In Vitro Antiviral Activity of Hyperbranched Poly-L-Lysine Modified by L-Arginine against Different SARS-CoV-2 Variants.

The emergence of SARS-CoV-2 variants requires close monitoring to prevent the reoccurrence of a new pandemic in the near future. The Omicron variant, in particular, is one of the fastest-spreading viruses, showing a high ability to infect people and evade neutralization by antibodies elicited upon infection or vaccination. Therefore, the search for broad-spectrum antivirals that can inhibit the infectious capacity of SARS-CoV-2 is still the focus of intense research. In the present work, hyperbranched poly-L-lysine nanopolymers, which have shown an excellent ability to block the original strain of SARS-CoV-2 infection, were modified with L-arginine. A thermal reaction at 240 °C catalyzed by boric acid yielded Lys-Arg hyperbranched nanopolymers. The ability of these nanopolymers to inhibit viral replication were assessed for the original, Delta, and Omicron strains of SARS-CoV-2 together with their cytotoxicity. A reliable indication of the safety profile and effectiveness of the various polymeric compositions in inhibiting or suppressing viral infection was obtained by the evaluation of the therapeutic index in an in vitro prevention model. The hyperbranched L-arginine-modified nanopolymers exhibited a twelve-fold greater therapeutic index when tested with the original strain. The nanopolymers could also effectively limit the replication of the Omicron strain in a cell culture.

Reply to Taylor et al. Comment on "Manna et al. SARS-CoV-2 Inactivation in Aerosol by Means of Radiated Microwaves. Viruses 2023, 15, 1443".

SARS-CoV-2 is inactivated in aerosol (its primary mode of transmission) by means of radiated microwaves at frequencies that have been experimentally determined. Such frequencies are best predicted by the mathematical model suggested by Taylor, Margueritat and Saviot. The alignment between such mathematical prediction and the outcomes of our experiments serves to reinforce the efficacy of the radiated microwave technology and its promise in mitigating the transmission of SARS-CoV-2 in its naturally airborne state.

SARS-CoV-2 Inactivation in Aerosol by Means of Radiated Microwaves.

Coronaviruses are a family of viruses that cause disease in mammals and birds. In humans, coronaviruses cause infections on the respiratory tract that can be fatal. These viruses can cause both mild illnesses such as the common cold and lethal illnesses such as SARS, MERS, and COVID-19. Air transmission represents the principal mode by which people become infected by SARS-CoV-2. To reduce the risks of air transmission of this powerful pathogen, we devised a method of inactivation based on the propagation of electromagnetic waves in the area to be sanitized. We optimized the conditions in a controlled laboratory environment mimicking a natural airborne virus transmission and consistently achieved a 90% (tenfold) reduction of infectivity after a short treatment using a Radio Frequency (RF) wave emission with a power level that is safe for people according to most regulatory agencies, including those in Europe, USA, and Japan. To the best of our knowledge, this is the first time that SARS-CoV-2 has been shown to be inactivated through RF wave emission under conditions compatible with the presence of human beings and animals. Additional in-depth studies are warranted to extend the results to other viruses and to explore the potential implementation of this technology in different environmental conditions.

Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients.

Despite new antivirals are being approved against SARS-CoV-2 they suffer from significant constraints and are not indicated for hospitalized patients, who are left with few antiviral options. Repurposed drugs have previously shown controversial clinical results and it remains difficult to understand why certain trials delivered positive results and other trials failed. Our manuscript contributes to explaining the puzzle: this might have been caused by a suboptimal drug exposure and, consequently, an incomplete virus suppression, also because the drugs have mostly been used as add-on monotherapies. As with other viruses (e.g., HIV and HCV) identifying synergistic combinations among such drugs could overcome monotherapy-related limitations. In a cell culture model for SARS-CoV-2 infection the following stringent criteria were adopted to assess drug combinations: 1) identify robust, synergistic antiviral activity with no increase in cytotoxicity, 2) identify the lowest drug concentration inhibiting the virus by 100% (LIC100) and 3) understand whether the LIC100 could be reached in the lung at clinically indicated drug doses. Among several combinations tested, remdesivir with either azithromycin or ivermectin synergistically increased the antiviral activity with no increase in cytotoxicity, improving the therapeutic index and lowering the LIC100 of every one of the drugs to levels that are expected to be achievable and maintained in the lung for a therapeutically relevant period of time. These results are consistent with recent clinical observations showing that intensive care unit admission was significantly delayed by the combination of AZI and RDV, but not by RDV alone, and could have immediate implications for the treatment of hospitalized patients with COVID-19 as the proposed "drug cocktails" should have antiviral activity against present and future SARS-CoV-2 variants without significant overlapping toxicity, while minimizing the onset of drug resistance. Our results also provide a validated methodology to help sort out which combination of drugs are most likely to be efficacious in vivo, based on their in vitro activity, potential synergy and PK profiles.

