HIV continues to spread globally, mainly through sexual contact. Despite advances in treatment and care, preventing transmission with vaccines or microbicides has proven difficult. A promising strategy to avoid transmission is prophylactic treatment with antiretroviral drugs before exposure to HIV. Clinical trials evaluating the efficacy of daily treatment with the reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) or Truvada (TDF plus emtricitabine) are under way. We hypothesized that intermittent prophylactic treatment with long-acting antiviral drugs would be as effective as daily dosing in blocking the earliest stages of viral replication and preventing mucosal transmission. We tested this hypothesis by intermittently giving prophylactic Truvada to macaque monkeys and then exposing them rectally to simian-human immunodeficiency virus (SHIV) once a week for 14 weeks. A simple regimen with an oral dose of Truvada given 1, 3, or 7 days before exposure followed by a second dose 2 hours after exposure was as protective as daily drug administration, possibly because of the long intracellular persistence of the drugs. In addition, a two-dose regimen initiated 2 hours before or after virus exposure was effective, and full protection was obtained by doubling the Truvada concentration in both doses. We saw no protection if the first dose was delayed until 24 hours after exposure, underscoring the importance of blocking initial replication in the mucosa. Our results show that intermittent prophylactic treatment with an antiviral drug can be highly effective in preventing SHIV infection, with a wide window of protection. They strengthen the possibility of developing feasible, cost-effective strategies to prevent HIV transmission in humans.
Preexposure prophylaxis (PrEP) with antiretroviral drugs is a novel human immunodeficiency virus (HIV) prevention strategy. It is generally thought that high systemic and mucosal drug levels are sufficient for protection. We investigated whether GS7340, a next-generation tenofovir (TFV) prodrug that effectively delivers tenofovir diphosphate (TFV-DP) to lymphoid cells and tissues, could protect macaques against repeated weekly rectal simian-human immunodeficiency virus (SHIV) exposures. Macaques received prophylactic GS7340 treatment 3 days prior to each virus exposure. At 3 days postdosing, TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) were about 50-fold higher than those seen with TFV disoproxil fumarate (TDF), and they remained above 1,000 fmol/10 6 cells for as long as 7 days. TFV-DP accumulated in lymphoid and rectal tissues, with concentrations at 3 days exceeding 500 fmol/10 6 mononuclear cells. Despite high mucosal and systemic TFV levels, GS7340 was not protective. Since TFV-DP blocks reverse transcription by competing with the natural dATP substrate, we measured dATP contents in peripheral lymphocytes, lymphoid tissue, and rectal mononuclear cells. Compared to those in circulating lymphocytes and lymphoid tissue, rectal lymphocytes had 100-fold higher dATP concentrations and dATP/TFV-DP ratios, likely reflecting the activated status of the cells and suggesting that TFV-DP may be less active at the rectal mucosa. Our results identify dATP/TFV-DP ratios as a possible correlate of protection by TFV and suggest that natural substrate concentrations at the mucosa will likely modulate the prophylactic efficacy of nucleotide reverse transcriptase inhibitors.The human immunodeficiency virus (HIV)/AIDS pandemic remains one of our greatest public health challenges. Globally, an estimated 33.2 million people were living with HIV infection or AIDS in 2007. In that year, the annual incidence of new infections was an estimated 2.7 million, and there were an estimated 2.0 million HIV-related deaths (20). The ongoing high incidence of HIV infection and the incomplete coverage of basic HIV prevention tools underscore the need for new, highly effective biomedical HIV interventions to complement existing prevention strategies.Oral administration of antiretroviral drugs prior to and during HIV exposure (preexposure prophylaxis [PrEP]) is a novel intervention to protect high-risk HIV-1-negative people from becoming infected (3, 12, 15). Drug candidates for oral PrEP have been selected from drugs currently approved for treatment of HIV-1-infected individuals. Among the drugs available, the well-established potency and tolerability of tenofovir disoproxil fumarate (TDF), the approved oral prodrug of the nucleotide analog tenofovir (TFV), makes it an attractive candidate for PrEP. A recently concluded human trial with a daily combination of TDF and emtricitabine (FTC) (Truvada) for HIV-seronegative men or transgender women who have sex with men has shown a 44% reduction in the incidence of HIV-1, giving ...
