The HIV/AIDS epidemic remains a major global public health challenge, and the emergence of drug resistance mutations compromises treatment efficacy. The aim of this study was to characterize HIV-1 genetic diversity and antiretroviral drug resistance mutations circulating in Peruvian infants under 18 months of age. A descriptive cross-sectional study was conducted using 28 samples collected between 2017 and 2018. Genetic material was obtained from whole blood (proviral DNA) and plasma (viral RNA), and then analyzed using nested PCR amplification and next-generation sequencing (NGS). HIV-1 subtypes were determined through a phylogenetic analysis, and resistance mutations were identified using the HYDRA and Stanford HIVdb platforms. Subtype B was the most prevalent (89%), followed by circulating recombinant forms CRF17_BF and CRF89_BF (11%). Four out of 28 samples (14.3%) harbored at least one resistance-associated mutation. The most frequently detected mutations included K103N (7.1%), V106I (3.6%), V179E (7.1%), and G190A (3.6%), with 21.4% of the identified mutations associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs). Notably, this study reports the first detection of CRF89_BF in Peruvian infants under 18 months of age. These findings highlight the importance of ongoing molecular surveillance of HIV-1 diversity and antiretroviral resistance mutations to optimize treatment strategies and strengthen HIV control programs.

The development of effective treatment strategies for human immunodeficiency virus (HIV) infection is a major achievement. Antiretroviral drugs inhibit key steps in the viral replication cycle and consist of six mechanistic classes: HIV entry inhibitors, reverse-transcriptase inhibitors (both nucleosides and nonnucleosides), capsid inhibitors, integrase inhibitors, and protease inhibitors. Antiretroviral therapy (ART) suppresses viral replication, thereby enhancing immune function, decreasing morbidity and mortality, and preventing viral transmission. Consequently, ART is recommended for all persons with HIV infection. On the basis of randomized clinical trials, the Food and Drug Administration has approved 36 antiretroviral drugs for the treatment of HIV infection since 1987; of these, 28 are currently available in the United States, and combination ART regimens are used. Initial preferred ART regimens are potent, convenient, and unlikely to cause side effects and consist of an HIV integrase inhibitor with a high barrier to resistance combined with one or two nucleoside reverse-transcriptase inhibitors. In the majority of patients using current ART regimens, viral replication is durably suppressed below detectable levels. Patients receiving ART are monitored for virologic response over time, and if virologic failure occurs, the next regimen is selected on the basis of treatment history and the results of drug-resistance testing; often, antiretroviral drugs from new classes are administered. Today, the life expectancy of someone with HIV infection who consistently takes ART approaches that of the general population.

BackgroundAccessing HIV prevention and treatment remains difficult throughout the United States (US). With the shortage of infectious disease physicians, increasing the number of clinicians offering HIV Pre-Exposure Prophylaxis (PrEP), HIV Post-Exposure Prophylaxis (PEP), and Test & Treat (T&T) is imperative. This exploratory project created a consolidated algorithm for HIV treatment and prevention that simplifies care for US providers with limited resources or experiences.MethodsThe algorithm was designed for PrEP, PEP, and treatment initiation using published guidelines from multiple clinical bodies. Three medications were included in the algorithm: tenofovir disoproxil fumarate, emtricitabine, and dolutegravir. US medical students completed an eight-question pretest unassisted then repeated questions with the algorithm to test the algorithm's functionality. Questions included clinical scenarios on HIV testing, PrEP, PEP, and T&T. Pearson's chi-squared compared pre vs post-test scores; total scores (number of items correct) were analyzed using Paired Wilcoxon signed rank test.Results97 students from 13 medical schools completed pre and post-test questions. Correctness increased from 3 of 8 (pretest) to 7 of 8 (post-test) (p< 0.001). All questions saw statistically significant improvement in correctness when assisted by the algorithm including correctly prescribing PEP, selecting appropriate labs for PrEP initiation, and screening patients with prior cabotegravir-based PrEP using HIV RNA quantitative (p<0.001 for all).ConclusionsThis algorithm improved medical students' abilities to accurately answer HIV clinical care questions about HIV prevention and treatment. Further studies are needed to understand the algorithm's effect in clinical settings and how to implement it in practice.