Effective SARS-CoV-2 antiviral activity of hyperbranched polylysine nanopolymers.

The coronavirus pandemic (COVID-19) had spread rapidly since December 2019, when it was first identified in Wuhan, China. As of April 2021, more than 130 million cases have been confirmed, with more than 3 million deaths, making it one of the deadliest pandemics in history. Different approaches must be put in place to confront a new pandemic: community-based behaviours (i.e., isolation and social distancing), antiviral treatments, and vaccines. Although behaviour-based actions have produced significant benefits and several efficacious vaccines are now available, there is still an urgent need for treatment options. Remdesivir represents the first antiviral drug approved by the Food and Drug Administration for COVID-19 but has several limitations in terms of safety and treatment benefits. There is still a strong request for other effective, safe, and broad-spectrum antiviral systems in light of future emergent coronaviruses. Here, we describe a polymeric nanomaterial derived from L-lysine, with an antiviral activity against SARS-CoV-2 associated with a good safety profile in vitro. Nanoparticles of hyperbranched polylysine, synthesized by L-lysine's thermal polymerization catalyzed by boric acid, effectively inhibit the SARS-CoV-2 replication. The virucidal activity is associated with the charge and dimension of the nanomaterial, favouring the electrostatic interaction with the viral surface being only slightly larger than the virions' dimensions. Low-cost production and easiness of synthesis strongly support the further development of such innovative nanomaterials as a tool for potential treatments of COVID-19 and, in general, as broad-spectrum antivirals.

Structure-Based Identification of HIV-1 Nucleocapsid Protein Inhibitors Active against Wild-Type and Drug-Resistant HIV-1 Strains.

HIV/AIDS is still one of the leading causes of death worldwide. Current drugs that target the canonical steps of the HIV-1 life cycle are efficient in blocking viral replication but are unable to eradicate HIV-1 from infected patients. Moreover, drug resistance (DR) is often associated with the clinical use of these molecules, thus raising the need for novel drug candidates as well as novel putative drug targets. In this respect, pharmacological inhibition of the highly conserved and multifunctional nucleocapsid protein (NC) of HIV-1 is considered a promising alternative to current drugs, particularly to overcome DR. Here, using a multidisciplinary approach combining in silico screening, fluorescence-based molecular assays, and cellular antiviral assays, we identified nordihydroguaiaretic acid (6), as a novel natural product inhibitor of NC. By using NMR, mass spectrometry, fluorescence spectroscopy, and molecular modeling, 6 was found to act through a dual mechanism of action never highlighted before for NC inhibitors (NCIs). First, the molecule recognizes and binds NC noncovalently, which results in the inhibition of the nucleic acid chaperone properties of NC. In a second step, chemical oxidation of 6 induces a potent chemical inactivation of the protein. Overall, 6 inhibits NC and the replication of wild-type and drug-resistant HIV-1 strains in the low micromolar range with moderate cytotoxicity that makes it a profitable tool compound as well as a good starting point for the development of pharmacologically relevant NCIs.

Safety, tolerability, and immunogenicity of repeated doses of dermavir, a candidate therapeutic HIV vaccine, in HIV-infected patients receiving combination antiretroviral therapy: results of the ACTG 5176 trial.

