anti-HIV Drugs Research Articles

IMPULSIVE DIFFERENTIAL EQUATION MODEL IN HIV-1 INHIBITION: ADVANCES IN DUAL INHIBITORS OF HIV-1 RT AND IN FOR THE PREVENTION OF HIV-1 REPLICATION

Reverse transcriptase (RT) and integrase (IN) are two pivotal enzymes in HIV-1 replication. RT converts the single-stranded viral RNA genome into double-stranded DNA and IN catalyzes the integration of viral double-stranded DNA into host DNA. Currently, dual inhibitors of HIV-1 RT and IN have become a hotspot in new anti-HIV drug research and development. A dual inhibitor of HIV-1 RT/IN does the same thing as the two independent drugs would do. In this paper, we develop a mathematical model comprising a system of nonlinear differential equations describing HIV-1 RT/IN catalyzed biochemical reactions based on Michaelis–Menten enzyme kinetic reaction. In the formulated model we incorporate HIV-1 RT/IN dual inhibitor which simultaneously works as a non-nucleoside RT inhibitor and IN inhibitor. To examine the efficacy of HIV-1 RT/IN dual inhibitor in the treatment of HIV-1 infection, we have introduced a one-dimensional impulsive differential equation model and determined an effective dosing regimen for applying the inhibitor numerically. Furthermore, the exact closed form solution of the impulsive differential equation model is carried out by using the Lambert W function and the local stability of the periodic solution is also obtained analytically. The results obtained from analytical as well as numerical studies provide a basic idea to investigate the minimum dose with the highest efficacy for administering HIV-1 RT/IN dual inhibitors to prevent HIV-1 infection.

The anti-HIV drug abacavir stimulates β-catenin activity in osteoblast lineage cells.

Bone mineral density (BMD) loss in people living with HIV occurs with the initiation of combined antiretroviral therapy (cART), particularly with tenofovir disoproxil fumarate (TDF) containing cART. Switching from TDF to abacavir (ABC) or dolutegravir (DTG) leads to increased BMD. Whether BMD gains are due to cessation of TDF or anabolic effects of ABC or DTG is unclear. We investigated the effects of ABC and DTG on osteoblast lineage cells in vitro and in vivo. Primary human osteoblasts and male C57BL/6 mice were treated with individual antiretrovirals (ARVs) or a combination of ABC/DTG/lamivudine (3TC). Nearly all ARVs and cART inhibited osteogenic activity in vitro. Due to the importance of Wnt/β-catenin in bone formation, we further investigated ARV effects on the Wnt/β-catenin pathway. ABC, alone and as part of ABC/DTG/3TC, increased osteoblastic β-catenin activity as indicated by increased TOPFlash activity, hypo-phosphorylated (active) β-catenin staining, and β-catenin targeted gene expression. Mice treated with TDF had decreased lumbar spine BMD and trabecular connectivity density in the vertebrae, while those treated with ABC/DTG/3TC reduced cortical area and thickness in the femur. Mice treated with ABC alone had no bone structural changes, increased circulating levels of the bone formation marker, P1NP, and elevated expression of the Wnt/β-catenin target gene, Lef1, in osteocyte enriched samples. Further, bones from ARV-treated mice were isolated to evaluate ARV distribution. All ARVs were detected in the bone tissue, which was inclusive of bone marrow, but when bone marrow was removed, only TDF, ABC, and DTG were detected at ~0.1% of the circulating levels. Overall, our findings demonstrate that ABC activates Wnt/β-catenin signaling, but whether this leads to increased bone formation requires further study. Assessing the impact of ARVs on bone is critical to informing ARV selection and/or discovery of regimens that do not negatively impact the skeleton.

Preparation of a Key Intermediate En Route to the Anti-HIV Drug Lenacapavir.

A very efficient four-step synthesis of the main fragment of Gilead's anti-HIV drug lenacapavir is described. The route showcases a 1,2-addition to an intermediate aldehyde using an organozinc halide derived from a commercially available difluorobenzyl Grignard reagent. This sets the stage for the oxidation of the resulting secondary alcohol to the desired ketone, which relies solely on catalytic amounts of TEMPO together with NaClO as the terminal oxidant, affording the targeted ketone in 67% overall yield.

