ALIGNMENT OF PREP USE WITH POTENTIAL HIV EXPOSURE IN YOUNG WOMEN AND MEN IN UGANDA.

Background: Despite high oral pre-exposure prophylaxis (PrEP) uptake among young heterosexual cisgender women, early discontinuation is frequent. It is unclear whether this aligns with potential HIV exposure.

Methods: Young women 16-25 years and ≥1 of their male partners were enrolled in separate but linked longitudinal HIV PrEP studies in Kampala, Uganda from 2018-2021.

AI-based IsAb2.0 for antibody design.

Therapeutic antibody design has garnered widespread attention, highlighting its interdisciplinary importance. Advancements in technology emphasize the critical role of designing nanobodies and humanized antibodies in antibody engineering. However, current experimental methods are costly and time-consuming.

Brief Report: HIV Drug Resistance Assessment Among Women Who Seroconverted During the MTN-025/HOPE Open-Label Extension Dapivirine Vaginal Ring Trial.

Background: Clinical trials of dapivirine (DPV) vaginal ring have shown it is safe, effective, and desired by women as an HIV prevention option. The risk of drug resistance is a potential concern for DPV ring users who acquire HIV. We conducted a comprehensive resistance evaluation of plasma samples from the women who seroconverted during the Microbicide Trials Network-025/HIV Open-label Prevention Extension (HOPE) study of DPV ring.

HIV-1 drug resistance among individuals who seroconverted in the ASPIRE dapivirine ring trial.

Introduction: A potential concern with the use of dapivirine (DPV) for HIV prevention is the selection of a drug-resistant virus that could spread and reduce the effectiveness of non-nucleoside reverse transcriptase (NNRTI)-based first-line antiretroviral therapy. We evaluated HIV-1 seroconversions in MTN-020/ASPIRE for selection of drug resistance and evaluated the genetic basis for observed reductions in susceptibility to DPV.

Methods: MTN-020/ASPIRE was a placebo-controlled, Phase III safety and effectiveness study of DPV ring for HIV-1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda between 2012 and 2015.

Discordance between Etravirine Phenotype and Genotype-Based Predicted Phenotype for Subtype C HIV-1 from First-Line Antiretroviral Therapy Failures in South Africa.

Etravirine (ETR) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used in treatment-experienced individuals. Genotypic resistance test-interpretation systems can predict ETR resistance; however, genotype-based algorithms are derived primarily from HIV-1 subtype B and may not accurately predict resistance in non-B subtypes. The frequency of ETR resistance among recombinant subtype C HIV-1 and the accuracy of genotypic interpretation systems were investigated.

Dapivirine vaginal ring for HIV prevention: modelling health outcomes, drug resistance and cost-effectiveness.

Introduction: A vaginal ring containing dapivirine is effective for HIV prevention as pre-exposure prophylaxis (PrEP). We evaluated the potential epidemiological impact and cost-effectiveness of dapivirine vaginal ring PrEP among 22- to 45-year-old women in KwaZulu-Natal, South Africa.

Methods: Using mathematical modelling, we studied dapivirine vaginal ring PrEP implementation, either unprioritized, or prioritized based on HIV incidence (≥3% per year), age (22 to 29 years) or female sex worker status, alongside the implementation of voluntary medical male circumcision and antiretroviral therapy scaled-up to UNAIDS Fast-Track targets.

Frequent cross-resistance to rilpivirine among subtype C HIV-1 from first-line antiretroviral therapy failures in South Africa.

Background Rilpivirine (TMC278LA) is a promising drug for pre-exposure prophylaxis of HIV-1 because of its sub-nanomolar potency and long-acting formulation; however, increasing transmission of non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 with potential cross-resistance to rilpivirine could reduce its preventive efficacy. This study investigated rilpivirine cross-resistance among recombinant subtype C HIV-1 derived from 100 individuals failing on first-line non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy in South Africa whose samples were sent for routine HIV-1 drug resistance testing to Lancet Laboratories (Johannesburg, South Africa). Methods Plasma samples were selected from individuals with HIV-1 RNA > 10,000 copies/ml and ≥1 non-nucleoside reverse transcriptase inhibitor-resistance mutation in reverse transcriptase.

Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa.

A vaginal ring containing dapivirine (DPV) has shown moderate protective efficacy against HIV-1 acquisition, but the activity of DPV against efavirenz (EFV)- and nevirapine (NVP)-resistant viruses that could be transmitted is not well defined. We investigated DPV cross-resistance of subtype C HIV-1 from individuals on failing NVP- or EFV-containing antiretroviral therapy (ART) in South Africa. Plasma samples were obtained from individuals with >10,000 copies of HIV RNA/ml and with HIV-1 containing at least one non-nucleoside reverse transcriptase (NNRTI) mutation.

Deciphering the Effects of Injectable Pre-exposure Prophylaxis for Combination Human Immunodeficiency Virus Prevention.

 A long-acting injectable formulation of rilpivirine (RPV), under investigation as antiretroviral pre-exposure prophylaxis (PrEP), may facilitate PrEP adherence. In contrast, cross-resistance between RPV and nonnucleoside reverse-transcriptase inhibitors comprising first-line antiretroviral therapy (ART) could promote human immunodeficiency virus (HIV) drug resistance and reduce PrEP's effectiveness.  We use novel mathematical modeling of different RPV PrEP scale-up strategies in KwaZulu-Natal, South Africa, to investigate their effects on HIV prevention and drug resistance, compared with a reference scenario without PrEP.

Objective Measurement of Inaccurate Condom Use Reporting Among Women Using Depot Medroxyprogesterone Acetate for Contraception.

Observational analyses have suggested that women using the injectable contraceptive depot medroxyprogesterone acetate (DMPA) may have heightened risk of acquiring HIV. However, those analyses were potentially confounded by sexual behavior, with possible differential condom use and reporting by women using DMPA versus no contraception. In a cross-sectional study, we measured the presence of a biomarker of recent condomless sex (Y chromosomal [Yc] DNA) in vaginal swabs from HIV-uninfected African women who had an HIV-infected partner and reported 100 % condom use.

Cost-effectiveness of Injectable Preexposure Prophylaxis for HIV Prevention in South Africa.

Background: Long-acting injectable antiretrovirals such as rilpivirine (RPV) could promote adherence to preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention. However, the cost-effectiveness of injectable PrEP is unclear.

Methods: We constructed a dynamic model of the heterosexual HIV epidemic in KwaZulu-Natal, South Africa, and analyzed scenarios of RPV PrEP scale-up for combination HIV prevention in comparison with a reference scenario without PrEP.

Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo.

Reservoirs of infectious HIV-1 persist despite years of combination antiretroviral therapy and make curing HIV-1 infections a major challenge. Most of the proviral DNA resides in CD4(+)T cells. Some of these CD4(+)T cells are clonally expanded; most of the proviruses are defective.

Selection of Rilpivirine-Resistant HIV-1 in a Seroconverter From the SSAT 040 Trial Who Received the 300-mg Dose of Long-Acting Rilpivirine (TMC278LA).

The injectable long-acting formulation of rilpivirine (TMC278LA) is a promising preexposure prophylaxis (PrEP) candidate for prevention of human immunodeficiency virus type 1 (HIV-1) infection. We evaluated HIV-1 in plasma obtained from an unexpected seroconverter in the 300-mg arm of the SSAT040 TMC278LA pharmacokinetic study for rilpivirine (RPV) resistance. Infection with wild-type HIV-1 was confirmed on day 84 after TMC278LA injection, and the K101E mutation was detected on day 115.

Influence of a loop electrosurgical excision procedure (LEEP) on levels of cytokines in cervical secretions.

Over the past decade, there has been heightened interest in determining if there is an increased risk of adverse reproductive outcomes among women who had a loop electrosurgical excision procedure (LEEP) to remove cervical intraepithelial neoplasia (CIN). The objective of this exploratory study was to determine if the treatment of CIN with a LEEP is associated with changes in cervical soluble immune markers. Cervical cytokine concentrations were measured in women treated with LEEP and a control group of women who had colposcopy only and did not undergo LEEP.