BACKGROUND: HIV-specific cellular immune responses are associated with control of viremia and delayed disease progression. An effective therapeutic vaccine could mimic these effects and reduce the need for continued antiretroviral therapy. DermaVir, a topically administered plasmid DNA-nanomedicine expressing HIV (CladeB) virus-like particles consisting of 15 antigens, induces predominantly central memory T-cell responses. METHODS: Treated HIV-infected adults (HIV RNA <50 and CD4 >350) were randomized to placebo or escalating DermaVir doses (0.1 or 0.4 mg of plasmid DNA at weeks 1, 7, and 13 in the low- and intermediate-dose groups and 0.8 mg at weeks 0, 1, 6, 7, 12, and 13 in the high-dose group), n = 5-6 evaluable subjects per group. Immunogenicity was assessed by a 12-day cultured interferon-γ enzyme-linked immunosorbent spot assay at baseline and at weeks 9, 17, and 37 using 1 Tat/Rev and 3 overlapping Gag peptide pools (p17, p24, and p15). RESULTS: Groups were comparable at baseline. The study intervention was well tolerated, without dose-limiting toxicities. Most responses were highest at week 17 (4 weeks after last vaccination) when Gag p24 responses were significantly greater among intermediate-dose group compared with control subjects [median (IQR): 67,600 (5633-74,368) versus 1194 (9-1667)] net spot-forming units per million cells, P = 0.032. In the intermediate-dose group, there was also a marginal Gag p15 response increase from baseline to week 17 [2859 (1867-56,933), P = 0.06], and this change was significantly greater than in the placebo group [0 (-713 to 297), P = 0.016]. CONCLUSIONS: DermaVir administration was associated with a trend toward greater HIV-specific, predominantly central memory T-cell responses. The intermediate DermaVir dose tended to show the greatest immunogenicity, consistent with previous studies in different HIV-infected patient populations.

VS411 reduced immune activation and HIV-1 RNA levels in 28 days: randomized proof-of-concept study for antiviral-hyperactivation limiting therapeutics.

BACKGROUND: A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4(+) T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects. METHODS: Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naïve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests. RESULTS: VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4(+) T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: -1.47 log(10) copies/mL; CD4(+) T cell count: +135 cells/mm(3)) and fewest adverse events. CONCLUSIONS: VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component. TRIAL REGISTRATION: ITEudraCT 2007-002460-98.

Single DermaVir immunization: dose-dependent expansion of precursor/memory T cells against all HIV antigens in HIV-1 infected individuals.

BACKGROUND: The GIHU004 study was designed to evaluate the safety and immunogenicity of three doses of DermaVir immunization in HIV-infected subjects on fully suppressive combination antiretroviral therapy (cART). METHODOLOGY/PRINCIPAL FINDINGS: This first-in-human dose escalation study was conducted with three topical DermaVir doses targeted to epidermal Langerhans cells to express fifteen HIV antigens in draining lymph nodes: 0.1 mg DNA targeted to two, 0.4 mg and 0.8 mg DNA targeted to four lymph nodes. Particularly, in the medium dose cohort 0.1 mg DNA was targeted per draining lymph node via ∼8 million Langerhans cells located in 80 cm(2) epidermis area. The 28-days study with 48-week safety follow-up evaluated HIV-specific T cell responses against Gag p17, Gag p24 and Gag p15, Tat and Rev antigens. DermaVir-associated side effects were mild, transient and not dose-dependent. Boosting of HIV-specific effector CD4(+) and CD8(+) T cells expressing IFN-gamma and IL-2 was detected against several antigens in every subject of the medium dose cohort. The striking result was the dose-dependent expansion of HIV-specific precursor/memory T cells with high proliferation capacity. In low, medium and high dose cohorts this HIV-specific T cell population increased by 325-, 136,202 and 50,759 counts after 4 weeks, and by 3,899, 9,878 and 18,382 counts after one year, respectively, compared to baseline. CONCLUSIONS/SIGNIFICANCE: Single immunization with the DermaVir candidate therapeutic vaccine was safe and immunogenic in HIV-infected individuals. Based on the potent induction of Gag, Tat and Rev-specific memory T cells, especially in the medium dose cohort, we speculate that DermaVir boost T cell responses specific to all the 15 HIV antigens expressed from the single DNA. For durable immune reactivity repeated DermaVir immunization might be required since the frequency of DermaVir-boosted HIV-specific memory T cells decreased during the 48-week follow up. TRIAL REGISTRATION: ClinicalTrial.gov NCT00712530.

