scholarly journals An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Subhra Mandal ◽  
Michael Belshan ◽  
Ashley Holec ◽  
You Zhou ◽  
Christopher J. Destache
Keyword(s):  
Hiv Infection ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Antiretroviral Drugs ◽  
Volume Distribution ◽  
Major Drawback ◽  
Peripheral Blood Mononuclear ◽  
Long Acting ◽  
Hiv 1

ABSTRACT Among various FDA-approved combination antiretroviral drugs (cARVs), emtricitabine (FTC) has been a very effective nucleoside reverse transcriptase inhibitor. Thus far, FTC is the only deoxycytidine nucleoside analog. However, a major drawback of FTC is its large volume distribution (averaging 1.4 liters/kg) and short plasma half-life (8 to 10 h), necessitating a high daily dosage. Thus, we propose an innovative fabrication method of loading FTC in poly(lactic-co-glycolic acid) polymeric nanoparticles (FTC-NPs), potentially overcoming these drawbacks. Our nanoformulation demonstrated enhanced FTC loading (size of <200 nm and surface charge of −23 mV) and no to low cytotoxicity with improved biocompatibility compared to those with FTC solution. An ex vivo endosomal release assay illustrated that NP entrapment prolongs FTC release over a month. Intracellular retention studies demonstrate sustained FTC retention over time, with approximately 8% (24 h) to 68% (96 h) release with a mean retention of ∼0.74 μg of FTC/105 cells after 4 days. An in vitro HIV-1 inhibition study demonstrated that FTC-NP treatment results in a 50% inhibitory concentration (IC50) ∼43 times lower in TZM-bl cells (0.00043 μg/ml) and ∼3.7 times lower (0.009 μg/ml) in peripheral blood mononuclear cells (PBMCs) than with FTC solution (TZM-bl cells, 0.01861, and PBMCs, 0.033 μg/ml). Further, on primary PBMCs, FTC-NPs also illustrate an HIV-1 infection blocking efficacy comparable to that of FTC solution. All the above-described studies substantiate that FTC nanoformulation prolongs intracellular FTC concentration and inhibition of HIV infection. Therefore, FTC-NPs potentially could be a long-acting, stable formulation to ensure once-biweekly dosing to prevent or treat HIV infection.

scholarly journals Formulation Development of Retrocyclin 1 Analog RC-101 as an Anti-HIV Vaginal Microbicide Product

2011 ◽  
Vol 55 (5) ◽  
pp. 2282-2289 ◽  
Author(s):  
A. B. Sassi ◽  
M. R. Cost ◽  
A. L. Cole ◽  
A. M. Cole ◽  
D. L. Patton ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Formulation Development ◽  
Peripheral Blood Mononuclear ◽  
Vaginal Microbicide ◽  
Safety Studies ◽  
Film Formulation ◽  
Hiv 1

ABSTRACTRC-101 is a synthetic microbicide analog of retrocyclin, which has shownin vitroactivity against X4 and R5 HIV-1. In an effort to develop a safe and effective RC-101 vaginal microbicide product, we assessed safety inex vivomacaque and human models and efficacy usingin vitroandex vivomodels. A polyvinyl-alcohol vaginal film containing RC-101 (100 μg/film) was developed. Formulation assessment was conducted by evaluating disintegration, drug content, mechanical properties, and stability. Efficacy was evaluated byin vitroperipheral blood mononuclear cells (PBMC) assay andex vivohuman ectocervical tissue explant model.Ex vivosafety studies were conducted by exposing RC-101 to an excised monkey reproductive tract and excised human ectocervical tissue. RC-101 100 μg films were shown to be safe to human and monkey tissue and effective against HIV-1in vitroandex vivoin human ectocervical tissue. The 90% inhibitory concentration (IC90) for RC-101 films at 2,000 μg (IC90= 57.5 μM) using anex vivomodel was 10-fold higher than the IC90observed using anin vitromodel (IC90= 5.0 μM). RC-101 films were stable for 1 month at 25°C, within vitrobioactivity maintained for up to 6 months. RC-101 was developed in a quick-dissolve film formulation that was shown to be safe in anex vivomodel and effective inin vitroandex vivomodels. RC-101 film formulations were shown to maintain bioactivity for a period of 6 months. Findings from the present study contribute to the development of a safe and effective topical microbicide product.

