Efficacy of the Dapivirine Vaginal Ring Accounting for Imperfect Adherence.

Product adherence is critical to obtaining objective estimates of efficacy of pre-exposure prophylactic interventions against HIV-1 infection. With imperfect adherence, intention-to-treat analyses assess the collective effects of complete, sub-optimal and non-adherence, providing a biased and attenuated estimate of the average causal effect of an intervention. Using data from the MTN-020/ASPIRE phase III trial evaluating HIV-1 efficacy of the dapivirine vaginal ring, we conducted per-protocol, and adherence-adjusted causal inference analyses using principal stratification and marginal structural models. We constructed two adherence cut offs of ≥ 0.9 mg (low cutoff) and > 4.0 mg (high cutoff) that represent drug released from the ring over a 28-day period. The HIV-1 efficacy estimate (95% CI) was 30.8% (3.6%, 50.3%) (P = 0.03) from the per-protocol analysis, and 53.6% (16.5%, 74.3%) (P = 0.01) among the highest predicted adherers from principal stratification analyses using the low cutoff. Marginal structural models produced efficacy estimates (95% CIs) ranging from 48.8 (21.8, 66.4) (P = 0.0019) to 56.5% (32.8%, 71.9%) (P = 0.0002). Application of adherence-adjusted causal inference methods are useful in interpreting HIV-1 efficacy in secondary analyses of PrEP clinical trials.

Changes in Inflammatory Cytokine Levels in Rectal Mucosa Associated With Neisseria gonorrheae and/or Chlamydia trachomatis Infection and Treatment Among Men Who Have Sex With Men in Lima, Peru.

BACKGROUND: Neisseria gonorrheae and Chlamydia trachomatis are associated with mucosal inflammation and human immunodeficiency virus 1 (HIV-1) transmission. We assessed levels of inflammatory cytokines in men who have sex with men (MSM) with and without rectal gonorrhea and/or chlamydia in Lima, Peru. METHODS: We screened 605 MSM reporting condomless receptive anal intercourse for rectal N. gonorrheae/C. trachomatis using nucleic acid testing. We identified 101 cases of gonorrhea and/or chlamydia and randomly selected 50 N. gonorrheae/C. trachomatis positive cases and matched 52 negative controls. We measured levels of IL-1ß, IL-6, IL-8, and TNF-α in rectal secretions. Tests for HIV-1, rectal N. gonorrheae/C. trachomatis, and mucosal cytokines were repeated after 3 and 6 months. Cytokine levels in cases and uninfected controls were compared using Wilcoxon rank-sum tests and linear regression. RESULTS: MSM with gonorrhea/chlamydia had elevated levels of all cytokines in rectal mucosa compared with matched controls (all P values <.001). Following antibiotic treatment there were no significant differences in cytokine levels at 3- or 6-month follow-up evaluations (all P values >.05). DISCUSSION: Rectal gonorrhea/chlamydia infection is associated with transient mucosal inflammation and cytokine recruitment. Our data provide proof of concept for rectal sexually transmitted infection screening as an HIV prevention strategy for MSM. Clinical Trials Registration. NCT03010020.

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate for Nonoccupational HIV-1 Postexposure Prophylaxis: A Prospective Open-Label Trial (DORAVIPEP).

