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1.  A Single Dose of a MIV-150/Zinc Acetate Gel Provides 24 h of Protection Against Vaginal Simian Human Immunodeficiency Virus Reverse Transcriptase Infection, with More Limited Protection Rectally 8–24 h After Gel Use 
AIDS Research and Human Retroviruses  2012;28(11):1476-1484.
Previously we showed that repeated vaginal application of a MIV-150/zinc acetate carrageenan (MIV-150/ZA/CG) gel and a zinc acetate carrageenan (ZA/CG) gel significantly protected macaques from vaginal simian human immunodeficiency virus reverse transcriptase (SHIV-RT) infection. Gels were applied either daily for 2 weeks or every other day for 4 weeks, and the animals were challenged 4–24 h later. Herein, we examined the effects of a single vaginal dose administered either before or after virus challenge. Encouraged by the vaginal protection seen with MIV-150/ZA/CG, we also tested it rectally. Vaginal applications of MIV-150/ZA/CG, ZA/CG, and CG gel were performed once 8–24 h before, 1 h after, or 24 h before and 1 h after vaginal challenge. Rectal applications of MIV-150/ZA/CG and CG gel were performed once 8 or 24 h before rectal challenge. While vaginal pre-challenge and pre/post-challenge application of MIV-150/ZA/CG gel offered significant protection (88%, p<0.002), post-challenge application alone did not significantly protect. ZA/CG gel reduced infection prechallenge, but not significantly, and the effect was completely lost post-challenge. Rectal application of MIV-150/ZA/CG gel afforded limited protection against rectal challenge when applied 8–24 h before challenge. Thus, MIV-150/ZA/CG gel is a highly effective vaginal microbicide that demonstrates 24 h of protection from vaginal infection and may demonstrate efficacy against rectal infection when given close to the time of HIV exposure.
PMCID: PMC3484818  PMID: 22737981
2.  The Nonnucleoside Reverse Transcription Inhibitor MIV-160 Delivered from an Intravaginal Ring, But Not from a Carrageenan Gel, Protects Against Simian/Human Immunodeficiency Virus-RT Infection 
AIDS Research and Human Retroviruses  2012;28(11):1467-1475.
We previously showed that a carrageenan (CG) gel containing 50 μM MIV-150 (MIV-150/CG) reduced vaginal simian/human immunodeficiency virus (SHIV)-RT infection of macaques (56%, p>0.05) when administered daily for 2 weeks with the last dose given 8 h before challenge. Additionally, when 100 mg of MIV-150 was loaded into an intravaginal ring (IVR) inserted 24 h before challenge and removed 2 weeks after challenge, >80% protection was observed (p<0.03). MIV-160 is a related NNRTI with a similar IC50, greater aqueous solubility, and a shorter synthesis. To objectively compare MIV-160 with MIV-150, herein we evaluated the antiviral effects of unformulated MIV-160 in vitro as well as the in vivo protection afforded by MIV-160 delivered in CG (MIV-160/CG gel) and in an IVR under regimens used with MIV-150 in earlier studies. Like MIV-150, MIV-160 exhibited potent antiviral activity against SHIV-RT in macaque vaginal explants. However, formulated MIV-160 exhibited divergent effects in vivo. The MIV-160/CG gel offered no protection compared to CG alone, whereas the MIV-160 IVRs protected significantly. Importantly, the results of in vitro release studies of the MIV-160/CG gel and the MIV-160 IVR suggested that in vivo efficacy paralleled the amount of MIV-160 released in vitro. Hundreds of micrograms of MIV-160 were released daily from IVRs while undetectable amounts of MIV-160 were released from the CG gel. Our findings highlight the importance of testing different modalities of microbicide delivery to identify the optimal formulation for efficacy in vivo.
PMCID: PMC3484820  PMID: 22816564
3.  An Antiretroviral/Zinc Combination Gel Provides 24 Hours of Complete Protection against Vaginal SHIV Infection in Macaques 
PLoS ONE  2011;6(1):e15835.
Repeated use, coitus-independent microbicide gels that do not contain antiretroviral agents also used as first line HIV therapy are urgently needed to curb HIV spread. Current formulations require high doses (millimolar range) of antiretroviral drugs and typically only provide short-term protection in macaques. We used the macaque model to test the efficacy of a novel combination microbicide gel containing zinc acetate and micromolar doses of the novel non-nucleoside reverse transcriptase inhibitor MIV-150 for up to 24 h after repeated gel application.