scholarly journals Buprenorphine Increases HIV-1 Infection In Vitro but Does Not Reactivate HIV-1 from Latency

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1472
Author(s):  
Germán Gustavo Gornalusse ◽  
Lucia N. Vojtech ◽  
Claire N. Levy ◽  
Sean M. Hughes ◽  
Yeseul Kim ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Hiv Infection ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Receptor Expression ◽  
People Living With Hiv ◽  
Peripheral Blood Mononuclear ◽  
In Vitro Susceptibility ◽  
Hiv 1

Background: medication-assisted treatment (MAT) with buprenorphine is now widely prescribed to treat addiction to heroin and other illicit opioids. There is some evidence that illicit opioids enhance HIV-1 replication and accelerate AIDS pathogenesis, but the effect of buprenorphine is unknown. Methods: we obtained peripheral blood mononuclear cells (PBMCs) from healthy volunteers and cultured them in the presence of morphine, buprenorphine, or methadone. We infected the cells with a replication-competent CCR5-tropic HIV-1 reporter virus encoding a secreted nanoluciferase gene, and measured infection by luciferase activity in the supernatants over time. We also surveyed opioid receptor expression in PBMC, genital epithelial cells and other leukocytes by qPCR and western blotting. Reactivation from latency was assessed in J-Lat 11.1 and U1 cell lines. Results: we did not detect expression of classical opioid receptors in leukocytes, but did find nociception/orphanin FQ receptor (NOP) expression in blood and vaginal lymphocytes as well as genital epithelial cells. In PBMCs, we found that at physiological doses, morphine, and methadone had a variable or no effect on HIV infection, but buprenorphine treatment significantly increased HIV-1 infectivity (median: 8.797-fold increase with 20 nM buprenorphine, eight experiments, range: 3.570–691.9, p = 0.0078). Using latently infected cell lines, we did not detect reactivation of latent HIV following treatment with any of the opioid drugs. Conclusions: our results suggest that buprenorphine, in contrast to morphine or methadone, increases the in vitro susceptibility of leukocytes to HIV-1 infection but has no effect on in vitro HIV reactivation. These findings contribute to our understanding how opioids, including those used for MAT, affect HIV infection and reactivation, and can help to inform the choice of MAT for people living with HIV or who are at risk of HIV infection.

scholarly journals REPLICATION OF HIV-1 SUBTYPE A6 IN THE PRESENCE OF HORMONES INCLUDED IN THE MODERN HORMONAL CONTRACEPTIVES

2019 ◽  
Vol 1 (1) ◽  
pp. 85-90
Author(s):  
M. N. Nosik ◽  
K. A. Ryzhov ◽  
A. V. Potapova
Keyword(s):  
Viral Replication ◽  
Mononuclear Cells ◽  
Virus Production ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Hormonal Contraceptives ◽  
Peripheral Blood Mononuclear ◽  
High Concentrations ◽  
Hiv 1

Aim. To study how female hormones included in oral contraceptives (β-estradiol and progesteron) affect HIV-1 replication and efficacy of antiviral drugs. Material and methods. Peripheral blood mononuclear cells (PBMC) and cell lines MT-4, Jurkat were infected with HIV-1 (subtype A6). Afterwards the cells were cultured for 6 days in the presence of β-estradiol/progesteron with or without the presence of antiretroviral drugs Lamivudin (3TC), Etravirin(ETR) and Indinavir (IDV), which are widely used for HIV treatment. Virus production was monitored by p24 levels in culture supernatants on day 6. The experemints were performed in eight repetitions. Results. There was a 1,3-1,8-fold increase of virus replication in the presence of high concentrations of both hormones (26,136 μg/ml). Incomplete suppression of viral replication was observed when infected cells were co-cultivated in the presence of hormones (26 μg, 136 μg) and antiretroviral drugs. The mean suppression rate of viral replication for β-estradiol was 77.3% and 69.8% for progesterone. However, in the absence of hormones the virus production was completely suppressed by those drugs. Conclusion. The high concentrations of steroid hormones induce HIV-1 replication and as a result reduce the efficacy of antiretroviral drugs NVP and IDV in vitro. Thus it is advisable for women at high risk of HIV infection to monitor hormone levels that change during the menstrual cycle and pregnancy before prescribing hormonal contraception.

