25 white males, 25 black males, 25 white females, 25 black females) were included, with 10 replicates from different visits to assess stability of β7 expression over time. Matched data were compared using the Wilcoxon matched-pairs signed-ranks test. The Mann-Whitney U test was used to compare racial differences in β7 expressing cells. Covariate associations were

72

CROI 2018