MECHANISTIC OUTCOMES OF LIPID CORE ON SOLID LIPID NANOPARTICLE CHARACTERIZATION

In our present study, solid lipid nanoparticles were fabricated by modified double emulsification followed by ultracentrifugation method. The SLNs of the anti-HIV drugs lamivudine, tenofovir disoproxil fumarate and efavirenz were synthesized using lipids Compritol 888 ATO, glyceryl monostearate, stearic acid and emulsifiers soy lecithin and Pluronic®F68. The synthesized SLNs were characterized for compatibility studies, mean particle size, PDI, zeta potential, surface morphology and entrapment studies. The higher amount of Compritol based SLNs formulation showed maximum entrapment efficiency with comparatively larger sized, homogenous particles. All the lipid based SLNs possessed no incompatibilities and showed high stability profiles. Based on the results of surface morphology, zeta potential and high entrapment efficiency values, the optimum lipid for SLNs formulation among the other lipids was determined to be Compritol 888 ATO.

Semisolid extrusion 3D printing of Dolutegravir-Chitosan nanoparticles laden polymeric buccal films: personalized solution for pediatric treatment.

In this work, the semi solid extrusion 3D printing process was utilized to incorporate anti-HIV drug Dolutegravir and its nanoparticles into the buccal film (BF) that was fabricated using the developed polymer ink. The composite made of polyvinyl alcohol (PVA) and sodium alginate was processed into a 3D printing polymer ink with optimum viscosity (9587 ± 219 cP) needed for the seamless extrusion through the nozzle of the 3D printer. The formulated BFs were assessed for its physical properties like weight (0.414 ± 0.3 g), thickness (1.54 ± 0.02 mm), swelling index (18.5 ± 0.91%), and mucoadhesiveness strength (0.165 ± 0.09 N) etc, The structural integrity and the surface morphology of the developed BFs were investigated by scanning electron microscopy analysis. The chemical stability and the solid-state nature of the drug in the BFs were assessed by Fourier transform infrared and x-ray diffraction analysis respectively. Further the BFs were assessed for drug dissolutionin-vitroandex-vivo, to study the effect of polymer composition and printing condition on the dissolution profile of the drug in the simulated salivary fluid. The results demonstrated that the developed PVA based polymer ink for 3D printing utilizing pressure is a versatile approach in the context of manufacturing mucoadhesive BFs customized in terms of shape and the amount of drug loaded.

HIV Reservoirs and Treatment Strategies toward Curing HIV Infection.

Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired immunodeficiency syndrome has transformed from a fatal disease to a treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce viral production in the body of the patient to below the detection limit, it cannot eliminate the HIV provirus integrated into the host cell genome; hence, the virus will be produced again after cART discontinuation. Therefore, research into a cure (or remission) for HIV has been widely conducted. In this review, we focus on drug development targeting cells latently infected with HIV and assess the progress including our current studies, particularly in terms of the "Shock and Kill", and "Block and Lock" strategies.

HIV-TB Coinfection: Current Therapeutic Approaches and Drug Interactions.

The co-occurrence of human immunodeficiency virus (HIV) and tuberculosis (TB) infection poses a significant global health challenge. Treatment of HIV and TB co-infection often necessitates combination therapy involving antiretroviral therapy (ART) for HIV and anti-TB medications, which introduces the potential for drug-drug interactions (DDIs). These interactions can significantly impact treatment outcomes, the efficacy of treatment, safety, and overall patient well-being. This review aims to provide a comprehensive analysis of the DDIs between anti-HIV and anti-TB drugs as well as potential adverse effects resulting from the concomitant use of these medications. Furthermore, such findings may be used to develop personalized therapeutic strategies, dose adjustments, or alternative drug choices to minimize the risk of adverse outcomes and ensure the effective management of HIV and TB co-infection.

Development of a Cr2AlC MAX phase/g-C3N4 composite-based electrochemical sensor for accurate cabotegravir determination in pharmaceutical and biological samples.