Cardiovascular (CV) disease is the leading cause of maternal mortality worldwide and has been partially linked to the cardiometabolic remodeling required to support fetal growth. In healthy pregnancies, these adaptations reverse postpartum without long-term consequences; however, impaired reverse remodeling (RR) increases future CV risk. Pregnant women living with HIV face additional risk, though it remains unclear whether this is driven by chronic low-level viremia or continuous antiretroviral therapy (ART). ART used during pregnancy often includes nucleoside reverse transcriptase inhibitors (NRTIs), which can affect mitochondria - organelles essential for maintaining cardiac function. Here, we tested the hypothesis that NRTI-containing ART negatively impacts the maternal heart. Using a rat model, we show that ART impairs pregnancy-associated cardiac RR. Mechanistically, ART induced mitochondrial alterations in both the heart and the liver, leading to dyslipidemia that collectively compromised cardiac function. These findings emphasize the importance of maternal cardiovascular health research and the need for further studies on the long-term effects of ART.

The NLRP3 inflammasome, along with inflammatory and metabolic biomarkers, has been implicated in atherosclerosis. This study aimed to investigate the association between subclinical atherosclerosis and NLRP3 rs10157379 T > C and rs10754558 C > G variants, inflammatory and metabolic biomarkers, and HIV-1 viral load in individuals living with HIV-1 infection. Seventy-eight HIV-1-infected individuals receiving antiretroviral therapy were included. Demographic, lifestyle, clinical data, inflammatory and metabolic biomarkers, CD4[+] and CD8[+] T lymphocyte counts, HIV-1 viral load, and NLRP3 rs10157379 and rs10754558 genotypes were determined. Carotid intima-media thickness (cIMT) was assessed and categorized as <0.9 mm (normal) or ≥ 0.9 mm (increased). The median age of the HIV-1-infected patients was 52 years (45-56) and 34 (43.6%) of them presented increased cIMT. After adjustment with age, sex, ethnicity, smoking, and metabolic syndrome, only non-Caucasian ethnicity, metabolic syndrome, CD4[+] T cell count <500 cells/mm[3], use of nucleoside reverse transcriptase inhibitors, high levels of interleukin 10 and tumor necrosis factor (TNF)-α were associated with increased cIMT (p < 0.05). No association was observed between cIMT and NLRP3 rs10157379 and rs10754558 variants. Patients carrying the GG genotype showed lower uric acid, low-density lipoprotein (LDL)-cholesterol, and higher adiponectin levels (p < 0.05), suggesting a more favorable metabolic and inflammatory profile. The prevalence of a 43.6% of increased cIMT is particularly relevant because participants with established atherosclerotic disease were excluded, indicating a high burden of subclinical atherosclerosis. These exploratory genetic findings require confirmation in larger cohorts to clarify these observations and identify additional biomarkers for early subclinical atherosclerosis detection in individuals living with HIV-1.

Human Immunodeficiency Virus (HIV) impacts the immune system and is rapidly evolving with a high number of newly infected cases leading to mortality. However, there is an unmet medical need to identify novel anti-HIV. To identify novel anti-HIV agents, marine products can be considered as a vital source. Previously, we reported cytotoxic activity of 13 compounds belonging to the dolabellane diterpenes scaffold. Here, we tested if our panel of dolabellane diterpene scaffolds also inhibits HIV using in vitro and in vivo assays. We found that dichodictyol E (5), dichodictyol H (8) and 12 inhibit HIV RT enzyme in vitro and infection in vivo. Molecular docking analysis reveals that dichodictyol E (5), dichodictyol H (8) and 12 bind to HIV 1 reverse transcriptase enzyme. We conclude that Dolabellane diterpenoids act as reverse transcriptase inhibitors and anti-HIV agents and are amenable to further structural modifications to make potent anti-HIV agents.