scholarly journals High Levels of TRIM5a Are Associated with Xenophagy in HIV-1-Infected Long-Term Nonprogressors

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1207
Author(s):  
Fabiola Ciccosanti ◽  
Marco Corazzari ◽  
Rita Casetti ◽  
Alessandra Amendola ◽  
Diletta Collalto ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Protective Role ◽  
Antiretroviral Drugs ◽  
Peripheral Blood Mononuclear ◽  
Successful Control ◽  
Special Subset ◽  
Hiv 1

Autophagy is a lysosomal-dependent degradative mechanism essential in maintaining cellular homeostasis, but it is also considered an ancient form of innate eukaryotic fighting against invading microorganisms. Mounting evidence has shown that HIV-1 is a critical target of autophagy that plays a role in HIV-1 replication and disease progression. In a special subset of HIV-1-infected patients that spontaneously and durably maintain extremely low viral replication, namely, long-term nonprogressors (LTNP), the resistance to HIV-1-induced pathogenesis is accompanied, in vivo, by a significant increase in the autophagic activity in peripheral blood mononuclear cells. Recently, a new player in the battle of autophagy against HIV-1 has been identified, namely, tripartite motif protein 5α (TRIM5α). In vitro data demonstrated that TRIM5α directly recognizes HIV-1 and targets it for autophagic destruction, thus protecting cells against HIV-1 infection. In this paper, we analyzed the involvement of this factor in the control of HIV-1 infection through autophagy, in vivo, in LTNP. The results obtained showed significantly higher levels of TRIM5α expression in cells from LTNP with respect to HIV-1-infected normal progressor patients. Interestingly, the colocalization of TRIM5α and HIV-1 proteins in autophagic vacuoles in LTNP cells suggested the participation of TRIM5α in the autophagy containment of HIV-1 in LTNP. Altogether, our results point to a protective role of TRIM5α in the successful control of the chronic viral infection in HIV-1-controllers through the autophagy mechanism. In our opinion, these findings could be relevant in fighting against HIV-1 disease, because autophagy inducers might be employed in combination with antiretroviral drugs.

Norepinephrine Enhances Adhesion of HIV-1-Infected Leukocytes to Cardiac Microvascular Endothelial Cells

2003 ◽  
Vol 228 (6) ◽  
pp. 730-740 ◽  
Author(s):  
J.B. Sundstrom ◽  
D.E. Martinson ◽  
M. Mosunjac ◽  
P. Bostik ◽  
L.K. McMullan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hiv Infection ◽  
Mononuclear Cells ◽  
Microvascular Endothelial Cells ◽  
Peripheral Blood Mononuclear ◽  
Microvascular Endothelial ◽  
Static Conditions ◽  
Hiv 1 ◽  
Cardiac Microvascular Endothelial Cells

Recent reports have indicated that norepinephrine (NE) enhances HIV replication in infected monocytes and promotes increased expression of select matrix metalloproteinases associated with dilated cardiomyopathy (DCM) in vitro in co-cultures of HIV-infected leukocytes and human cardiac microvascular endothelial cells (HMVEC-C). The influence of NE on HIV infection and leukocyte-endothelial interactions suggests a pathogenic role in AIDS-related cardiovascular disease. This study examined the effects of norepinephrine (NE) and HIV-1 infection on leukocyte adhesion to HMVEC-C. Both flow and static conditions were examined and the expression of selected adhesion molecules and cytokines were monitored in parallel. NE pretreatment resulted in a detectable, dose-dependent increase of leukocyte-endothelial adhesion (LEA) with both HIV-1-infected and -uninfected peripheral blood mononuclear cells (PBMCs) relative to media controls after 48 hr in co-culture with HMVEC-C in vitro. However, the combination of NE plus HIV infection resulted in a significant ( P < 0.0001) 18-fold increase in LEA over uninfected media controls. Increased levels in both cell-associated and -soluble ICAM-1 and E-Selectin but not VCAM-1 correlated with increased LEA and with HIV-1 infection or NE pretreatment. Blocking antibodies specific for ICAM-1 or E-Selectin inhibited HIV-NE-induced LEA. These data suggest a model in which NE primes HIV-1-infected leukocytes for enhanced adhesion and localization in HMVEC-C where they can initiate and participate in vascular injury associated with AIDS-related cardiomyopathy.