Ahighly sensitive electrochemical sensor is reportedthat employs a modified electrode for the precise measurement of cabotegravir, a potent anti-HIV drug. Cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS) were utilized for this purpose. Electrode modification involved the immobilization of Cr2AlC MAX phase/g-C3N4 onto a glassy carbon electrode (GCE) to enhance its electrocatalytic activity and selectivity for cabotegravir detection. Under the optimal experimental conditions, the working potential (vs. Ag/AgCl) was to 0.93V. The developed sensor exhibited a good linear relationship in the range 0.05µM to 9.34µM with a low limit of detection of 4.33nM, signifying its exceptional sensitivity. Additionally, it demonstrated successful cabotegravir detection in pharmaceutical formulations and biological samples, achieving an RSD below 3.0%. The recoveries fell within the range 97.7 to 102%, confirming the sensor's potential for real-sample applications. This innovative electrochemical sensor represents a significant advancement, providing a simple, reliable, and sensitive tool for the accurate measurement of cabotegravir. Its potential applications include optimizing drug dosages, monitoring treatment responses, and supporting the development of cabotegravir-based pharmaceutical products, thereby contributing to advancements in HIV therapy and prevention strategies.

Anti-HIV drugs (emtricitabine and lamivudine) mediated micellization behavior of anionic and cationic surfactants: A thermodynamic investigation

Aggregation behavior of conventional surfactants; SDS (anionic) and CTAB (cationic) in aqueous medium has been investigated in the presence of anti-HIV drugs; Emtricitabine (ECT) and Lamivudine (LMV) using conductometry, UV–Visible spectroscopy, and fluoroscence measurements over a temperature range of T = (298.15–313.15) K. The CMC values calculated from the conventional study i.e. conductance measurements corroborate very well with those obtained from spectroscopic techniques i.e. UV–Visible spectroscopy and fluorometry. The calculated CMC values have been used to determine thermodynamic parameters such as standard changes in enthalpy of micellization (ΔHmo), entropy of micellization (ΔSmo) and free energy of micellization (ΔGmo) using pseudo-phase separation model. These parameters have been analyzed in terms of the hydrophobic-hydrophilic interactions present in the surfactant-water-drug ternary system. It has been observed from the thermodynamic analysis that both the drugs favor micellization of studied ionic surfactants (SDS and CTAB) in aqueous medium, with Lamivudine exhibiting a more pronounced effect. Further, the micellar stability of studied systems has been analyzed in terms of enthalpy-entropy compensation graphs. This in-depth exploration of anti-HIV drug-surfactant interactions holds promising implications for enhancing pharmaceutical formulations in the context of HIV infection diseases.

Aggregation behavior and thermodynamic parameters of biosurfactants (NaC/NaDC) in aqueous medium of Emtricitabine and Lamivudine (anti-HIV drugs)

Abstract This paper investigates the interactions and aggregation behavior of biosurfactants, sodium cholate (NaC) and sodium deoxycholate (NaDC) in aqueous solutions of Emtricitabine and Lamivudine (anti-HIV drugs). The study uses conductometry and UV–visible spectroscopy techniques to evaluate the critical micelle concentration (CMC) at different temperatures ranging from 298.15 K to 313.15 K with a variation of 5 K. The temperature dependence of the CMC was examined, and the stability of micelles was analyzed in light of the hydrophobic-hydrophilic interactions involved in this system. The CMC obtained from both the methods are in agreement. Various thermodynamic parameters, such as ∆ H m 0 ${\increment}{H}_{m}^{0}$ , ∆ S m 0   ${\increment}{S}_{m}^{0\hspace{0.17em}}$ and ∆ G m 0 ${\increment}{G}_{m}^{0}$ have been estimated using a “pseudo-phase separation model” to understand the contribution of the chemical and de-solvation part in the micellization process. Furthermore, the enthalpy-entropy compensation plots validate the micellar stability of the studied systems.

Experiences of Adolescents on Antiretroviral Therapy at Rustenburg Sub-District, Northwest Province, South Africa.

Antiretroviral therapy (ART) is the treatment of people infected with human immunodeficiency virus (HIV) using anti-HIV drugs. The standard treatment consists of a combination of drugs (often called highly active antiretroviral therapy or HAART) that suppress HIV replication. As a result, people who have been infected live longer while on ART, which was initiated in South Africa in 2004. The study aimed to explore the experiences of adolescents on antiretroviral therapy in two primary health care clinics in Rustenburg sub-district Northwest Province. Qualitative, explorative, descriptive, and contextual approaches were adopted. Non-probability purposive sampling was used to select the healthcare facilities, and adolescents were chosen using convenience sampling. In-depth individual interviews were used to collect data from the participants. Only 13 adolescents between the ages of 15 and 19 years were interviewed. Collected data were analyzed using Tesch's eight steps. Qualitative themes identified included a description of the experiences of adolescents living HIV to adulthood and challenges experienced from childhood to adolescence period. Each theme had different sub-themes which included the paradoxical experiences of being diagnosed with HIV and being on antiretroviral treatment. Adolescents experienced poor adherence to ART due to treatment side effects such as drowsiness, change in body image, and headaches. Self-stigma resulted in adolescents not disclosing their status to their peers, closest and sexual partners which also made them not to adhere well in treatment. The study findings revealed that HIV-positive adolescents encounter various experiences while on ART, which causes them not to adhere to treatment. In the study, adolescents also experienced self-stigma which also affected their treatment adherence and brought fear of losing their loved ones.

Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: Investigation of lymphatic uptake

The lymphatic system possesses the main viral replication sites in the body following viral infection. Unfortunately, current antiretroviral agents penetrate the lymph nodes insufficiently when administered orally and, therefore, cannot access the lymphatic system sufficiently to interrupt this viral replication. For this reason, novel drug delivery systems aimed at enhancing the lymphatic uptake of antiretroviral drugs are highly desirable. Dissolving polymeric microarray patches (MAPs) may help to target the lymph intradermally. MAPs are intradermal drug delivery systems used to deliver many types of compounds. The present work describes a novel work investigating the lymphatic uptake of two anti-HIV drugs: cabotegravir (CAB) and rilpivirine (RPV) when delivered intradermally using dissolving MAPs containing nanocrystals of both drugs. Maps were formulated using NCs obtained by solvent-free milling technique. The polymers used to prepare the NCs of both drugs were PVA 10 Kda and PVP 58 Kda. Both NCs were submitted to the lyophilization process and reconstituted with deionized water to form the first layer of drug casting. Backing layers were developed for short application times and effective skin deposition. In vivo biodistribution profiles of RPV and CAB after MAP skin application were investigated and compared with the commercial intramuscular injection using rats. After a single application of RPV MAPs, a higher concentration of RPV was delivered to the axillary lymph nodes (AL) (Cmax 2466 ng/g – Tmax 3 days) when compared with RPV IM injection (18 ng/g - Tmax 1 day), while CAB MAPs delivered slightly lower amounts of drug to the AL (5808 ng/g in 3 days) when compared with CAB IM injection (9225 ng/g in 10 days). However, CAB MAPs delivered 7726 ng/g (Tmax 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (Cmax 8282 ng/g - Tmax 7 days). This work provides strong evidence that MAPs were able to enhance the delivery of CAB and RPV to the lymphatic system compared to the IM delivery route.

Alkaloids as Potential Anti-HIV Agents.

Alkaloids are nitrogen-containing compounds that are naturally occurring and have a variety of biological activities, including antimicrobial properties. In this study, the authors used a molecular docking approach to evaluate the anti-HIV potential of 64 alkaloids. The authors used the Molegro Virtual Docker software to dock the alkaloids into the active sites of three HIV enzymes: protease, integrase, and non-nucleoside reverse transcriptase (NNRT). The docking scores were used to assess the potential of the alkaloids to inhibit the enzymes. The results showed the alkaloids to have good potential to inhibit the enzymes. Tubocurarine and reserpine were found to be the most potent alkaloids, with docking scores of -123.776 and - 114.956, respectively. The authors concluded that tubocurarine and reserpine could be further promoted as potential lead molecules for the development of new anti-HIV drugs.

Design, Synthesis, Docking Studies, and Biological Evaluation of Novel 2-Hydroxyacetophenone Derivatives as Anti-HIV-1 Agents.

The persistence of HIV mutations and the existence of multidrug resistance have produced an opportunity for an array of innovative anti-HIV medicines with a variety of structures that target HIV key enzymes. The goal of this work was to find a new class of anti-HIV drugs founded on HIV integrase inhibitor pharmacophores. A novel class of 2-hydroxy acetophenone analogs featuring substituted benzamide or N-phenylthiourea groups was designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors (INs). Most of the synthesized analogs were found to be moderately active against the virus, with EC50 values ranging from 40 to 140 μM. Additionally, it was found that most of the compounds presented no considerable cytotoxicity (CC50 > 500 μΜ). The most potent compounds substituting with 4-fluorobenzamide (compound 7) and 4-methylbenzamide (compound 9) rings inhibited the HIV-1 replication by EC50 values of 40 and 45 μΜ, respectively. Docking studies using the crystallographic data available for PFV IN indicated that the Mg2+ coordination might be the possible mechanism of the anti-viral activity. Our findings proved that the synthesized analogs may suggest a very good basis for the development of new anti-HIV-1 agents.

