Curing HIV: Seeking to Target and Clear Persistent Infection.

Human immunodeficiency virus type 1 (HIV-1) infection persists despite years of antiretroviral therapy (ART). To remove the stigma and burden of chronic infection, approaches to eradicate or cure HIV infection are desired. Attempts to augment ART with therapies that reverse viral latency, paired with immunotherapies to clear infection, have advanced into the clinic, but the field is still in its infancy. We review foundational studies and highlight new insights in HIV cure research. Together with advances in ART delivery and HIV prevention strategies, future therapies that clear HIV infection may relieve society of the affliction of the HIV pandemic.

Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease.

Dysfunction of virus-specific CD4+ T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4+ T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (TFH cell)-like profile characterized HIV-specific CD4+ T cells in viremic infection. HIV-specific CD4+ T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the TH1, TH17 and TH22 subsets of helper T cells. Viral suppression by ART resulted in a distinct transcriptional landscape, with a reduction in the expression of genes associated with TFH cells, but persistently low expression of genes associated with TH1, TH17 and TH22 cells compared to the elite controller profile. Thus, altered differentiation is central to the impairment of HIV-specific CD4+ T cells and involves both gain of function and loss of function.

Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice.

Latent reservoirs of HIV-1-infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, immunologically invisible, and may undergo homeostatic proliferation, a "shock and kill" approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.

Exploring concentration response in HIV pre-exposure prophylaxis to optimize clinical care and trial design.

HIV pre-exposure prophylaxis trials with antiretroviral drugs have been variably successful. Even trials demonstrating the best efficacy leave room for improvement. Pharmacological data illuminate several sources of outcome variability, especially the impact of poor adherence, which is critical to manage PrEP in the clinic and to develop the next generation of PrEP candidates.

An integrated overview of HIV-1 latency.

Despite significant advances in our understanding of HIV, a cure has not been realized for the more than 34 million infected with this virus. HIV is incurable because infected individuals harbor cells where the HIV provirus is integrated into the host's DNA but is not actively replicating and thus is not inhibited by antiviral drugs. Similarly, these latent viruses are not detected by the immune system. In this Review, we discuss HIV-1 latency and the mechanisms that allow this pathogenic retrovirus to hide and persist by exploiting the cellular vehicles of immunological memory.

Combination anti-HIV antibodies provide sustained virological suppression.

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.

Pathogenesis of HIV-Related Lung Disease: Immunity, Infection, and Inflammation.

Despite anti-retroviral therapy (ART), human immunodeficiency virus-1 (HIV)-related pulmonary disease continues to be a major cause of morbidity and mortality for people living with HIV (PLWH). The spectrum of lung diseases has changed from acute opportunistic infections resulting in death to chronic lung diseases for those with access to ART. Chronic immune activation and suppression can result in impairment of innate immunity and progressive loss of T cell and B cell functionality with aberrant cytokine and chemokine responses systemically as well as in the lung. HIV can be detected in the lungs of PLWH and has profound effects on cellular immune functions. In addition, HIV-related lung injury and disease can occur secondary to a number of mechanisms including altered pulmonary and systemic inflammatory pathways, viral persistence in the lung, oxidative stress with additive effects of smoke exposure, microbial translocation, and alterations in the lung and gut microbiome. Although ART has had profound effects on systemic viral suppression in HIV, the impact of ART on lung immunology still needs to be fully elucidated. Understanding of the mechanisms by which HIV-related lung diseases continue to occur is critical to the development of new preventive and therapeutic strategies to improve lung health in PLWH.

Kinetic coevolutionary models predict the temporal emergence of HIV-1 resistance mutations under drug selection pressure.

