Mahidol University

About: Mahidol University is a education organization based out in Bangkok, Nakhon Pathom, Thailand. It is known for research contribution in the topics: Population & Malaria. The organization has 23758 authors who have published 39761 publications receiving 878781 citations.

The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand.

Abstract: On the western border of Thailand, Plasmodium falciparum has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the pfmdr1 gene in 54 parasites collected from the western border of Thailand to determine the relationship of pfmdr1 copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC(50)) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; P = 0.003). Overall 35% of the isolates (19 of 54) had an increase in pfmdr1 copy number, and all 19 carried the wild-type allele at codon 86. Increased pfmdr1 copy number was associated with higher IC(50)s of mefloquine (P = 0.04) and artesunate (P = 0.005), independent of polymorphism at codon 86. The relationship between pfmdr1 and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.

Recognition determinants of broadly neutralizing human antibodies against dengue viruses

Abstract: Dengue disease is caused by four different flavivirus serotypes, which infect 390 million people yearly with 25% symptomatic cases and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3, 4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies. We recently isolated human antibodies potently neutralizing all four dengue virus serotypes. Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell, explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus.

Magnitude and Breadth of the Neutralizing Antibody Response in the RV144 and Vax003 HIV-1 Vaccine Efficacy Trials

Abstract: It is widely believed that a neutralizing antibody (NAb) response of sufficient magnitude, breadth, and duration would be highly beneficial for human immunodeficiency virus type 1 (HIV-1) vaccines [1–3]. Indeed, Nabs protect against experimental challenge with simian human immunodeficiency virus (SHIV) in nonhuman primates [4–6], and they exert strong selective pressure on HIV-1 after infection in humans [7, 8]. Neutralization occurs when antibodies bind to functional envelope glycoprotein (Env) spikes on the virus surface to prevent entry into host cells [9–11]. Each Env spike consists of 3 surface gp120 molecules bound noncovalently to 3 transmembrane gp41 molecules [12, 13]. These glycoproteins exhibit an extraordinary degree of genetic and antigenic variability that poses major challenges for vaccine development [14, 15]. Moreover, the virus uses a number of mechanisms to evade NAbs [7, 12, 16]. As a result, a minor subset of circulating variants exhibit a highly neutralization-sensitive tier 1 phenotype and are often susceptible to vaccine-elicited NAbs, whereas most circulating strains exhibit a less sensitive tier 2 phenotype and have proven difficult to target with vaccines[1, 2, 15]. A recently completed HIV-1 vaccine efficacy trial in Thailand (RV144) showed that priming with a recombinant canarypox vector (vCP1521) and boosting with this vector plus bivalent gp120 protein (AIDSVAX B/E) can provide partial protection against the acquisition of HIV-1 infection in a community-based heterosexual population [17]. The same bivalent gp120 immunogen, when used alone and with an increased number of inoculations (Vax003 trial), showed no protection in a cohort of Thai injection drug users [18]. In addition, no overall protection was seen when a similar regimen of bivalent gp120 (AIDSVAX B/B) was used alone in a cohort of mostly men who have sex with men (MSM) in North America and the Netherlands (Vax004 trial) [19]. The gp120 protein component in all 3 clinical trials was designed to elicit NAbs [20, 21]. In Vax004, strong NAb responses were seen against a subset of tier 1 viruses, and sporadic weak responses were seen against tier 2 viruses [22]. Here we assessed the magnitude and breadth of NAb responses in RV144 and Vax003.

Serotype-specific differences in the risk of dengue hemorrhagic fever: an analysis of data collected in Bangkok, Thailand from 1994 to 2006.

Abstract: Background: It is unclear whether dengue serotypes differ in their propensity to cause severe disease. We analyzed differences in serotype-specific disease severity in children presenting for medical attention in Bangkok, Thailand. Methodology/Principal Findings: Prospective studies were conducted from 1994 to 2006. Univariate and multivariate logistic and multinomial logistic regressions were used to determine if dengue hemorrhagic fever (DHF) and signs of severe clinical disease (pleural effusion, ascites, thrombocytopenia, hemoconcentration) were associated with serotype. Crude and adjusted odds ratios were calculated. There were 162 (36%) cases with DENV-1, 102 (23%) with DENV-2, 123 (27%) with DENV-3, and 64 (14%) with DENV-4. There was no significant difference in the rates of DHF by serotype: DENV-2 (43%), DENV-3 (39%), DENV-1 (34%), DENV-4 (31%). DENV-2 was significantly associated with increased odds of DHF grade I compared to DF (OR 2.9 95% CI 1.1, 8.0), when using DENV-1 as the reference. Though not statistically significant, DENV-2 had an increased odds of total DHF and DHF grades II, III, and IV. Secondary serologic response was significantly associated with DHF (OR 6.2) and increased when considering more severe grades of DHF. DENV-2 (9%) and -4 (3%) were significantly less often associated with primary disease than DENV-1 (28%) and -3 (33%). Restricting analysis to secondary cases, we found DENV-2 and DENV-3 to be twice as likely to result in DHF as DEN-4 (p=0.05). Comparing study years, we found the rate of DHF to be significantly less in 1999, 2000, 2004, and 2005 than in 1994, the study year with the highest percentage of DHF cases, even when controlling for other variables. Conclusions/Significance: As in other studies, we find secondary disease to be strongly associated with DHF and with more severe grades of DHF. DENV-2 appears to be marginally associated with more severe dengue disease as evidenced by a significant association with DHF grade I when compared to DENV-1. In addition, we found non-significant trends with other grades of DHF. Restricting the analysis to secondary disease we found DENV-2 and -3 to be twice as likely to result in DHF as DEN-4. Differences in severity by study year may suggest that other factors besides serotype play a role in disease severity.