Background: New regimens may provide better tolerability, convenience, and safety for nonoccupational human immunodeficiency virus (HIV) postexposure prophylaxis (PEP). For this reason, we evaluated the single-tablet regimen of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) for 28 days. Methods: This was a prospective, open-label, single-arm trial including individuals with potential HIV-1 exposure within 72 hours. The primary endpoint was noncompletion of PEP at day 28. Secondary endpoints were adverse effects, adherence, and rate of seroconversion. We performed follow-up at day 7, week 4, and week 12. Results: Between September 2019 and March 2022, the study enrolled 399 individuals. Median age was 30 (interquartile range [IQR], 27-36) years, and 91% (n = 364) were male. The mode of exposure was sex between men in 84% (n = 331) of cases; risk assessment for HIV-1 transmission was considered as "high" in 97% (n = 385) of the participants. Median time from exposure to consultation was 24 (IQR, 13-40) hours. Noncompletion of PEP was 29% (n = 114) (95% confidence interval [CI], 24%-33%) and 20% (n = 72) (95% CI, 16%-25%) per modified intention-to-treat. Main reasons for noncompletion were loss to follow-up (n = 104 [91%]) and intolerance (n = 8 [7%]). Older age was associated with a lower risk of premature discontinuation (OR, 0.94; P < .001). One hundred twenty-three (31%) participants reported adverse events, mostly mild and self-limited (82%); discontinuation occurred in 8 cases (2%). Adherence to PEP in the assessed users was 96%. There were no HIV seroconversions. Conclusions: DOR/3TC/TDF is a well-tolerated option for nonoccupational PEP. Clinical Trials Registration. NCT04233372.

Predicting neutralization susceptibility to combination HIV-1 monoclonal broadly neutralizing antibody regimens.

Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 infection. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) approach. However, prediction performance for some individual bnAbs has exceeded that for the combination, leading to another possibility: combining the individual-bnAb predicted values and using these to predict combination regimen neutralization; we call this the predict-then-combine (PC) approach. We explore both approaches in both simulated data and data from the Los Alamos National Laboratory's Compile, Neutralize, and Tally NAb Panels repository. The CP approach is superior to the PC approach when the neutralization outcome of interest is binary (e.g., neutralization susceptibility, defined as inhibitory concentration < 1 µg/mL. For continuous outcomes, the CP approach performs at least as well as the PC approach, and is superior to the PC approach when the individual-bnAb prediction algorithms have poor performance. This knowledge may be used when building prediction models for novel antibody combinations in the absence of in vitro neutralization data for the antibody combination; this, in turn, will aid in the evaluation and down-selection of these antibody combinations into prevention efficacy trials.

Long-Acting Formulations for the Prevention and Treatment of Human Immunodeficiency Virus (HIV)-1 Infection: Strategic Leveraging and Integration of Multidisciplinary Knowledge to Advance Public Health.

The landscape for the development of therapeutics for prevention and treatment of human immunodeficiency virus (HIV)-1 infection has pivoted towards long-acting antiretrovirals (LA-ARVs). LA-ARVs have the potential to transform global implementation of HIV-1 prevention and treatment strategies. The ability to identify potential knowledge gaps early in development, proactively address missing information or data gaps, and strategically leverage all the available information is the key to streamline the development of safe and effective LA-ARV therapeutics. The purpose of this article is to discuss some potential considerations for development of LA-ARVs. Three possible drug development scenarios are briefly discussed and include developing (1) a novel LA-ARV, (2) a novel LA formulation of an approved oral ARV, and (3) an LA pro-drug of an approved oral ARV. For each of these scenarios, we briefly describe what type(s) of information may be helpful and discuss potential opportunities to leverage available information. Additionally, we discuss some unique LA-ARV drug development considerations, including the use of an oral lead-in, and assessing the impact of residual ARV exposures on subsequent regimens and evaluation of LA-ARVs in specific populations. We strongly believe that efficient integration of multidisciplinary knowledge can advance the development, availability, and accessibility of therapeutics not only for HIV-1 prevention and treatment but also for other chronic viral infections.

HIV-1 bispecific antibody iMab-N6 exhibits enhanced breadth but not potency over its parental antibodies iMab and N6.