Drug resistance in HIV type 1 (HIV-1) is a pervasive problem that affects the lives of millions of people worldwide. Although records of drug-resistant mutations (DRMs) have been extensively tabulated within public repositories, our understanding of the evolutionary kinetics of DRMs and how they evolve together remains limited. Epistasis, the interaction between a DRM and other residues in HIV-1 protein sequences, is key to the temporal evolution of drug resistance. We use a Potts sequence-covariation statistical-energy model of HIV-1 protein fitness under drug selection pressure, which captures epistatic interactions between all positions, combined with kinetic Monte-Carlo simulations of sequence evolutionary trajectories, to explore the acquisition of DRMs as they arise in an ensemble of drug-naive patient protein sequences. We follow the time course of 52 DRMs in the enzymes protease, RT, and integrase, the primary targets of antiretroviral therapy. The rates at which DRMs emerge are highly correlated with their observed acquisition rates reported in the literature when drug pressure is applied. This result highlights the central role of epistasis in determining the kinetics governing DRM emergence. Whereas rapidly acquired DRMs begin to accumulate as soon as drug pressure is applied, slowly acquired DRMs are contingent on accessory mutations that appear only after prolonged drug pressure. We provide a foundation for using computational methods to determine the temporal evolution of drug resistance using Potts statistical potentials, which can be used to gain mechanistic insights into drug resistance pathways in HIV-1 and other infectious agents.

Roadmap for Achieving Universal Antiretroviral Treatment.

Modern antiretroviral therapy safely, potently, and durably suppresses human immunodeficiency virus (HIV) that, if left untreated, predictably causes acquired immunodeficiency syndrome (AIDS), which has been responsible for tens of millions of deaths globally since it was described in 1981. In one of the most extraordinary medical success stories in modern times, a combination of pioneering basic science, innovative drug development, and ambitious public health programming resulted in access to lifesaving, safe drugs, taken as an oral tablet daily, for most of the world. However, substantial challenges remain in the fields of prevention, timely access to diagnosis, and treatment, especially in pediatric and adolescent patients. As HIV-positive adults age, treating their comorbidities will require understanding the course of different chronic diseases complicated by HIV-related and antiretroviral toxicities and finding potential treatments. Finally, new long-acting antiretrovirals on the horizon promise exciting new options in both the prevention and treatment fields.

Second-Line Switch to Dolutegravir for Treatment of HIV Infection.

BACKGROUND: Data to inform the switch from a ritonavir-boosted protease inhibitor (PI) to dolutegravir in patients living with human immunodeficiency virus (HIV) infection who do not have genotype information and who have viral suppression with second-line therapy containing a ritonavir-boosted PI have been limited. METHODS: In a prospective, multicenter, open-label trial conducted at four sites in Kenya, we randomly assigned, in a 1:1 ratio, previously treated patients without genotype information who had viral suppression while receiving treatment containing a ritonavir-boosted PI to either switch to dolutegravir or continue the current regimen. The primary end point was a plasma HIV type 1 RNA level of at least 50 copies per milliliter at week 48, assessed on the basis of the Food and Drug Administration snapshot algorithm. The noninferiority margin for the between-group difference in the percentage of participants who met the primary end point was 4 percentage points. Safety up to week 48 was assessed. RESULTS: A total of 795 participants were enrolled, with 398 assigned to switch to dolutegravir and 397 assigned to continue taking their ritonavir-boosted PI; 791 participants (397 in the dolutegravir group and 394 in the ritonavir-boosted PI group) were included in the intention-to-treat exposed population. At week 48, a total of 20 participants (5.0%) in the dolutegravir group and 20 (5.1%) in the ritonavir-boosted PI group met the primary end point (difference, -0.04 percentage points; 95% confidence interval, -3.1 to 3.0), a result that met the criterion for noninferiority. No mutations conferring resistance to dolutegravir or the ritonavir-boosted PI were detected at the time of treatment failure. The incidence of treatment-related grade 3 or 4 adverse events was similar in the dolutegravir group and the ritonavir-boosted PI group (5.7% and 6.9%, respectively). CONCLUSIONS: In previously treated patients with viral suppression for whom there were no data regarding the presence of drug-resistance mutations, dolutegravir treatment was noninferior to a regimen containing a ritonavir-boosted PI when the patients were switched from a ritonavir-boosted PI-based regimen. (Funded by ViiV Healthcare; 2SD ClinicalTrials.gov number, NCT04229290.).