scholarly journals The Anthrax Vaccine Adsorbed Vaccine Generates Protective Antigen (PA)-Specific CD4+ T Cells with a Phenotype Distinct from That of Naïve PA T Cells

2008 ◽  
Vol 76 (10) ◽  
pp. 4538-4545 ◽  
Author(s):  
William W. Kwok ◽  
Junbao Yang ◽  
Eddie James ◽  
John Bui ◽  
Laurie Huston ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Protective Antigen ◽  
Ex Vivo ◽  
Cytokine Profile ◽  
T Cell Epitopes ◽  
Peripheral Blood Mononuclear ◽  
Anthrax Vaccine ◽  
Cellular Immune

ABSTRACT Cellular immune responses against protective antigen (PA) of Bacillus anthracis in subjects that received the anthrax vaccine adsorbed (AVA) vaccine were examined. Multiple CD4+ T-cell epitopes within PA were identified by using tetramer-guided epitope mapping. PA-reactive CD4+ T cells with a CD45RA− phenotype were also detected by direct ex vivo staining of peripheral blood mononuclear cells (PBMC) with PA-specific tetramers. Surprisingly, PA-specific T cells were also detected in PBMC of nonvaccinees after a single cycle of in vitro PA stimulation. However, PA-reactive CD4+ T cells in nonvaccinees occurred at lower frequencies than those in vaccinees. The majority of PA-reactive T cells from nonvaccinees were CD45RA+ and exhibited a Th0/Th1 cytokine profile. In contrast, phenotyping and cytokine profile analyses of PA-reactive CD4+ T cells from vaccinees indicated that vaccination leads to commitment of PA-reactive T cells to a Th2 lineage, including generation of PA-specific, pre-Th2 central memory T cells. These results demonstrate that the current AVA vaccine is effective in skewing the development of PA CD4+ T cells to the Th2 lineage. The data also demonstrated the feasibility of using class II tetramers to analyze CD4+ cell responses and lineage development after vaccination.

scholarly journals Interferon Induction By HbS, SERINC5 Upregulation and Reduction of HIV-1 Nef and AP2 Contribute to HIV-1 Restriction in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Namita Kumari ◽  
Marina Jerebtsova ◽  
Songping Wang ◽  
Sharmin Diaz ◽  
Sergei Nekhai
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Interferon Response ◽  
Cell Disease ◽  
Restriction Factors ◽  
Peripheral Blood Mononuclear ◽  
Hiv 1