The recently published AMP trial (HVTN 703/HPTN 081 and HVTN704/HPTN 085) results have validated broad neutralising antibodies (bNAbs) as potential anti-HIV-1 agents. However, single bNAb preparations are unlikely to cope with the onslaught of existing and de novo resistance mutations, thus necessitating the use of bNAb combinations to achieve clinically relevant results. Specifically engineered antibodies incorporating two bNAbs into a single antibody structure have been developed. These bispecific antibodies (bibNAbs) retain the benefits of bNAb combinations, whilst several conformations exhibit improved neutralisation potency over the parental bNAbs. Here we report on the engineering of a bibNAb comprising of an HIV-1 spike targeting bNAb N6 and a host CD4 targeting antibody ibalizumab (iMab). Antibodies were expressed in HEK293T cells and purified by protein-A affinity chromatography followed by size exclusion chromatography to achieve homogenous, monomeric, bibNAb preparations. Antibody purity was confirmed by SDS-PAGE whilst epitope specificity and binding were confirmed by ELISA. Finally, antibody breadth and potency data were generated by HIV-1 neutralisation assay (n = 21, inclusive of the global panel). iMab-N6 exhibited better neutralisation breadth (100% coverage) in comparison to its parental bNAbs iMab (90%) and N6 (95%). This is encouraging as exceptional neutralisation breadth is necessary for HIV-1 treatment or prevention. Unfortunately, iMab-N6 did not exhibit any enhancement in potency over the most potent parental antibody, iMab (p = 0.1674, median IC50 of 0.0475 µg/ml, and 0.0665 µg/ml respectively) or the parental combination, iMab + N6 (p = 0.1964, median IC50: combination 0.0457 µg/ml). This result may point to a lack of dual engagement of the bibNAb Fab moieties necessary for potency enhancement. Against the previously reported bibNAbs; iMab-CAP256, 10E08-iMab, and PG9-iMab; iMab-N6 was the lowest performing bibNAb. The re-engineering of iMab-N6 to enhance its potency, while retaining breadth, is a worthwhile endeavour due to its clinical potential.

Prediction of serum HIV-1 neutralization titers of VRC01 in HIV-uninfected Antibody Mediated Prevention (AMP) trial participants.

VRC01 is being evaluated in the AMP efficacy trials, the first assessment of a passively administered broadly neutralizing monoclonal antibody (bnAb) for HIV-1 prevention. A key analysis will assess serum VRC01-mediated neutralization as a potential correlate of protection. To prepare for this analysis, we conducted a pilot study where we measured longitudinal VRC01 serum concentrations and serum VRC01-mediated neutralization in 47 and 31 HIV-1 uninfected AMP participants, respectively. We applied four different statistical approaches to predict serum VRC01-mediated neutralization titer against Env-pseudotyped viruses, including breakthrough viruses isolated from AMP placebo recipients who became HIV-1 infected during the trial, using VRC01 serum concentration and neutralization potency (IC50 or IC80) of the VRC01 clinical lot against the same virus. Approaches 3 and 4, which utilized pharmacokinetics/pharmacodynamics joint modeling of concentration and neutralization titer, generally performed the best or comparably to Approaches 1 and 2, which, respectively, utilized only measured and model-predicted concentration. For prediction of ID80 titers against breakthrough viruses, Approaches 1 and 2 rendered comparable performance to Approaches 3 and 4, and could be reasonable approaches to adopt in practice as they entail reduced assay cost and less complicated statistical analysis. Our results may be applied to future studies of other bnAbs and bnAb combinations to maximize resource efficiency in serum neutralization titer measurement.

