The HIV-1 envelope (Env) spike is a trimer of gp120/gp41 heterodimers that mediates viral entry. Binding to CD4 on the host cell membrane is the first essential step for infection but disrupts the native antigenic state of Env, posing a key obstacle to vaccine development. We locked the HIV-1 Env trimer in a pre-fusion configuration, resulting in impaired CD4 binding and enhanced binding to broadly neutralizing antibodies. This design was achieved via structure-guided introduction of neo-disulfide bonds bridging the gp120 inner and outer domains and was successfully applied to soluble trimers and native gp160 from different HIV-1 clades. Crystallization illustrated the structural basis for CD4-binding impairment. Immunization of rabbits with locked trimers from two different clades elicited neutralizing antibodies against tier-2 viruses with a repaired glycan shield regardless of treatment with a functional CD4 mimic. Thus, interdomain stabilization provides a widely applicable template for the design of Env-based HIV-1 vaccines.

IntroductionWhile mortality following primary cervical cancers (PCCs) continues to decline due to advancements in screening and treatment, a small subset of women who developed PCCs will develop second malignancies after their initial diagnosis. Little is known about these women. ObjectiveThis study aims to determine the common second malignancies among patients with primary cervical cancers and the factors associated with improved overall survival. MethodologyWe conducted a retrospective analysis of all PCCs in the SEER database between 1975 and 2016. We identified a subset of patients who subsequently developed secondary malignancies after a primary cervical cancer diagnosis. We then determined the factors associated with a prolonged latency interval, defined as the time between the PCC diagnosis and a subsequent secondary malignancy diagnosis. In a sub-analysis, we also determined the commonest secondary malignancies following a PCC diagnosis. ResultsA total of 1,494 patients with cervical cancers developed a second malignancy during the study period. The mean age at diagnosis of the PCCs was 56.0 ± 14.0 years. The mean latency interval between PCC and a subsequent secondary malignancy was 9.6 ± 9.3 years. Cytoreductive surgery (odds ratio (OR) = 1.40; 95% confidence interval (CI) = 1.05-1.86) and radiotherapy (OR = 1.52; 95% CI = 1.14-2.03) during the PCC are associated with a prolonged latency interval.Patients who received chemotherapy (OR = 0.23; 95% CI = 0.16-0.33) or those of Hispanic ethnicity (OR = 0.63; 95% CI = 0.44-0.90) were more likely to develop second malignancies within 10 years after a PCC diagnosis. The most common second malignancies were abdominal malignancies with rectal cancers (12.2%), pancreatic cancers (10.1%), stomach cancers (9.2%), cecum cancers (8.4%), and sigmoid colon cancers (8.3%). ConclusionThere is a significant association between Hispanic ethnicity and a shorter latency interval among patients with PCC. The findings from this study may help optimize screening for secondary cancers among cervical cancer survivors.

Background Alternative approaches to syndromic management are needed to reduce high rates of sexually transmitted infections (STI) in resource-limited settings. We aimed to determine the impact of point-of-care (POC) versus central laboratory-based testing on early STI treatment initiation and reporting of adverse events (AEs) that were STIs (STI-AE). Methods We used Kaplan-Meier and Cox regression models to compare times to STI treatment initiation and STI-AE reporting among HVTN702 HIV vaccine trial participants at three research clinics in South Africa. Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) were diagnosed with POC assays at eThekwini clinic and with central laboratory-based systems at Verulam and Isipingo clinics. All clinics used POC assays for Trichomonas vaginalis (TV) testing. Results Among 959 women (median age 23 years, IQR 21-26), median days (95%CI) to NG/CT treatment initiation and NG/CT-AE reporting were 0.20 (0.16-0.25) and 0.24 (0.19-0.27) at eThekwini versus 14.22 (14.12-15.09) and 15.12 (13.22-21.24) at Verulam/Isipingo clinics (all p < 0.001). Median days (95%CI) to TV treatment initiation and TV-AE reporting were 0.17 (0.12-0.27) and 0.25 (0.20-0.99) at eThekwini versus 0.18 (0.15-0.2) and 0.24 (0.15-0.99) at Verulam/Isipingo clinics (all p > 0.05). Cox regression analysis revealed that NG/CT treatment initiation (aHR = 39.62, 95%CI 15.13-103.74) and NG/CT-AE reporting (aHR = 3.38, 95%CI 2.23-5.13) occurred faster at eThekwini compared to Verulam/Isipingo clinics, while times to TV treatment initiation (aHR = 0.93, 95%CI 0.59-1.48) and TV-AE reporting (aHR = 1.38, 95%CI 0.86-2.21) were similar between clinics. Conclusions POC testing led to prompt STI management with potential therapeutic and prevention benefits, highlighting the utility as diagnostic tools in endemic resource-limited settings.

e18541 Background: The relationship between a subsequent ovarian cancer and a prior malignancy is complex with possible etiological, genetic, and therapeutic implications. Little is known about the epidemiological and clinical profile of this category of patients. The aim of the present study is to determine the factors associated with the development of ovarian cancer as a subsequent malignancy after a prior malignancy from another organ and determinants of improved survival in these women. Methods: We utilized the SEER 18 Registry 1975-2016 to conduct a retrospective analysis of women who developed a second primary ovarian malignancy following a prior cancer diagnosis. The outcome of interest was the latency interval between the initial primary malignancy diagnosis and a subsequent ovarian cancer diagnosis. Utilizing the cox regression model, we determined the factors associated with the overall survival of these women. Results: There were 10, 800 women who subsequently developed ovarian cancers following a prior malignancy. The commonest prior malignancies were breast cancers (38.2%), endometrial cancers (23.7%), and colorectal cancers (9.5%). The latency interval from developing a subsequent ovarian malignancy was 6.8±6.3 yrs. (Breast cancers) and 0.6 ± 2.5 yrs. (Endometrial cancers). A prior surgical treatment (OR = 1.19; 95% CI 1.02-1.40) or radiotherapy (OR = 1.34, 95% CI 1.21-1.49) in the initial primary malignancy is associated with a > 5years development of a subsequent ovarian malignancy. Black patients (OR = 1.63, 95% CI 1.39-1.92) have the worst survival even after controlling for disease stage and treatment modalities. Determinants of improved overall survival include White race, private insurance, age < 45 years at first primary malignancy diagnosis, prior surgical therapy, and increased latency interval. A prolonged latency interval is associated with a 74% increase in survival (OR = 0.26; 95%CI 0.23-0.30). Conclusions: Determinants of improved survival among patients with subsequent ovarian cancers following a prior primary malignancy include White race, private insurance, and a prolonged latency interval of progression from an initial primary malignancy to a subsequent ovarian cancer.