Rubella virus infection is typically diagnosed by the identification of rubella virus-specific immunoglobulinSymptomatic rubella is characterized by a mild fever and a maculopapular rash of short duration. The clinical diagnosis of rubella is unreliable, and many rash illnesses, such as those caused by measles virus and parvovirus B19, mimic rubella (2). Therefore, laboratory confirmation is essential for the diagnosis of rubella and is typically done by testing serum samples for rubella virus (RV)-specific immunoglobulin M (IgM) antibodies. Serum IgM and IgG responses to RV develop rapidly in the first few days after the onset of rash. However, approximately 50% of samples collected on the day of rash onset test negative for RV-specific IgM antibodies (1, 9, 17). Often, only a single serum sample taken near the time of rash onset is available, resulting in the lack of serologic confirmation of many rubella cases. Thus, the development of a rapid laboratory diagnostic tool for the confirmation of rubella within the first few days of symptom onset would improve the ability to confirm rubella.The isolation of virus in cell culture or the detection of viral RNA by reverse transcription-PCR (RT-PCR) also provides reliable evidence of RV infection (26). Unfortunately, blood is not a good sample for use for the detection of RV, because the highest viral titers in blood typically occur before the onset of rash and virus is undetectable in blood by 2 days after rash onset (6). The virus titer in throat swabs, however, usually reaches a peak titer on the day of rash onset and the titers in throat swabs decline more slowly than those in blood, so that virus can be detected for up to 5 to 7 days after rash onset (6). Several RT-PCR assays for the detection of the RV genome in clinical samples have been described (3,7,15,16,20,25). Templates for the determination of viral sequences for molecular epidemiology can also be made by using RT-PCR.The use of alternative specimens could help reduce the obstacles to specimen collection, storage, and transport in the field (22). Oral fluid (OF), which is collected by rubbing an absorptive device between the gum and the cheek, can be obtained by a method that is relatively noninvasive, is easier to obtain than blood, and has the advantage that it can be used for both RVspecific antibody detection and RV genome detection (12,19,20). Currently, in the United Kingdom, OF samples from notified clinically diagnosed cases are collected between 1 and 6 weeks after the onset of symptoms and are transported by mail to the Central Public Health Laboratory, where they are tested for specific antibody and viral RNA by RT-PCR. By the use of this strategy, specimens from 54.6% of rubella notifications from 1995 through 2001 were obtained for laboratory testing and specimens from 12.7% of the rubella notifications were confirmed to represent rubella cases (20,21).
Stalk lodging resistance, which is mainly measured by stem diameter (SD), stalk bending strength (SBS), and rind penetrometer resistance (RPR) in maize, seriously affects the yield and quality of maize (Zea mays L.). To dissect its genetic architecture, in this study multi-locus genome-wide association studies for stalk lodging resistance-related traits were conducted in a population of 257 inbred lines, with tropical, subtropical, and temperate backgrounds, genotyped with 48,193 high-quality single nucleotide polymorphisms. The analyses of phenotypic variations for the above traits in three environments showed high broad-sense heritability (0.679, 0.720, and 0.854, respectively). In total, 423 significant Quantitative Trait Nucleotides (QTNs) were identified by mrMLM, FASTmrEMMA, ISIS EM-BLASSO, and pLARmEB methods to be associated with the above traits. Among these QTNs, 29, 34, and 48 were commonly detected by multiple methods or across multiple environments to be related to SD, SBS, and RPR, respectively. The superior allele analyses in 30 elite lines showed that only eight lines contained more than 50% of the superior alleles, indicating that stalk lodging resistance can be improved by the integration of more superior alleles. Among sixty-three candidate genes of the consistently expressed QTNs, GRMZM5G856734 and GRMZM2G116885, encoding membrane steroid-binding protein 1 and cyclin-dependent kinase inhibitor 1, respectively, possibly inhibit cell elongation and division, which regulates lodging resistance. Our results provide the further understanding of the genetic foundation of maize lodging resistance.
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