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. Plasma from individuals who seroconverted in ASPIRE was analysed for HIV-1 drug resistance using both population Sanger sequencing and next-generation sequencing (NGS) with unique molecular identifiers to report mutations at ≥1% frequency. DPV susceptibility of plasma-derived recombinant HIV-1 containing bulk-cloned full-length reverse transcriptase sequences from MTN-020/ASPIRE seroconversions was determined in TZM-bl cells. Statistical significance was calculated using the Fisher's exact test. RESULTS: Plasma from all 168 HIV seroconversions were successfully tested by Sanger sequencing; 57 of 71 DPV arm and 82 of 97 placebo (PLB) arm participants had NGS results at 1% sensitivity. Overall, 18/168 (11%) had NNRTI mutations including K101E, K103N/S, V106M, V108I, E138A/G, V179D/I/T and H221Y. Five samples from both arms had low-frequency NNRTI mutations that were not detected by Sanger sequencing. The frequency of NNRTI mutations from the DPV arm (11%) was not different from the PLB arm (10%; p = 0.80). The E138A mutation was detected in both the DPV (3 of 71 [4.2%]) and PLB arm (5 of 97 [5.2%]) and conferred modest reductions in DPV susceptibility in some reverse transcriptase backgrounds but not others. CONCLUSIONS: HIV-1 drug resistance including NNRTI resistance did not differ between the DPV and placebo arms of the MTN-020/ASPIRE study, indicating that drug resistance was not preferentially acquired or selected by the DPV ring and that the preventive benefit of DPV ring outweighs resistance risk.

Correlates of Adherence to the Dapivirine Vaginal Ring for HIV-1 Prevention.

Understanding characteristics associated with adherence to pre-exposure prophylaxis (PrEP) methods for HIV-1 prevention may assist with optimizing implementation efforts. The dapivirine vaginal ring is a novel topical PrEP delivery method. Using data from a randomized, double-blind, placebo-controlled, phase III trial of the dapivirine vaginal ring conducted in four African countries, generalized estimating equation models were used to evaluate correlates of ring adherence. Two levels of quarterly dapivirine blood plasma, and dapivirine released from returned rings defined measures of adherence for recent and cumulative use, respectively. Time on study, calendar time, primary partner knowledge that the participant was taking part in the study, and use of long-acting contraceptive methods were associated with ring adherence whereas younger age, ring worries, condom use, episodes of menstrual bleeding and vaginal washing were associated with non-adherence. These findings may be useful for recruitment into future clinical studies and dapivirine ring implementation efforts.

Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing Human Immunodeficiency Virus Type 1 (HIV-1) Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants.

BACKGROUND: Perinatal human immunodeficiency virus type 1 (HIV-1) continues to occur due to barriers to effective antiretroviral prevention that might be mitigated by long-acting broadly neutralizing monoclonal antibodies (bNAbs). METHODS: An extended half-life bNAb, VRC01LS, was administered subcutaneously at 80 mg/dose after birth to HIV-1-exposed, nonbreastfed (cohort 1, n = 10) and breastfed (cohort 2, n = 11) infants. Cohort 2 received a second dose (100 mg) at 12 weeks. All received antiretroviral prophylaxis. VRC01LS levels were compared to VRC01 levels determined in a prior cohort. RESULTS: Local reactions (all grade ≤2) occurred in 67% and 20% after dose 1 and dose 2, respectively. The weight-banded dose (mean 28.8 mg/kg) of VRC01LS administered subcutaneously achieved a mean (standard deviation) plasma level of 222.3 (71.6) µg/mL by 24 hours and 44.0 (11.6) µg/mL at week 12, prior to dose 2. The preestablished target of ≥50 µg/mL was attained in 95% and 32% at weeks 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after 1 dose was significantly greater (P <.002) than after a VRC01 dose (20 mg/kg). No infants acquired HIV-1. CONCLUSIONS: VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with antiretrovirals to prevent infant HIV-1 transmission.

CD34T+ Humanized Mouse Model to Study Mucosal HIV-1 Transmission and Prevention.

Humanized mice are critical for HIV-1 research, but humanized mice generated from cord blood are inefficient at mucosal HIV-1 transmission. Most mucosal HIV-1 transmission studies in mice require fetal tissue-engraftment, the use of which is highly restricted or prohibited. We present a fetal tissue-independent model called CD34T+ with enhanced human leukocyte levels in the blood and improved T cell homing to the gut-associated lymphoid tissue. CD34T+ mice are highly permissive to intra-rectal HIV-1 infection and also show normal env diversification in vivo despite high viral replication. Moreover, mucosal infection in CD34T+ mice can be prevented by infusion of broadly neutralizing antibodies. CD34T+ mice can be rapidly and easily generated using only cord blood cells and do not require any complicated surgical procedures for the humanization process. Therefore, CD34T+ mice provide a novel platform for mucosal HIV-1 transmission studies as well as rapid in vivo testing of novel prevention molecules against HIV-1.