DermaVir: a plasmid DNA-based nanomedicine therapeutic vaccine for the treatment of HIV/AIDS.

The HIV global pandemic continues to rage with over 33 million people living with the disease. Although multidrug therapy has improved the prognosis for those infected by the virus, it has not eradicated the infection. Immunological therapies, including therapeutic vaccines, are needed to supplement drug therapy in the search for a 'functional cure' for HIV. DermaVir (Genetic Immunity Kft, Budapest, Hungary and McLean, Virginia, USA), an experimental HIV/AIDS therapeutic vaccine, combines three key elements of rational therapeutic vaccine design: a single plasmid DNA (pDNA) immunogen expressing 15 HIV antigens, a synthetic pDNA nanomedicine formulation and a dendritic cell-targeting topical-vaccine administration. DermaVir's novel mechanism of action, natural transport by epidermal Langerhans cells to the lymph nodes to express the pDNA-encoded HIV antigens and induce precursor/memory T cells with high proliferation capacity, has been consistently demonstrated in mouse, rabbit, primate and human subjects. Safety, immunogenicity and preliminary efficacy of DermaVir have been clinically demonstrated in HIV-infected human subjects. The DermaVir technology platform for dendritic cell-based therapeutic vaccination might offer a new treatment paradigm for cancer and infectious diseases.

A plasmid DNA immunogen expressing fifteen protein antigens and complex virus-like particles (VLP+) mimicking naturally occurring HIV.

We describe here a single plasmid DNA immunogen representing the broadest antigen repertoire among HIV vaccine candidates. This pDNA was "ANTIGENeered" for the regulated expression of thirteen complete and two non-functional HIV protein antigens. These proteins self assemble into complex virus-like particles (VLP(+)). Multiple irreversible safety features were introduced by genetic modifications including the complete impairment of integration, reverse transcription, the function of Nef and the 3'LTR. Epitope analysis predicted that the pDNA-derived protein repertoire can potentially present over 3000 T cell epitopes. However, the expressed antigens have different potential to induce HIV-specific CD4(+) and CD8(+) T cells supporting our hypothesis that HIV vaccines should contain all possible regulatory and structural proteins. This immunogen is the active pharmaceutical ingredient of DermaVir, a therapeutic vaccine product candidate that recently successfully completed Phase II clinical trials and meets the safety, immunogenicity and cost requirements of an HIV vaccine.

Beneficial effect of TRAIL on HIV burden, without detectable immune consequences.

BACKGROUND: During uncontrolled HIV disease, both TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptor expression are increased. Enhanced TRAIL sensitivity is due to TRAIL receptor up-regulation induced by gp120. As a result of successful antiretroviral therapy TRAIL is down-regulated, and there are fewer TRAIL-sensitive cells. In this setting, we hypothesized that all cells that contain virus, including those productively- and latently-infected, have necessarily been "primed" by gp120 and remain TRAIL-sensitive, whereas uninfected cells remain relatively TRAIL-resistant. METHODS AND FINDINGS: We evaluated the immunologic and antiviral effects of TRAIL in peripheral blood lymphocytes collected from HIV-infected patients with suppressed viral replication. The peripheral blood lymphocytes were treated with recombinant TRAIL or an equivalent amount of bovine serum albumin as a negative control. Treated cells were then analyzed by quantitative flow cytometry, ELISPOT for CD4+ and CD8+ T-cell function, and limiting dilution microculture for viral burden. Alterations in the cytokine milieu of treated cells were assessed with a multiplex cytokine assay. Treatment with recombinant TRAIL in vitro reduced viral burden in lymphocytes collected from HIV-infected patients with suppressed viral load. TRAIL treatment did not alter the cytokine milieu of treated cells. Moreover, treatment with recombinant TRAIL had no adverse effect on either the quantity or function of immune cells from HIV-infected patients with suppressed viral replication. CONCLUSIONS: TRAIL treatment may be an important adjunct to antiretroviral therapy, even in patients with suppressed viral replication, perhaps by inducing apoptosis in cells with latent HIV reservoirs. The absence of adverse effect on the quantity or function of immune cells from HIV-infected patients suggests that there is not a significant level of "bystander death" in uninfected cells.