3D printing of dolutegravir-loaded polylactide filaments as a long-acting implantable system for HIV treatment

3D printing was used to prepare implantable systems or tablets loaded with dolutegravir to explore their potential as long-acting implantables (LAIs). Our strategy relies on preparing a polylactide (PLA) filament loaded with the anti-HIV drug. Subsequently, 3D printing was performed under conditions that allowed the PLA to be simultaneously melted and the drug encapsulated within the printed strand. The dolutegravir release profiles indicated its sustained release for 47 days. Furthermore, neat and drug-loaded tablets were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), while their morphology was assessed by scanning electron microscopy (SEM). Finally, their biocompatibility was proved by MTT assay against ISO standards recommended L929 mouse and human Hs68 skin fibroblast cells. All the results indicated that the 3D printing of PLA-based tablets could produce customized medications with potential applications against HIV.

Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators.

Optimization of compound 11L led to the identification of novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, displaying potent antiviral activities against both HIV-1 and HIV-2. Notably, derivatives 12a2 and 21a2 showed significant improvements, with 2.5-fold over 11L and 7.3-fold over PF74 for HIV-1, and approximately 40-fold over PF74 for HIV-2. The X-ray co-crystal structures confirmed the multiple pocket occupation of 12a2 and 21a2 in the binding site. Mechanistic studies revealed a dual-stage inhibition profile, where the compounds disrupted capsid-host factor interactions at the early stage and promoted capsid misassembly at the late stage. Remarkably, 12a2 and 21a2 significantly promoted capsid misassembly, outperforming 11L, PF74, and LEN. The substitution of easily metabolized amide bond with quinolin-4-one marginally enhanced the stability of 12a2 in human liver microsomes compared to controls. Overall, 12a2 and 21a2 highlight their potential as potent HIV capsid modulators, paving the way for future advancements in anti-HIV drug design.

Rapid HIV-1 genotyping assay for the detection of capsid mutations.

Human immunodeficiency virus (HIV) capsid is one of the most recent viral proteins successfully targeted for the development of antiretrovirals. Lenacapavir is a first in class HIV-1 capsid inhibitor that was recently approved for the treatment of highly treatment-experienced people with HIV in combination with other anti-HIV drugs. Owing to the novelty of the viral target, methods to characterize the potential resistance-associated mutations present in capsid upon treatment failure have not been fully established yet. Here, we describe a rapid and simple method to amplify capsid fragments and to determine their sequence from various clinical samples including diverse HIV-1 subtypes. These methods could easily be implemented in laboratories, including hospital laboratories often caring for this patient population.

The Construction of the Self-Induced Sal System and Its Application in Salicylic Acid Production

The design and construction of more complex and delicate genetic control circuits suffer from poor orthogonality in quorum sensing (QS) systems. The Sal system, which relies on salicylic acid as a signaling molecule, is an artificially engineered regulatory system with a structure that differs significantly from that of natural QS signaling molecules. Salicylic acid is an important drug precursor, mainly used in the production of drugs such as aspirin and anti-HIV drugs. However, there have been no reports on the construction of a self-induced Sal system in single cells. In this study, a high-copy plasmid backbone was used to construct the regulatory proteins and a self-induced promoter of salicylic acid in E. coli by adjusting the precise regulation of key gene expression; the sensitivity and induction range of this system were improved. Subsequently, the exogenous gene pchBA was introduced in E. coli to extend the shikimate pathway and synthesize salicylic acid, resulting in the construction of the first complete self-induced Sal system. Finally, the self-induced Sal System was combined with artificial trans-encoded sRNAs (atsRNAs) to repress the growth-essential gene ppc and accumulate the precursor substance PEP, thereby increasing the titer of salicylic acid by 151%. This construction of a self-induced artificial system introduces a new tool for selecting communication tools and induction systems in synthetic biology and metabolic engineering, but also demonstrates a self-inducible pathway design strategy for salicylic acid biosynthesis.

Efficacy and Safety of Pre-Exposure Prophylaxis to Control HIV and Sexually Transmitted Infection Among Men Who Have Sex With Men: Protocol for a Single-Arm Interventional Study.