In vitro Study on Synergistic Interactions Between Free and Encapsulated Q-Griffithsin and Antiretrovirals Against HIV-1 Infection.

INTRODUCTION: Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV), raltegravir (RAL), and dapivirine (DAP) have been developed to prevent and treat HIV-1 via different mechanisms of action. In parallel, a promising biological candidate, griffithsin (GRFT), has demonstrated outstanding preclinical safety and potency against HIV-1. While ARV co-administration has been shown to enhance virus inhibition, synergistic interactions between ARVs and the oxidation-resistant variant of GRFT (Q-GRFT) have not yet been explored. Here, we co-administered Q-GRFT with TFV, RAL, and DAP, in free and encapsulated forms, to identify unique protein-drug synergies. METHODS: Nanoparticles (NPs) were synthesized using a single or double-emulsion technique and release from each formulation was assessed in simulated vaginal fluid. Next, each ARV, in free and encapsulated forms, was co-administered with Q-GRFT or Q-GRFT NPs to evaluate the impact of co-administration in HIV-1 pseudovirus assays, and the combination indices were calculated to identify synergistic interactions. Using the most synergistic formulations, we investigated the effect of agent incorporation in NP-fiber composites on release properties. Finally, NP safety was assessed in vitro using MTT assay. RESULTS: All active agents were encapsulated in NPs with desirable encapsulation efficiency (15-100%), providing ~20% release over 2 weeks. The co-administration of free Q-GRFT with each free ARV resulted in strong synergistic interactions, relative to each agent alone. Similarly, Q-GRFT NP and ARV NP co-administration resulted in synergy across all formulations, with the most potent interactions between encapsulated Q-GRFT and DAP. Furthermore, the incorporation of Q-GRFT and DAP in NP-fiber composites resulted in burst release of DAP and Q-GRFT with a second phase of Q-GRFT release. Finally, all NP formulations exhibited safety in vitro. CONCLUSIONS: This work suggests that Q-GRFT and ARV co-administration in free or encapsulated forms may improve efficacy in achieving prophylaxis.

Engineering and characterising a novel, highly potent bispecific antibody iMab-CAP256 that targets HIV-1.

The existing repertoire of HIV-1 patient derived broadly neutralising antibodies (bNAbs) that target the HIV-1 envelope glycoprotein (Env) present numerous and exciting opportunities for immune-based therapeutic and preventative strategies against HIV-1. Combination antibody therapy is required to ensure greater neutralization coverage and limit Env mediated escape mutations following treatment pressure. Engineered bispecific bNAbs (bibNAbs) assimilate the advantages of combination therapy into a single antibody molecule with several configurations reporting potency enhancement as a result of the increased avidity and simultaneous engagement of targeted epitopes. We report the engineering of a novel bibNAb (iMab-CAP256) comprising the highly potent, CAP256.VRC26.25 bNAb with anticipated extension in neutralization coverage through pairing with the host directed, anti-CD4 antibody, ibalizumab (iMab). Recombinant expression of parental monoclonal antibodies and the iMab-CAP256 bibNAb was performed in HEK293T (Human embryonic kidney 293 T antigen) cells, purified to homogeneity by Protein-A affinity chromatography followed by size exclusion chromatography. Antibody assembly and binding functionality of Fab moieties was confirmed by SDS-PAGE (sodium dodecyl sulphate polyacrylamide gel electrophoresis) and ELISA, respectively. Breadth and potency were evaluated against a geographical diverse HIV-1 pseudovirus panel (n = 20). Overall, iMab-CAP256 demonstrated an expanded neutralizing coverage, neutralizing single, parental antibody resistant pseudovirus strains and an enhanced neutralization potency against all dual sensitive strains (average fold increase over the more potent parental antibody of 11.4 (range 2 to 31.8). Potency enhancement was not observed for the parental antibody combination treatment (iMab + CAP256) suggesting the presence of a synergistic relationship between the CAP256 and iMab paratope combination in this bibNAb configuration. In addition, iMab-CAP256 bibNAbs exhibited comparable efficacy to other bibNAbs PG9-iMab and 10E08-iMab previously reported in the literature. The enhanced neutralization coverage and potency of iMAb-CAP256 over the parental bNAbs should facilitate superior clinical performance as a therapeutic or preventative strategy against HIV-1.