Concerted action of numerous positively acting cellular factors is essential for Human immunodeficiency virus type 1 (HIV-1) replication but in turn is challenged by anti-viral restriction factors. Previously we showed that ex vivo one round HIV-1 replication and replication of fully competent T-tropic HIV-1(IIIB) is significantly reduced in peripheral blood mononuclear cells (PBMCs) obtained from patients with Sickle Cell Disease (SCD). Further, we identified and confirmed CDKN1A (p21) and CH25H as host restriction factors expressed in SCD PBMCs that may contribute to the HIV-1 inhibition, in addition to the previously reported SAMHD1 and IKBα. Since CH25H is an interferon stimulated gene (ISG), we analyzed IRFs and interferon expression in SCD PBMCs. Higher levels of IRF7 and IFNβ mRNA were observed in SCD PBMCs compared to controls. We probed further to ascertain if hemin or sickle Hb was responsible for interferon response. We found upregulation of IFNβ in THP-1 - derived macrophages treated with lysates of HbSS RBCs or purified HbS as compared to untreated or HbA treated controls. HbSS RBCs lysates and purified HbS inhibited HIV-1 gag mRNA expression in monocyte-derived macrophages infected with HIV-1(Ba-L). Recent clinical study showed increased levels of CD4 in HIV-1 infected SCD patients in Africa. Thus we analyzed CD4 levels in HIV-1 IIIB infected SCD PBMCs, and found them to be higher compared to controls. Levels of HIV-1 nef mRNA, that controls CD4 expression was lower in HIV-1 IIIB infected SCD PBMCs. As Nef counteracts SERINC3/5 restriction factor, we analyzed its expression as well as the expression of AP2 clathrin adaptor that is required for Nef mediated internalization of CD4. AP2 expression was lower and SERINC5 expression was higher in SCD PBMCs. CONCLUSIONS: SCD PBMCs could resist HIV-1 infection because of the increased IFNβ production by macrophages exposed to HbSS or sickle cell RBCs. SCD PBMC have increased levels of SERNIC5 and lower levels of HIV-1 Nef and host AP2 expression that, culumlatively, can increased CD4 levels and lead to the overall improved immunological health of SCD patients. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants (1P50HL118006, 1R01HL125005, 1SC1HL150685, 5U54MD007597, 1UM1AI26617 and P30AI087714). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Disclosures No relevant conflicts of interest to declare.

HTLV-II down-regulates HIV-1 replication in IL-2–stimulated primary PBMC of coinfected individuals through expression of MIP-1α

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2760-2769 ◽  
Author(s):  
Claudio Casoli ◽  
Elisa Vicenzi ◽  
Andrea Cimarelli ◽  
Giacomo Magnani ◽  
Paolo Ciancianaini ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Peripheral Blood Mononuclear ◽  
Human T Cell ◽  
Cc Chemokines ◽  
Kinetics Of ◽  
Hiv 1

The influence of human T-cell leukemia/lymphoma virus type II (HTLV-II) in individuals also infected with HIV-1 is poorly understood. To evaluate the reciprocal influence of HTLV-II and HIV-1 infection, primary peripheral blood mononuclear cell (PBMC) cultures from coinfected individuals were established in the presence of interleukin 2 (IL-2). In these cultures, the kinetics of HTLV-II replication always preceded those of HIV-1. Noteworthy, the kinetics of HIV-1 production were inversely correlated to the HTLV-II proviral load in vivo and its replication ex vivo. These observations suggested a potential interaction between the 2 retroviruses. In this regard, the levels of IL-2, IL-6, and tumor necrosis factor- (TNF-) were measured in the same coinfected PBMC cultures. Endogenous IL-2 was not produced, whereas IL-6 and TNF- were secreted at levels compatible with their known ability to up-regulate HIV-1 expression. The HIV-suppressive CC-chemokines RANTES, macrophage inflammatory protein-1 (MIP-1), and MIP-1β were also determined in IL-2–stimulated PBMC cultures. Of interest, their kinetics and concentrations were inversely related to those of HIV-1 replication. Experiments were performed in which CD8+ T cells or PBMCs from HTLV-II monoinfected individuals were cocultivated with CD4+ T cells from HIV-1 monoinfected individuals separated by a semipermeable membrane in the presence or absence of antichemokine neutralizing antibodies. The results indicate that HTLV-II can interfere with the replicative potential of HIV-1 by up-regulating viral suppressive CC-chemokines and, in particular, MIP-1. This study is the first report indicating that HTLV-II can influence HIV replication, at least in vitro, via up-regulation of HIV-suppressive chemokines.

scholarly journals Ex Vivo Expanded Human Vγ9Vδ2 T-Cells Can Suppress Epithelial Ovarian Cancer Cell Growth

2019 ◽  
Vol 20 (5) ◽  
pp. 1139 ◽  
Author(s):  
Tsui Mao ◽  
Carol Miao ◽  
Yi Liao ◽  
Ying Chen ◽  
Chia Yeh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Ovarian Cancer Cells ◽  
Cytotoxic Activities ◽  
Antitumor Effects ◽  
Peripheral Blood Mononuclear