Pre-exposure prophylaxis (PrEP) against HIV infection is a new approach that involves the prophylactic use of the anti-HIV drug Truvada (tenofovir disoproxil fumarate [TDF] and emtricitabine [FTC]) by people not infected with HIV. The objective of this investigator-initiated clinical study of PrEP was to evaluate the incidence of HIV and sexually transmitted infection (STI), safety and efficacy of PrEP in PrEP users, and their compliance with PrEP medication. The social, medical, and economic benefits of PrEP in Japan was assessed. This single-center feasibility study of PrEP was conducted at the National Center for Global Health and Medicine, Tokyo, Japan, where a cohort of men who have sex with men without HIV was established in January 2017. This single-arm interventional study compared the efficacy and safety of PrEP in a single group of men who have sex with men who participated in PrEP cohort studies. For reference, the cohort study participants who did not participate in the PrEP study were included for comparison. Blood samples were collected for storage at baseline and clinic visits at 1, 3, and 6 months after starting PrEP and every 3 months thereafter. The participants were administered with 1 tablet of Truvada once daily as PrEP. They underwent blood and anal swab tests 1 and 3 months after starting PrEP and then HIV and STI infection assessments at 3-month intervals. Blood samples were centrifuged at the AIDS Clinical Center Laboratory. PrEP safety was evaluated by monitoring serum creatinine levels for symptoms of renal function disorders. The primary end point was the incidence of HIV in PrEP users (100 person-years). The secondary end points were the incidence of STI in PrEP users (100 person-years), incidence of adverse events caused by Truvada, frequency of high-risk sexual activity, and adherence to periodic visits and medication. The study protocol was reviewed and approved by the certified review board of the National Center for Global Health and Medicine (NCGM-C-003129-03) on April 20, 2020. Changes to the study plan were submitted for review by the certified review board and approved before implementation. Recruitment was completed on March 28, 2019, and the study was completed (last adult participant and last time point) on March 31, 2021. The data were analyzed, and the main results of the study have been published in a peer-reviewed journal. The findings indicated that PrEP is a highly effective and feasible strategy against HIV infection in terms of prophylactic response, retention, and compliance. UMIN Clinical Trials Registry UMIN000031040; https://tinyurl.com/3msdkeb8 and Japan Registry of Clinical Trials jRCTs031180134; https://tinyurl.com/2p88mhyr. RR1-10.2196/50919.

Machine Learning-Assisted Discovery of Novel Anti-HIV Drug Candidates: An Analysis Using Molecular Datasets

Human Immunodeficiency Virus (HIV) serves as a crisis of global public health, necessitating new anti-HIV agents due to the virus's rapid mutation and subsequent drug resistance. While current Combination Antiretroviral Therapy (CART) has helped control the infection and mortality rates, traditional drug development approaches are costly and inefficient. This study aims to address this issue by applying machine learning algorithms for lead compound discovery using the extensive, quality-assured DTP Antiviral Screen Databases. Three molecular datasets—Extended-Connectivity Fingerprints (ECFP), Simplified Molecular-Input Line-Entry System (SMILES), and 2D molecular IMAGES—were processed using Principal Component Analysis (PCA), train-test splitting, and dataset balancing. Six machine learning algorithms were employed, including linear and nonlinear models, optimized through 5-fold cross-validation. The Area Under the Receiver Operating Characteristic (AUROC) curve was utilized to evaluate the models' performance, as well as the macro averaged precision, averaged recall, averaged F1 score, and balanced accuracy metrics. The ensemble models were constructed from the top-performing individual models. The best individual model, a SVM model trained on the ECFP dataset, achieved performance metrics of 0.78 on macro-averaged precision; 0.68 on macro-averaged recall; 0.72 on macro-averaged F1 score; 0.71 on balanced accuracy; and 0.75 on AUROC when evaluated on the testing data. The best ensemble model, fused with SVM, kNN, and logistic regression trained on the ECFP dataset, achieved performance metrics of 0.82 on macro-averaged precision; 0.67 on macro-averaged recall; 0.72 on macro-averaged F1 score; and 0.70 on balanced accuracy when evaluated on the testing data. The models were then applied to a Pubmed-extracted drug dataset, identifying several promising anti-HIV drug candidates, fulfilling the study's objective to improve the efficiency and success rate of new anti-HIV drug screening and discovery. In summary, this research demonstrates the transformative potential of machine learning in accelerating and optimizing the drug discovery process for HIV treatment.