Suppression of Active HIV-1 Infection in CD34+ Hematopoietic Humanized NSG Mice by a Combination of Combined Antiretroviral Therapy and CCR5 Targeting Drugs.

Significant progress has been made in the diagnostics and treatment of AIDS since the discovery of the human immunodeficiency virus type 1 (HIV-1) in 1983. The remarkable effectiveness of combined antiretroviral therapy (cART) is evidenced by mortality reduction, control of peripheral blood viral load, and in a nearly normal quality of HIV patients' lives. Remaining obstacles in treatment and cure are drug toxicities and side effects, viral resistance, persistence of HIV-1 reservoirs on termination of cART treatment, the cost of lifelong antiretroviral therapy, and the stigma associated with taking antiretroviral drugs. As determined by plasma viral RNA and peripheral blood mononuclear cells (PBMC) proviral DNA, we show improved suppression of productive HIV infection in human CD34+ hematopoietic stem cell-engrafted NOD (nonobese diabetic)-SCID (severe combined immunodeficiency)-il2rg-/- (NSG) mice by combined treatment with cART and CCR5 targeting drugs, compared with cART alone, as well as an increased preservation of human CD4+ T cells (defined as CD45+ CD3+ CD4+ cells) and CD4+/CD8+ cell ratios in infected mice. The data also suggest a possible reduction in viral reservoirs. Our data confirm that this animal model is suitable for detection of productive HIV infection, replication, and establishment of viral reservoirs. The data also provide proof of principle for the utility of combining CCR5 targeting drugs, maraviroc and rapamycin, with traditional cART to improve control of viremia and reduce viral reservoirs. This study thus serves as a model for future HIV-1 studies that could lead to the clinical development of new generations of antiretroviral drugs.

Nanoencapsulation introduces long-acting phenomenon to tenofovir alafenamide and emtricitabine drug combination: A comparative pre-exposure prophylaxis efficacy study against HIV-1 vaginal transmission.

Daily oral antiretroviral (ARV) drugs for pre-exposure prophylaxis (PrEP) has proven efficacy for diverse groups of high-risk individuals. However, daily dosing regimen has augmented non-adherence. These experiments comparatively investigated the long-acting (LA) PrEP potency of subcutaneous (SubQ) administrated tenofovir alafenamide (TAF) and emtricitabine (FTC) loaded nanoparticles (NPs) to solution in humanized (hu) mice. TAF + FTC NPs and TAF + FTC solution (each drug at 200 mg/kg) were administered to hu-CD34-NSG mice (n = 3/time point) for plasma and tissue pharmacokinetic parameter estimation using LC-MS/MS. NP enhanced tissue ARV assimilation compared to plasma. The same dose was administered for PrEP efficacy in HIV-1 challenged hu-BLT mice (n = 5/group). The hu-BLT mice were vaginally challenged with a transmission-founder (T/F) virus at 5 × 105 TCID50 inoculation, on day 4, 7 and 14 post-SubQ treatments (PT) and were compared to infected-untreated-control hu-BLT mice. By 21 days PT, 100% TAF + FTC solution-treated and control-untreated mice were infected. However, TAF + FTC NPs resulted in significant (p = .0002) protection from HIV-1 (day 4: 80%, day 7 and 14: 60%, respectively) compared to control mice. This proof-of-concept study demonstrated detectable TAF/FTC vaginal levels among TAF + FTC NP-treated hu-BLT mice correlating with prolonged PrEP efficacy, thus establishing long-acting TAF + FTC NPs as a potential PrEP modality.