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion.

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.

Connection Between HIV and Mitochondria in Cardiovascular Disease and Implications for Treatments.

HIV infection and antiretroviral therapy alter mitochondrial function, which can progressively lead to mitochondrial damage and accelerated aging. The interaction between persistent HIV reservoirs and mitochondria may provide insight into the relatively high rates of cardiovascular disease and mortality in persons living with HIV. In this review, we explore the intricate relationship between HIV and mitochondrial function, highlighting the potential for novel therapeutic strategies in the context of cardiovascular diseases. We reflect on mitochondrial dynamics, mitochondrial DNA, and mitochondrial antiviral signaling protein in the context of HIV. Furthermore, we summarize how toxicities related to early antiretroviral therapy and current highly active antiretroviral therapy can contribute to mitochondrial dysregulation, chronic inflammation, and poor clinical outcomes. There is a need to understand the mechanisms and develop new targeted therapies. We further consider current and potential future therapies for HIV and their interplay with mitochondria. We reflect on the next-generation antiretroviral therapies and HIV cure due to the direct and indirect effects of HIV persistence, associated comorbidities, coinfections, and the advancement of interdisciplinary research fields. This includes exploring novel and creative approaches to target mitochondria for therapeutic intervention.

Clinical targeting of HIV capsid protein with a long-acting small molecule.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.

Optimised prevention of postnatal HIV transmission in Zambia and Burkina Faso (PROMISE-EPI): a phase 3, open-label, randomised controlled trial.

BACKGROUND: Transmission through breastfeeding accounts for more than half of the unacceptably high number of new paediatric HIV infections worldwide. We hypothesised that, in addition to maternal antiretroviral therapy (ART), extended postnatal prophylaxis with lamivudine, guided by point-of-care assays for maternal viral load, could reduce postnatal transmission. METHODS: We did a phase 3, open-label, randomised controlled trial at four health-care facilities in Zambia and four health-care facilities in Burkina Faso. Mothers with HIV and their breastfed infants without HIV attending the second visit of the Expanded Programme of Immunisation (EPI-2; infant age 6-8 weeks) were randomly assigned 1:1 to intervention or control groups. In the intervention group, maternal viral load was measured using Xpert HIV viral load assay at EPI-2 and at 6 months, with results provided immediately. Infants whose mothers had a viral load of 1000 copies per mL or higher were started on lamivudine syrup twice per day for 12 months or 1 month after breastfeeding discontinuation. The control group followed national guidelines for prevention of postnatal transmission of HIV. The primary outcome assessed by modified intention to treat was infant HIV infection at age 12 months, with HIV DNA point-of-care testing at 6 months and at 12 months. This trial is registered with ClinicalTrials.gov (NCT03870438). FINDINGS: Between Dec 12, 2019 and Sept 30, 2021, 34 054 mothers were screened for HIV. Among them, 1506 mothers with HIV and their infants without HIV, including 1342 mother and infant pairs from Zambia and 164 from Burkina Faso, were eligible and randomly assigned 1:1 to the intervention (n=753) or control group (n=753). At baseline, the median age of the mothers was 30·6 years (IQR 26·0-34·7), 1480 (98·4%) of 1504 were receiving ART, and 169 (11·5%) of 1466 had a viral load ≥1000 copies/mL. There was one case of HIV transmission in the intervention group and six in the control group, resulting in a transmission incidence of 0·19 per 100 person-years (95% CI 0·005-1·04) in the intervention group and 1·16 per 100 person-years (0·43-2·53) in the control group, which did not reach statistical significance (p=0·066). HIV-free survival and serious adverse events were similar in both groups. INTERPRETATION: Our intervention, initiated at EPI-2 and based on extended single-drug postnatal prophylaxis guided by point-of-care maternal viral load could be an important strategy for paediatric HIV elimination. FUNDING: The EDCTP2 programme with the support of the UK Department of Health & Social Care.

Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study. METHODS: In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26. RESULTS: A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions). CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).