IL-15 as memory T-cell adjuvant for topical HIV-1 DermaVir vaccine.

IL-7 and IL-15 are key cytokines involved in the generation and maintenance of memory CD8+ T-cells. We evaluated these cytokines as molecular adjuvants for topical HIV-1 DermaVir vaccine. We found that mice receiving DermaVir formulated with HIV-1 Gag plasmid in the presence of IL-7- or IL-15-encoding plasmid significantly enhanced Gag-specific central memory T-cells, as measured by a peptide-based cultured IFN-gamma ELISPOT. Additionally, IL-15 significantly improved DermaVir-induced Gag-specific effector memory CD8+ T-cell responses, measured by standard IFN-gamma ELISPOT. In a DermaVir prime/vaccinia vector boost regimen, the inclusion of IL-15 together with DermaVir significantly improved Gag-specific effector memory T-cell responses. Our study demonstrates that IL-15 is more potent than IL-7 in enhancing HIV-1-specific central memory T-cells induced by topical DermaVir. IL-15 adjuvanted DermaVir might be an alternative prime in a prophylactic vaccine regimen.

HIV-1-specific T cell precursors with high proliferative capacity correlate with low viremia and high CD4 counts in untreated individuals.

Evidences have recently suggested that the preservation of vaccine-induced memory rather than effector T cells is essential for better outcome and survival following pathogenic SIV challenge in macaques. However, an equivalent demonstration in humans is missing, and the immune correlates of HIV-1 control have been only partially characterized. We focused on the quantification of Ag-specific T cell precursors with high proliferative capacity (PHPC) using a peptide-based cultured IFN-gamma ELISPOT assay (PHPC assay), which has been shown to identify expandable memory T cells. To determine which responses correlate with viral suppression and positive immunologic outcome, PBMC from 32 chronically untreated HIV-1-infected individuals were evaluated in response to peptide pools, representing the complete HIV-1 Gag, Nef, and Rev proteins, by PHPC and IFN-gamma ELISPOT assay, which instead identifies effector T cells with low proliferative capacity. High magnitude of Gag-specific PHPC, but not ELISPOT, responses significantly correlated with low plasma viremia, due to responses directed toward p17 and p15 subunits. Only Gag p17-specific PHPC response significantly correlated with high CD4 counts. Analysis of 20 additional PBMC samples from an independent cohort of chronically untreated HIV-1-infected individuals confirmed the correlation between Gag p17-specific PHPC response and either plasma viremia (inverse correlation) or CD4 counts (direct correlation). Our results indicate that the PHPC assay is quantitatively and qualitatively different from the ELISPOT assay, supporting that different T cell populations are being evaluated. The PHPC assay might be an attractive option for individual patient management and for the design and testing of therapeutic and prophylactic vaccines.

Treating HIV/AIDS by reducing immune system activation: the paradox of immune deficiency and immune hyperactivation.

PURPOSE OF REVIEW: To collect published evidence in support of a novel immune therapeutic approach to reduce the excess of immune activation that ultimately turns into immune deficiency in HIV/AIDS. RECENT FINDINGS: A large body of evidence has been collected in support of the pathogenetic interpretation that prolonged immune overactivation induced by HIV during the course of chronic infection exhausts the immune system and leads to AIDS. Some groups are exploring the possibility of therapeutic interventions to limit the immune system overload. Cytostatic drugs appear promising candidates to achieve the goal, as they restrain cell proliferation without blocking it. At the same time, they do not affect cellular response to antigenic stimulation, and at appropriate dosages are not immune suppressive. SUMMARY: Presently available antiretrovirals only partially reduce immune system activation during chronic HIV infection. Further clinical research is warranted to test cytostatic drugs to avert immune overactivation and prevent progression to AIDS.

The potential of topical DNA vaccines adjuvanted by cytokines.