New anionic carbosilane dendrons functionalized with a DO3A ligand at the focal point for the prevention of HIV-1 infection.

Novel third-generation polyanionic carbosilane dendrons with sulfonate or carboxylate end-groups and functionalized with a DO3A ligand at the focal point, and their corresponding copper complexes, have been prepared as antiviral compounds to prevent HIV-1 infection. The topology enables the compound to have an excellent chelating agent, DO3A, while keeping anionic peripheral groups for a therapeutic action. In this study, the cytotoxicity and anti-HIV-1 abilities of carboxylate- (5) or sulfonate-terminated (6) dendrons containing DO3A and their copper complexes (7 or 8) were evaluated. All compounds showed low cytotoxicity and demonstrated potent and broad-spectrum anti-HIV-1 activity in vitro. We also assessed the mode of antiviral action on the inhibition of HIV-1 through a panel of different in vitro antiviral assays. Our results show that copper-free dendron 6 protects the epithelial monolayer from short-term cell disruption. Copper-free dendrons 5 and 6 exert anti-HIV-1 activity at an early stage of the HIV-1 lifecycle by binding to the envelope glycoproteins of HIV-1 and by interacting with the CD4 cell receptor and blocking the binding of gp120 to CD4, and consequently HIV-1 entry. These findings show that copper-free dendrons 5 and 6 have a high potency against HIV-1 infection, confirming their non-specific ability and suggesting that these compounds deserve further study as potential candidate microbicides to prevent HIV-1 transmission.

An update on multipurpose prevention technologies for the prevention of HIV transmission and pregnancy.

INTRODUCTION: Multipurpose Prevention Technologies (MPTs) are designed to address two or more indications from a single product. The overall goal is to prevent unintended pregnancy and transmission of one or more STIs including HIV-1. AREAS COVERED: The topics covered herein are advances in over the past three years. Advances include development of novel intravaginal rings capable of releasing microbicides to prevent transmission of HIV-1 and unintended pregnancy. These rings include the potential to prevent transmission of more than one STI and unintended pregnancy. There are also gels that can potentially accomplish the same thing. Finally, combination of a drug and barrier device are also covered. EXPERT OPINION: There has been considerable advance in this field over the past three years. There is one ring currently in a Phase I clinical trial and others are soon to follow. Some of these drug delivery systems are by necessity rather complicated and hence could be prohibitively expensive in the developing world. Conducting multiple clinical trials to support regulatory approval of two or more indications represents a significant barrier. It remains unclear that women will be more motivated to use MPT products than has been observed in recent microbicide-only clinical trials. Despite these challenges, the need for MPTs remain acute hopefully ensuring they will continue to be developed over the coming years.

HSV-1/HSV-2 Infection-Related Cancers in Bantu Populations Driving HIV-1 Prevalence in Africa: Tracking the Origin of AIDS at the Onset of the 20th Century.