Dolutegravir in Pregnancy as Compared with Current HIV Regimens in the United States.

BACKGROUND: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited. METHODS: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results. RESULTS: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar. CONCLUSIONS: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Incorporating temporal dynamics of mutations to enhance the prediction capability of antiretroviral therapy's outcome for HIV-1.

MOTIVATION: In predicting HIV therapy outcomes, a critical clinical question is whether using historical information can enhance predictive capabilities compared with current or latest available data analysis. This study analyses whether historical knowledge, which includes viral mutations detected in all genotypic tests before therapy, their temporal occurrence, and concomitant viral load measurements, can bring improvements. We introduce a method to weigh mutations, considering the previously enumerated factors and the reference mutation-drug Stanford resistance tables. We compare a model encompassing history (H) with one not using this information (NH). RESULTS: The H-model demonstrates superior discriminative ability, with a higher ROC-AUC score (76.34%) than the NH-model (74.98%). Wilcoxon test results confirm significant improvement of predictive accuracy for treatment outcomes through incorporating historical information. The increased performance of the H-model might be attributed to its consideration of latent HIV reservoirs, probably obtained when leveraging historical information. The findings emphasize the importance of temporal dynamics in acquiring mutations. However, our result also shows that prediction accuracy remains relatively high even when no historical information is available. AVAILABILITY AND IMPLEMENTATION: This analysis was conducted using the Euresist Integrated DataBase (EIDB). For further validation, we encourage reproducing this study with the latest release of the EIDB, which can be accessed upon request through the Euresist Network.

HIV-AIDS: much accomplished, much to do.

As a result of decades of research-driven breakthroughs in basic and clinical science and recent advances in the broad-scale implementation of interventions for the prevention and treatment of infection with HIV, a turning point has been reached in the global HIV-AIDS pandemic. To end the pandemic and achieve the goal of an AIDS-free generation, researchers and clinicians must follow the dual pathway of optimizing the implementation of existing prevention and treatment interventions and discovering with basic and clinical research new and effective tools in both of these arenas.

CD8(+) T Cells and cART: A Dynamic Duo?

A new macaque study by Cartwright et al. (2016) suggests that CD8(+) T cells could play a previously unrecognized role in the suppression of HIV-1 during ongoing antiretroviral therapy.

Human immunodeficiency virus infection challenges: Current therapeutic limitations and strategies for improved management through long-acting injectable formulation.

HIV infection has been a severe global health burden, with millions living with the virus and continuing new infections each year. Antiretroviral therapy can effectively suppress HIV replication but requires strict lifelong adherence to daily oral medication regimens, which presents a significant challenge. Long-acting formulations of antiretroviral drugs administered infrequently have emerged as a promising strategy to improve treatment outcomes and adherence to HIV therapy and prevention. Long-acting injectable (LAI) formulations are designed to gradually release drugs over extended periods of weeks or months following a single injection. Critical advantages of LAIs over conventional oral dosage forms include less frequent dosing requirements, enhanced patient privacy, reduced stigma associated with daily pill regimens, and optimised pharmacokinetic/pharmacodynamic profiles. Several LAI antiretroviral products have recently gained regulatory approval, such as the integrase strand transfer inhibitor cabotegravir for HIV preexposure prophylaxis and the Cabotegravir/Rilpivirine combination for HIV treatment. A leading approach for developing long-acting antiretroviral depots involves encapsulating drug compounds in polymeric microspheres composed of biocompatible, biodegradable materials like poly (lactic-co-glycolic acid). These injectable depot formulations enable high drug loading with customisable extended-release kinetics controlled by the polymeric matrix. Compared to daily oral therapies, LAI antiretroviral formulations leveraging biodegradable polymeric microspheres offer notable benefits, including prolonged therapeutic effects, reduced dosing frequency for improved adherence, and the potential to kerb the initial HIV transmission event. The present manuscript aims to review the pathogenesis of the virus and its progression and propose therapeutic targets and long-acting drug delivery strategies that hold substantial promise for enhancing outcomes in HIV treatment and prevention.