To improve the efficacy of DNA immunization epidermal Langerhans cells are attractive targets to deliver antigen-encoding plasmid DNA. Topical vaccination with naked plasmid DNA has been shown to induce immune responses, and their potency might be improved by chemical and physical methods aimed to enhance the efficiency of plasmid DNA delivery into the skin. Cytokines have also been evaluated as adjuvants for DNA vaccines because they influence the host immune response. This review focuses on the action of several cytokines tested as molecular adjuvants for DNA vaccines and the combination of them with the DermaVir Patch vaccine. DermaVir vaccine, topically administered under a patch, consists of a plasmid DNA that is chemically formulated into a nanoparticle to support vaccine delivery into epidermal Langerhans cells and to induce antigen-specific memory T cells.

A checkpoint in the cell cycle progression as a therapeutic target to inhibit HIV replication.

Human immunodeficiency virus (HIV) expression is boosted after T lymphocyte stimulation. It is not known, however, in which phase(s) of the cell cycle HIV is maximally expressed. We demonstrate here that cell activation induces limited HIV expression and that progression to cell proliferation is required for optimal HIV replication. We also show that the G1/S cell cycle transition is a critical checkpoint in this process and that limiting progression at this step with antiproliferative drugs suppresses HIV replication. These results identify a specific phase of the cell cycle progression that is critical for HIV expression and suggest a new discrete target for anti-HIV treatment.

Effects of structured treatment interruptions on metabolic, anthropometric, immunologic, and quality of life outcomes in HIV-positive adults on HAART.

Structured treatment interruptions may have beneficial effects on metabolic parameters, while data on anthropometric parameters and on the quality of life are scanty. This study was designed to evaluate the effects of structured treatment interruptions on plasma cholesterol, triglycerides, anthropometric, immunologic, virologic changes and quality of life. A total of 112 HIV-infected patients under HAART with undetectable viremia for longer than 6 months were randomized to undergo 6 cycles of 1-month off and 1-month on therapy or to continue HAART. Patients treated with structured treatment interruptions (STI group) were evaluated monthly, patients in the control group (CTRL group) were evaluated every two months. Anthropometric and quality of life data were collected every four months. The study was designed as a two-arm, prospective, multicentred, controlled trial. Results on the primary endpoints showed a significant decrease in the cholesterol levels in the STI group compared to the CTRL group (total cholesterol median AUC [IQR] was 193.5 mg/dL/month [173.4-209.4], and 210.8 mg/dL/month [194-242.4], respectively, p=0.0009). Although the triglyceride levels were lower in the STI group, the results did not reach statistical significance (triglyceride median AUC [IQR] was 166.8 mg/dL/month [IQR: 112.5-234.9] in the CTRL group, and 169 [IR: 124.7-256.7] in the STI group; p=0.37). As for the secondary endpoints no major differences among groups were noted. Cyclic structured treatment interruptions may have a favorable, although limited, impact on plasma total cholesterol levels in HIV-infected subjects. No modifications of anthropometric and quality of life values were noted.

HIV-1 prophylactic vaccine comprised of topical DermaVir prime and protein boost elicits cellular immune responses and controls pathogenic R5 SHIV162P3.

Topical DNA vaccination (DermaVir) facilitates antigen presentation to naive T cells. DermaVir immunization in mice, using HIV-1 Env and Gag, elicited cellular immune responses. Boosting with HIV-1 gp120 Env and p41 Gag augmented Th1 cytokine levels. Intramuscular DNA administration was less efficient in priming antigen-specific cytokine production and memory T cells. In rhesus macaques, DermaVir immunization induced Gag- and Env-specific Th1 and Th2 cytokines and generation of memory T cells. Boosting of DermaVir-primed serum antibody levels was noted following gp140(SHIV89.6P)/p27(SIV) immunization. Rectal challenge with pathogenic R5-tropic SHIV162P3 resulted in control of plasma viremia (4/5 animals) that was reflected in jejunum, colon and mesenteric lymph nodes. An inverse correlation was found between Gag- and Env-specific central memory T cell responses on the day of challenge and plasma viremia at set point. Overall, the topical DermaVir/protein vaccination yields central memory T cell responses and facilitates control of pathogenic SHIV infection.