CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

1012 The Role of Maternal Broadly Neutralizing Antibody Activity in Perinatal Transmission of HIV-1 Krithika Karthigeyan 1 , Dieter Mielke 2 , Christian R. Binuya 1 , Ria Goswami 1 , Olusola Omonije 1 , Elena Giorgi 3 , Justin Pollara 4 , John Isaac 1 , Joshua Eudailey 1 , Megan Connors 1 , Carolyn Weinbaum 1 , Sallie Permar 1 1 Weill Cornell Medicine, New York, NY, USA, 2 Duke University, Durham, NC, USA, 3 Fred Hutchinson Cancer Center, Seattle, WA, USA, 4 Duke University School of Medicine, Durham, NC, USA Background: Despite increased availability to antiretroviral therapy, up to 5% of people living with HIV (PLH) still transmit HIV-1 to the infant. Broadly neutralizing antibodies (bNAbs) are the immunologic goal of HIV-1 vaccine candidates; however, in postnatal cohorts, we have reported the presence of bNAbs targeting a single epitope, which contributes to viral escape. We hypothesize that PLH with bNAbs against single epitopes of the HIV envelope are at higher risk of perinatal transmission due to viral escape. Methods: Plasma was acquired around delivery from 21 perinatal transmitters and 70 non-transmitters with HIV matched 1:3, from the Mother-Infant Cohort Study and the NISDI Perinatal study. Plasma was screened for neutralization breadth against a 10-virus HIV-1 panel. For participants with breadth (neutralizing ≥ 5 viruses with ID50 ≥ 40), plasma was screened against viruses with epitope mutations in the CD4 binding site, V2, V3 Glycan, and the membrane proximal external region of HIV-1 Env. Antibody dependent cellular cytotoxicity (ADCC) was assessed against cells infected with a transmitted/ founder subtype B virus (WITO). Results: Transmitters had higher neutralization breadth (p = 0.0005) and potency (p = 0.0008) compared to non-transmitters (two-sided Fisher’s test). bNAb activity in 6 out of 7 transmitters (87%) were mappable, with 5 out of 7 mapping to the CD4 binding site (71%) and one transmitter mapping to both CD4bs and V3 Glycan. In comparison, 4 out of 14 non-transmitters mapped to a single epitope (29%), while the majority remain unmapped. Overall, a higher proportion of transmitters had epitope-mappable plasma-bNAb activity (p = 0.02, two-sided Fisher’s test). Additionally, regression analysis on pooled data suggests that when adjusted for cohort, transmitters have significantly higher ADCC against subtype B WITO compared to non-transmitters (p = 0.02, ANOVA). Conclusions: Our findings suggest the existence of increased bNAb activity in transmitters that is primarily specific to a single epitope, which could lead to emergence of bNAb-resistant viral variants that can be transmitted perinatally. While ADCC has been implicated in protection against transmission, our analyses indicates that transmitters have higher ADCC against a subtype B virus, though ADCC breadth analysis could reveal additional details. In conclusion, bNAb-based pediatric HIV prevention and treatments that are synergistic with ART will likely need to be multi-specific to effectively eliminate pediatric HIV. 1013 ART Reverses Negative Natural Selection of HIV Disease-Linked HLA-I in KwaZulu-Natal, South Africa Nicholas G. Herbert 1 , Gabriela Z. L. Cromhout 2 , Nomonde Bengu 2 , Thilona Arumagam 3 , Veron Ramsuran 3 , Thumbi Ndung'u 2 , Sunetra Gupta 1 , Christian Brander 4 , Mary Carrington 5 , Bridget Penman 6 , Philip Goulder 1 1 University of Oxford, Oxford, UK, 2 Africa Health Research Institute, Mtubatuba, South Africa, 3 University of KwaZulu-Natal, Durban, South Africa, 4 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 5 Frederick National Laboratory for Cancer Research, Frederick, MD, USA, 6 University of Warwick, Coventry, UK Background: HLA is the most polymorphic region in the human genome, as the differential HLA-dependent impact of certain infections, inflammatory conditions, autoimmune diseases and cancers drive its evolution. However, clear examples of infection-driven evolution are rare. Here, we investigated antenatal cohorts in KwaZulu-Natal (KZN), South Africa, the region most severely affected by the global HIV pandemic, to evaluate the influence of HIV-1 infection on population-level HLA-I frequencies, and the impact of antiretroviral therapy (ART) in reversing this process. Methods: In a historical cohort of antenatal mothers living with HIV (LWH) in KZN, South Africa, in the pre-ART era between 2002-2005, we compared frequencies of ‘protective’ HLA-B alleles (HLA-B*57/B*58:01/B*81:01) associated with low viral setpoints and slow disease progression, and ‘disease susceptible’ HLA-B alleles (HLA-B*18/B*45:01/B*58:02) associated with high viral setpoints and rapid disease progression, among non-transmitting mothers (n=559) and transmitting mother-child pairs (n=112) . Next, we compared these HLA-B frequencies to those in a contemporary antenatal cohort of mothers LWH in KZN enrolled in the ART era between 2015-2023 (n=233). Lastly, we constructed an epidemiological model from 1990 to 2035 simulating