Methods and Findings
Rhesus macaques were vaginally challenged with SHIV-RT up to 24 h after repeated administration of microbicide versus placebo gels. Infection status was determined by measuring virologic and immunologic parameters. Combination microbicide gels containing 14 mM zinc acetate dihydrate and 50 µM MIV-150 afforded full protection (21 of 21 animals) for up to 24 h after 2 weeks of daily application. Partial protection was achieved with the MIV-150 gel (56% of control at 8 h after last application, 11% at 24 h), while the zinc acetate gel afforded more pronounced protection (67% at 8–24 h). Marked protection persisted when the zinc acetate or MIV-150/zinc acetate gels were applied every other day for 4 weeks prior to challenge 24 h after the last gel was administered (11 of 14 protected). More MIV-150 was associated with cervical tissue 8 h after daily dosing of MIV-150/zinc acetate versus MIV-150, while comparable MIV-150 levels were associated with vaginal tissues and at 24 h.
A combination MIV-150/zinc acetate gel and a zinc acetate gel provide significant protection against SHIV-RT infection for up to 24 h. This represents a novel advancement, identifying microbicides that do not contain anti-viral agents used to treat HIV infection and which can be used repeatedly and independently of coitus, and underscores the need for future clinical testing of their safety and ability to prevent HIV transmission in humans.
PMCID: PMC3016413  PMID: 21246052
4.  Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G▿ †  
Journal of Virology  2008;83(2):884-895.
Human immunodeficiency virus (HIV) is taken up by and replicates in immature dendritic cells (imDCs), which can then transfer virus to T cells, amplifying the infection. Strategies known to boost DC function were tested for their ability to overcome this exploitation when added after HIV exposure. Poly(I:C), but not single-stranded RNA (ssRNA) or a standard DC maturation cocktail, elicited type I interferon (IFN) and interleukin-12 (IL-12) p70 production and the appearance of unique small (15- to 20-kDa) fragments of APOBEC3G (A3G) and impeded HIVBal replication in imDCs when added up to 60 h after virus exposure. Comparable effects were mediated by recombinant alpha/beta IFN (IFN-α/β). Neutralizing the anti-IFN-α/β receptor reversed poly(I:C)-induced inhibition of HIV replication and blocked the appearance of the small A3G proteins. The poly(I:C)-induced appearance of small A3G proteins was not accompanied by significant differences in A3G mRNA or A3G monomer expression. Small interfering RNA (siRNA) knockdown of A3G could not be used to reverse the poly(I:C)-induced protective effect, since siRNAs nonspecifically activated the DCs, inducing the appearance of the small A3G proteins and inhibiting HIV infection. Notably, the appearance of small A3G proteins coincided with the shift of high-molecular-mass inactive A3G complexes to the low-molecular-mass (LMM) active A3G complexes. The unique immune stimulation by poly(I:C) with its antiviral effects on imDCs marked by the expression of IFN-α/β and active LMM A3G renders poly(I:C) a promising novel strategy to combat early HIV infection in vivo.
PMCID: PMC2612396  PMID: 19004943
5.  Health Services Research as a Source of Legislative Analysis and Input: The Role of the California Health Benefits Review Program 
Health Services Research  2006;41(3 Pt 2):1124-1158.
This article examines the role of the California Health Benefits Review Program (CHBRP) as a source of information in state health policy making. It explains why the California benefits review process relies heavily on university-based researchers and employs a broad set of criteria for review, which set it apart from similar programs in other states. It then analyzes the politics of health insurance mandates and how independent research and analysis might alter the perceived benefits and costs of health insurance mandates and thus political outcomes. It considers how research and analysis is typically used by policy makers, and illustrates how participants inside and outside of state government have used the reports prepared by CHBRP as both guidance in policy design and as political ammunition. Although there is consensus that the review process has reduced the number of mandate bills that are passed out of the legislature, both supporters and opponents favor the new process and generally believe the reports strengthen their case in legislative debates over health insurance mandates. The role of the CHBRP is narrowly defined by statute at the present time, but the program may well face pressure to evolve from its current academic orientation into a more interactive, advisory role for legislators in the future.
PMCID: PMC1713221  PMID: 16704675
State health policy; health insurance; politics; legislative decision making

Results 1-5 (5)