INTRODUCTION: At the onset of the 20th century, ancient clinical observations of cancer epidemics in Bantu populations of Sub-Saharan Africa were discovered. They were reported from 1914 to 1960, but remained unexplained. In 1983, in San Francisco, Calif., USA, cancer epidemics were related to infections by the human immunodeficiency virus type 1 (HIV-1) known as AIDS disease. Yet since 1996, it is known that HIV-1 strains are not the only ones involved. In Sub-Saharan Africa, recurrent orobuccal herpes simplex virus type 1 (HSV-1) and genital recurrent herpes simplex virus type 2 (HSV-2) appeared many times prior to infection by HIV-1. CASE REPORTS: Data on these ancient medical observations regarding African cancer epidemics can today be referred to as the relationship between the unfortunate immune deficiency of herpes in Bantu populations and HIV-1 viral strains. For centuries, the Bantu populations dispersed in forests were living in close proximity to chimpanzees infected by simian immunodeficiency virus (SIV) and were exposed to SIV contamination which became HIV-1 in human beings. Presently, these unexplained Bantu cancer epidemics can be linked to the viral partnership of HSV-1/HSV-2 to HIV-1 strains. CONCLUSION: The key issue is now to prevent HSV-1/HSV-2 diseases related to HIV-1. An anti-herpes treatment administered early during childhood to Bantu populations will offer a mean of preventing herpes diseases related to HIV-1 infection and hence avoid cancer epidemics.

Prevention vaginally of HIV-1 transmission in humanized BLT mice and mode of antiviral action of polyanionic carbosilane dendrimer G2-S16.

The development of a safe, effective, and low-priced topical microbicide to prevent HIV-1 sexual transmission is urgently needed. The emerging field of nanotechnology plays an important role in addressing this challenge. We demonstrate that topical vaginal administration of 3% G2-S16 prevents HIV-1JR-CSF transmission in humanized (h)-BLT mice in 84% with no presence of HIV-1 RNA and vaginal lesions. Second-generation polyanionic carbosilane dendrimer G2-S16 with silica core and 16 sulfonate end-groups exerts anti-HIV-1 activity at an early stage of viral replication, blocking the gp120/CD4 interaction, acting on the virus, and inhibiting the cell-to-cell HIV-1 transmission, confirming its multifactorial and non-specific ability. This study represents the first demonstration that transmission of HIV-1 can be efficiently blocked by vaginally applied G2-S16 in h-BLT mice. These findings provide a step forward in the development of G2-S16-based vaginal microbicides to prevent vaginal HIV-1 transmission in humans. FROM THE CLINICAL EDITOR: HIV infections remain a significant problem worldwide and the major route of transmission is through sexual activity. In this article, the authors developed an antiviral agent containing polyanionic carbosilane dendrimer with silica core and 16 sulfonate end-groups. When applied vaginally, this was shown to exert anti-HIV protection. These positive findings may offer hope in the fight against the spread of HIV epidemic.

Multipurpose prevention technologies: products in development.

Multipurpose prevention technologies (MPTs) are broadly defined as products capable of simultaneously addressing multiple sexual and reproductive health needs including unintended pregnancy, STIs including HIV-1, and other reproductive tract infections. MPTs have been discussed for a few decades but little product development has occurred. With the recent proof-of-concept that a topically applied antiretroviral (ARV) can effectively reduce sexual transmission of HIV-1 (tenofovir 1% gel) the impetus to develop MPTs is gaining momentum. Products currently in development are broadly categorized as either long-acting or on-demand. Long-acting MPTs include intravaginal rings (IVRs) and long-acting injectable products. Several IVR MPTs are under development including one designed to release tenofovir to prevent transmission of HIV-1 and levonorgestrel (LNG) to prevent unintended pregnancy over a 90-day period. Another MPT IVR under development is designed to release the ARV dapivirine and LNG for 2 months. Long-acting injectable pre-exposure prophylaxis (PrEP) formulations of rilpivirine (TMC278) and GSK1265744 have entered clinical evaluation and could form the basis of long-acting injectable products for HIV-1 prevention and prevention of unintended pregnancy. On-demand products include TFV 1% gel (HIV-1/HSV-2 prevention), a zinc/carrageenan zinc gel (HIV-1/HSV-2 prevention), and the SILCS diaphragm administered with TFV 1% gel. Significant technical, funding, and regulatory hurdles must be overcome to develop most MPTs; however, the significant reproductive health benefits to many women around the world should provide motivation to overcome these hurdles. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies", held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research.