Islatravir (ISL; MK-8591; 4'-ethynyl-2-fluoro-2'-deoxyadenosine; EFdA) is the first antiviral drug that acts as a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Unlike classic nucleoside and nucleotide analogue reverse transcriptase inhibitors (nRTIs) that terminate viral DNA chain extension upon incorporation because they lack the 3'-hydroxyl group, ISL primarily interferes with reverse transcriptase (RT) translocation. After ISL-triphosphate (ISL-TP) is incorporated into viral DNA, RT has a reduced ability to shift along the template to effectively position the subsequent nucleotide for incorporation, thereby inhibiting further DNA synthesis. In addition, ISL is frequently misincorporated by RT, leading to mismatched primer termini that further reduces productive DNA elongation. ISL has highly potent antiviral activity against both wildtype HIV-1 (50% effective concentration [EC₅₀], ∼0.07-0.20 nM) and a broad panel of nRTI-resistant clinical isolates in vitro. It is also active against HIV-2, with an EC50 on average 4.8-fold more potent than observed for HIV-1. In late 2025, a fixed-dose combination of the nonnucleoside reverse transcriptase inhibitor (NNRTI) doravirine (DOR) and ISL (DOR/ISL 100/0.25 mg once daily) was filed with the US Food and Drug Administration for therapy in adults with HIV who are virologically suppressed on their antiretroviral (ARV) regimens and have no known resistance to either drug. In parallel, a once-weekly oral regimen combining ISL with the capsid inhibitor lenacapavir is currently undergoing phase III clinical investigation as maintenance therapy for people with HIV-1 who are virologically suppressed. People with HIV who are expected to be eligible for combinations with ISL may have been previously exposed to ARV therapy or preexposure prophylaxis, during which resistance mutations may have emerged. In addition, some individuals may have acquired virus containing resistance mutations through the transmission of a resistant strain.

Ritonavir-boosted atazanavir (atazanavir/r) is an effective once-daily option for pediatric subsequent-line antiretroviral therapy when used with two nucleoside reverse transcriptase inhibitors (NRTIs). Tuberculosis co-treatment complicates its use because rifampicin markedly induces atazanavir/r clearance. Although twice-daily atazanavir/r can overcome this interaction in adults, data in children are lacking. We aimed to characterize atazanavir population pharmacokinetics in children with HIV and simulate the effect of rifampicin co-treatment. Atazanavir concentration-time data in African children with HIV from CHAPAS-4 (ISRCTN22964075) and VirTUAL (NCT03923231) were analyzed by nonlinear mixed-effect modeling. We investigated the effect of weight, age, atazanavir formulation, ritonavir dose, and NRTI backbone (tenofovir alafenamide [TAF]-emtricitabine, abacavir-lamivudine, or zidovudine-lamivudine). Simulations were performed across weight bands to evaluate atazanavir/r exposures under standard conditions and, using adult-derived induction effects, predict exposures and possible dosing regimens during rifampicin co-treatment. Seventy children were included, with a median (range) age of 10.9 (3.2-17.7) years and weight of 29 (15-85) kg. A two-compartment model with sequential zero- and first-order absorption best described atazanavir disposition. The estimated typical value of atazanavir clearance was 4.8 L/h for a 27-kg individual. Atazanavir pharmacokinetics in children were unaffected by the NRTI backbone. Once-daily atazanavir/r with current dosing guidelines achieved adequate exposures across weight bands. When simulating pharmacokinetics during rifampicin co-treatment, twice-daily atazanavir/r is expected to restore exposures to levels comparable to once-daily dosing without rifampicin. These findings provide a framework for future clinical evaluation in children with HIV and tuberculosis.

Considering the exceptional anti-HIV-1 potency of rilpivirine (RPV) against diverse mutant strains and its remarkable human ether-a-go-go related gene (hERG) potassium channel inhibition (IC50 = 0.50 μmol/L) as well as low selectivity (SI = 3989), a series of novel furo-[3,2-d]pyrimidine derivatives were rationally designed through a scaffold hopping strategy. Encouragingly, compound 10 revealed a striking reduction in hERG channel inhibition (IC50 > 30 μmol/L) and significant increase in selectivity (SI = 161580). Notably, 10 exhibited excellent antiviral activity against various HIV-1 strains (EC50 = 1.9-46.3 nmol/L). In particular, 10 displayed prominent inhibitory potency against Y188L (EC50 = 15.5 nmol/L) and F227L + V106A strain (EC50 = 8.7 nmol/L), which was superior to those of RPV (EC50 (Y188L) = 79.4 nmol/L, EC50 (F227L + V106A) = 81.6 nmol/L). Besides, no apparent cytotoxicity (CC50 = 314.8 μmol/L) and negligible suppression of CYP isoenzymes were detected. Overall, these findings illustrated that 10 was a potentially promising NNRTI for HIV-1 therapy.