group. Mean Z-scores for length were comparable at 1 (-1.418 vs -0.789, p=0.2), 6 (-0.345 vs -0.754, p=0.3), and 12 (-0.604 vs -1.058, p=0.3) months after birth between groups. Mean Z-scores for weight and head circumference were also comparable between PrEP exposed and non-exposed populations up to one year of birth. Conclusions: Steady state TFV-DP concentrations in PBMCs from directly observed therapy of daily oral F/TDF PrEP were reassuringly comparable in pregnant and non-pregnant African women. Consistent with previous studies, birth and infant growth outcomes up to one year were also comparable between PrEP-exposed and unexposed pregnancies.

1011 Vertical HIV Transmission: Substantial Reductions but Not Elimination With Universal ART Nisha Jacob 1 , Emma Kalk 1 , Alexa Heekes 1 , Florence Phelanyane 1 , Kim Anderson 1 , Mary-Ann Davies 1 , Brian Rice 2 , Andrew Boulle 1 1 University of Cape Town, Cape Town, South Africa, 2 University of Sheffield, Sheffield, UK Background: Despite universal test and treat for HIV, vertical transmission continues to occur. We evaluated the temporal effectiveness of vertical transmission prevention (VTP) over three maternal antiretroviral treatment (ART) policy periods (1. three-drug ART accessible to those with CD4 counts <200 cells/µl; 2. <350 cells/µl; 3. universal ART) in Western Cape, South Africa using routine provincial public sector individuated data. Methods: We conducted a retrospective cohort study with child HIV acquisition as the primary outcome. Pregnancies between 2010 and 2020 were enumerated using the Provincial Health Data Centre Maternity Cascade which links electronic records of patients with administrative or laboratory evidence indicative of pregnancy. A child was deemed HIV exposed if their mother had electronic records indicative of HIV antenatally or ≤2 years from delivery. HIV and ART status were determined using indicators from laboratory, pharmacy and administrative information systems. Multivariable logistic regression was used to explore associations with vertical transmission. Results: The proportion of mothers initiating ART prior to pregnancy increased from 20.9% in 2010 to 71.1% in 2020. Of the 842 641 pregnancies included, 17.1% were HIV exposed and 16.3% had a recorded child HIV outcome. Of children with maternal HIV exposure, 2.1% (95% CI 2.1 – 2.2) were diagnosed with HIV. The proportion of exposed children with unknown HIV status decreased (66.9% in 2010 to 12.8% in 2020) whilst those testing HIV negative increased (30.4% in 2010 to 85.5% in 2020). Overall, 22.9% of the 3966 children with HIV had apparent negative or unknown maternal exposure. Median time from birth to HIV diagnosis was 181 days (IQR 33 – 603). Children born in maternal ART policy period 3 were less likely to be diagnosed with HIV than children born in policy period 2 (aOR 0.66; 95% CI 0.60 – 0.72), mediated through expanded ART access. Young maternal age, no antenatal ART, previous TB diagnosis and no evidence of antenatal care attendance prior to delivery were associated with vertical transmission of HIV. Conclusions: Our study demonstrates the positive impact of maternal ART policy change on VTP. The higher risk of vertical transmission amongst young women and those without antenatal care, highlights the need for targeted interventions for high-risk groups. The number of infections in children without established exposure emphasizes the importance of repeat antenatal and postnatal testing.

Poster Abstracts

CROI 2025 322