Y chromosome and HIV DNA detection in vaginal swabs as biomarkers of semen and HIV exposure in women.

Background: The inability to quantify sexual exposure to HIV limits the power of HIV prevention trials of vaccines, microbicides, and preexposure prophylaxis in women. We investigated the detection of HIV-1 and Y chromosomal (Yc) DNA in vaginal swabs from 83 participants in the HPTN 035 microbicide trial as biomarkers of HIV exposure and unprotected sexual activity.

Methods: One hundred forty-three vaginal swabs from 85 women were evaluated for the presence of Yc DNA (Quantifiler Duo DNA quantification kit; Applied Biosystems) and total HIV-1 DNA (single-copy in-house quantitative polymerase chain reaction assay).

Cross-protective vaccine efficacy of the bivalent HPV vaccine against HPV31 is associated with humoral immune responses: results from the Costa Rica Vaccine Trial.

Background: We investigated the role of antibody responses as potential mechanism for the cross-protective vaccine-efficacies (VE) observed from randomized clinical trials of the HPV16/18 bivalent vaccine. Results HPV31 cases had lower HPV16 antibody levels than controls (OR 4th quartile compared with 1st quartile = 0.63; 95%CI: 0.

Kinetic and HPV infection effects on cross-type neutralizing antibody and avidity responses induced by Cervarix(®).

Background: We previously demonstrated that Cervarix(®) elicits antibody responses against vaccine-related types for which clinical efficacy was demonstrated (HPV-31 and -45). Here, we evaluated the kinetics of neutralization titers and avidity of Cervarix(®)-induced antibodies up to 36 months of follow-up in unexposed and HPV infected women.

Methods: A subset of women who participated in the Cost Rica HPV-16/18 Vaccine Trial had pre- and post-vaccination sera tested for antibody responses to HPV-16, -18, -31, -45, and -58 using a pseudovirion-based neutralization assay, and HPV-16 antibody avidity using an HPV-16 L1 VLP (virus-like particle)-based ELISA developed in our laboratory.

Gateway vectors for the production of combinatorially-tagged His6-MBP fusion proteins in the cytoplasm and periplasm of Escherichia coli.

Many proteins that accumulate in the form of insoluble aggregates when they are overproduced in Escherichia coli can be rendered soluble by fusing them to E. coli maltose binding protein (MBP), and this will often enable them to fold in to their biologically active conformations. Yet, although it is an excellent solubility enhancer, MBP is not a particularly good affinity tag for protein purification.

Three-dimensional structure of a macromolecular assembly that regulates type III secretion in Yersinia pestis.

Yersinia pestis, the causative agent of plague, utilizes a type III secretion system (T3SS) to inject effector proteins directly into the cytosol of mammalian cells where they interfere with signal transduction pathways that regulate actin cytoskeleton dynamics and inflammation, thereby enabling the bacterium to avoid engulfment and destruction by macrophages. Type III secretion normally does not occur in the absence of close contact with eukaryotic cells. Negative regulation is mediated in part by a multiprotein complex that has been proposed to act as a physical impediment to type III secretion by blocking the entrance to the secretion apparatus prior to contact with mammalian cells.

Casein Kinase II phosphorylation-induced conformational switch triggers degradation of the papillomavirus E2 protein.

The major phosphorylation sites of the bovine papillomavirus E2 transactivator protein are two serine residues, 298 and 301, that are located in a flexible hinge region between the DNA binding and transactivation domains. Phosphorylation of serine residue 301 promotes ubiquitination and rapid degradation of the E2 protein by the proteasome pathway. To understand the mechanism through which phosphorylation regulates the intracellular levels of this unique papillomavirus regulatory protein, we have carried out an extensive mutational analysis of the region surrounding the phosphorylation sites of the E2 protein.