γδ-T-cells have attracted attention because of their potent cytotoxicity towards tumors. Most γδ-T-cells become activated via a major histocompatibility complex (MHC)-independent pathway by the interaction of their receptor, Natural Killer Group 2 Member D (NKG2D) with the tumor-specific NKG2D ligands, including MHC class I-related chain A/B (MICA/B) and UL16-binding proteins (ULBPs), to kill tumor cells. However, despite their potent antitumor effects, the treatment protocols specifically targeting ovarian tumors require further improvements. Ovarian cancer is one of the most lethal and challenging female malignancies worldwide because of delayed diagnoses and resistance to traditional chemotherapy. In this study, we successfully enriched and expanded γδ-T-cells up to ~78% from peripheral blood mononuclear cells (PBMCs) with mostly the Vγ9Vδ2-T-cell subtype in the circulation. We showed that expanded γδ-T-cells alone exerted significant cytotoxic activities towards specific epithelial-type OVCAR3 and HTB75 cells, whereas the combination of γδ-T cells and pamidronate (PAM), a kind of aminobisphosphonates (NBPs), showed significantly enhanced cytotoxic activities towards all types of ovarian cancer cells in vitro. Furthermore, in tumor xenografts of immunodeficient NSG mice, γδ-T-cells not only suppressed tumor growth but also completely eradicated preexisting tumors with an initial size of ~5 mm. Thus, we concluded that γδ-T-cells alone possess dramatic cytotoxic activities towards epithelial ovarian cancers both in vitro and in vivo. These results strongly support the potential of clinical immunotherapeutic application of γδ-T-cells to treat this serious female malignancy.

scholarly journals MDL 74,968, a new acyclonucleotide analog: activity against human immunodeficiency virus in vitro and in the hu-PBL-SCID.beige mouse model of infection.

1996 ◽  
Vol 40 (5) ◽  
pp. 1072-1077 ◽  
Author(s):  
C G Bridges ◽  
D L Taylor ◽  
P S Ahmed ◽  
T M Brennan ◽  
J M Hornsperger ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Placebo Control ◽  
Intravenous Route ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Orally Bioavailable

The novel acyclonucleotide derivative of guanine, 9-[2-methylidene-3-(phosphonomethoxy)propyl] guanine (MDL 74,968), had antiviral activity comparable to those of 9-(2-phosphonomethoxyethyl) adenine (PMEA) and 2',3'-dideoxyinosine against laboratory strains of both human immunodeficiency virus (HIV) types 1 and 2 cultured in MT-4 cells and several clinical HIV isolates cultured in human peripheral blood mononuclear cells (PBMCs). MDL 74,968 was at least fourfold less toxic than PMEA to MT-4 cells or PBMCs, thereby producing a more favorable in vitro selectivity index for the former compound. Studies of acute toxicity in CD-1 mice showed that MDL 74,968 was not toxic at doses of 1,600 mg/kg of body weight via the intraperitoneal route or at doses of 500 mg/kg via the intravenous route. Furthermore, no adverse effects of MDL 74,968 were apparent when mice were treated at doses of 200 mg/kg twice daily for 5 days. Treatment by continuous subcutaneous infusion of MDL 74,968 or PMEA at the daily dose of 20 mg/kg in the hu-PBL-SCID.beige murine model of HIV infection significantly reduced the severity of infection compared with that in placebo-treated controls. Quantitation of virus recovery by endpoint titration of spleen cells in coculture with mitogen-activated PBMCs demonstrated that MDL 74,968 as well as PMEA significantly reduced the amount of virus (P < 0.02). Moreover, by using DNA extracted from spleens, the mean HIV:HLA PCR product ratio, which takes into account individual variation in immune system reconstitution, were 0.50 and 0.40 for MDL 74,968 and PMEA treatments, respectively, whereas animals receiving the placebo control had significantly higher levels of HIV proviral DNA (mean 0.78; P < 0.02). Taken together, these promising findings suggest that an orally bioavailable prodrug of MDL 74,968 should be developed for the treatment of HIV infection.

Sign in / Sign up

Export Citation Format

Share Document