CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

781 HCMV Induces CCR5 Expression, Activation and HIV Infection at Feto-Maternal Interface Erica L. Johnson 1 ; Sahithi Boggavarapu 2 ; Elan S. Johnson 2 ; Asim Lal 2 ; Parth Agrawal 2 ; Rana Chakraborty 2 1 Emory Univ Sch of Med, Atlanta, GA, USA; 2 Emory Univ, Atlanta, GA, USA

Background: Despite effective administration of combination antiretroviral therapy to HIV-1–infected pregnant women, mother-to-child transmission (MTCT) of HIV-1 remains a significant global public health concern. Co-pathogens that pose threats to the developing fetus include human cytomegalovirus (HCMV), may also facilitate in utero transmission of HIV-1 in populations where co-infection is common. HCMV infects up to 90% of reproductive-age women in developing and developed countries. We hypothesize that HCMV promotes in utero transmission through increased immune activation, local inflammation, and maternal stimulation of fetal/placental macrophages (or Hofbauer cells [HC]) to increase susceptibility to HIV-1. Strong associations between in utero HCMV infection and a higher incidence of MTCT of HIV-1 have been documented; however, the mechanisms that increase MTCT remain unknown. Methods: With written informed consent, placentae/cord blood were collected from 15 HIV-1/Hep B/HCMV seronegative women (>18 years) at Emory Midtown Hospital in Atlanta, GA. In this study, myeloid subsets were exposed to HCMV in vitro , followed by HIV-1BaL. Cells were also treated with IFN-α/IFN-β. Viral replication was determined by HIV-1 p24 ELISA. qPCR, FACS, and Western blot analysis determined the expression of CCR5, activation markers, and antiviral ISGs. Cytokines and IFNs were measured by ELISA. Data were analyzed by using Student’s t-test and Mann-Whitney test. Results: HCMV exposure upregulated expression of the HIV-1 co-receptor CCR5, along with activation markers (CD16, CD80 and HLA-DR) on HCs . HCMV significantly induced the secretion of proinflammatory cytokines (IL-6 and TNF-α) by HCs, which enhanced their susceptibility to HIV-1 infection. We also showed type-I IFNs alone potently restrict HIV-1 replication in HCs, however HCMV infection inhibits Stat2 activation, which may override type-I IFN-induced protection to promote HIV-1 infection. Conclusions: These data suggest that activation and local inflammation induced by maternal HCMV in utero alter CCR5 expression in macrophages at the feto-maternal interface to promote MTCT of HIV-1. We also present evidence that HCMV inhibits type-I IFN-dependent Stat2 signaling in the placenta, which may disrupt the intrinsic antiviral response in this compartment. Identifying biological determinants of MTCT provides a sentinel foundation upon which to design strategies for prenatal prophylaxis and the development of effective immunotherapies. 782 Population-Level Declines in Vertical HIV TransmissionWith Changing PMTCT Guidelines Jean Maritz 1 ; Nei-Yuan Hsiao 2 ;Wolfgang Preiser 1 ; Landon Myer 2 1 Stellenbosch Univ, Cape Town, South Africa; 2 Univ of Cape Town, Cape Town, South Africa Background: Despite major shifts in policies for prevention of mother-to-child HIV transmission (PMTCT) there are few population-level data on the changing epidemiology of perinatal HIV in South Africa (SA). Methods: We examined data on all HIV PCR tests conducted by the SA National Health Laboratory Service in children ≤6 months of age in the Western Cape province between January 2009 and August 2015. During this period, PMTCT policies moved from zidovudine monotherapy with antiretroviral therapy (ART) for pregnant women based on CD4+ thresholds of ≤200 cells/µL before July 2010, to ≤350 cells/µL by June 2013, to ART for all HIV+ pregnant women (“Option B+”) from July 2013. Breastfeeding guidance shifted to support exclusive breastfeeding with nevirapine prophylaxis for the first 6 months of life from 2011. Analyses examined changes in HIV PCR testing (i) annually as well as (ii) by PMTCT policy period (with time lags to allow for delivery and postpartum testing), and (iii) distinguished positive tests from birth testing (conducted at ≤7 days of age) from routine early infant diagnostic (EID) testing at primary care clinics, from hospital-based testing associated with symptomatic clinical presentations. Results: Overall 99,684 children underwent HIV PCR testing. Among all children tested at ≤6 months of age, the HIV PCR positivity rate dropped from 5.9% in 2009 to 1.5% in 2015 (Figure); the rate of positive tests after implementation of “Option B+” (2.0%) was significantly lower than the period when ART thresholds were based on ≤350 cells/µL (2.5%; p<0.001). The mean age at first HIV PCR test decreased from 59.1 days in 2009 to 44.7 days in 2015 (p<0.001); approximately half of this change was explained by increasing numbers of HIV PCR tests conducted at birth during this period, which grew from<1% to 14% of all tests conducted (Figure). Among tests conducted beyond 7 days of age, a growing proportion took place as part of routine EID testing over time rather than hospital-based testing (p<0.001). Despite increases in birth testing, during 2014-2015 only 13% of all newly diagnosed HIV+ infants were identified through birth testing; the new infections were identified either through routine EID (56%) or hospital-based testing (31%). Conclusions: There have been major reductions in perinatal HIV infections with changing PMTCT policies in this setting. Despite the rise of birth testing, the majority of HIV+ infants are still identified through routine EID programmes.

Poster Abstracts

783 Introduction of Birth Testing Into the South African National Consolidated Guidelines Ahmad Haeri Mazanderani 1 ;Tendesayi Kufa-Chakezha 1 ; Gayle Sherman 2 1 NICD, Johannesburg, South Africa; 2 Univ of the Witwatersrand, Johannesburg, South Africa

Background: Birth testing of all HIV-exposed infants was introduced into the South African National Consolidated Guidelines on 1 June 2015.Prior to this, routine HIV PCR testing was performed in infants at 6 weeks of age, with earlier testing in symptomatic infants. In 2014, when the estimated 6-week transmission rate was 1.8%, targeted birth testing of high risk neonates was introduced. We describe at a national level, the number and results of HIV PCR tests done at <7 days, <2 months, and <3 months of age during the period 01 June to 31 August 2015 and compare with the same period for 2012-2014 to determine immediate uptake of birth testing following implementation of new guidelines. Methods: HIV PCR test data from 2012-2015 was extracted from the Corporate Data Warehouse of the National Health Laboratory Service, a central data repository of all registered test-sets within the public health sector in South Africa. Data was extracted by year, month, age and result. Birth testing coverage was calculated as a proportion of HIV exposed neonates tested for HIV at age <7 days over the number of HIV exposed neonates requiring testing (live births x maternal HIV seroprevalence). The estimated intra-uterine HIV transmission rate for South Africa was determined by calculating the positivity rate of all HIV PCR specimens in neonates aged <7 days.

326

CROI 2016