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Background: Countries within the Greater Mekong Sub-region (GMS) of Southeast Asia have committed to eliminating malaria by 2030. Although the malaria situation has greatly improved, malaria transmission remains at international border regions. In some areas, Plasmodium vivax has become the predominant parasite. To gain a better understanding of transmission dynamics, knowledge on the changes of P. vivax populations after the scale-up of control interventions will guide more effective targeted control efforts. Methods: This study investigated genetic diversity and population structures in 206 P. vivax clinical samples collected at two time points in two international border areas: the China-Myanmar border (CMB) (n = 50 in 2004 and n = 52 in 2016) and Thailand-Myanmar border (TMB) (n = 50 in 2012 and n = 54 in 2015). Parasites were genotyped using 10 microsatellite markers. Results: Despite intensified control efforts, genetic diversity remained high (HE = 0.66–0.86) and was not significantly different among the four populations (P > 0.05). Specifically, HE slightly decreased from 0.76 in 2004 to 0.66 in 2016 at the CMB and increased from 0.80 in 2012 to 0.86 in 2015 at the TMB. The proportions of polyclonal infections varied significantly among the four populations (P < 0.05), and showed substantial decreases from 48.0% in 2004 to 23.7 at the CMB and from 40.0% in 2012 to 30.7% in 2015 at the TMB, with corresponding decreases in the multiplicity of infection. Consistent with the continuous decline of malaria incidence in the GMS over time, there were also increases in multilocus linkage disequilibrium, suggesting more fragmented and increasingly inbred parasite populations. There were considerable genetic differentiation and sub-division among the four tested populations. Temporal genetic differentiation was observed at each site (FST = 0.081 at the CMB and FST = 0.133 at the TMB). Various degrees of clustering were evident between the older parasite samples collected in 2004 at the CMB and the 2016 CMB and 2012 TMB populations, suggesting some of these parasites had shared ancestry. In contrast, the 2015 TMB population was genetically distinctive, which may reflect a process of population replacement. Whereas the effective population size (Ne) at the CMB showed a decrease from 4979 in 2004 to 3052 in 2016 with the infinite allele model, the Ne at the TMB experienced an increase from 6289 to 10,259. Conclusions: With enhanced control efforts on malaria, P. vivax at the TMB and CMB showed considerable spatial and temporal differentiation, but the presence of large P. vivax reservoirs still sustained genetic diversity and transmission. These findings provide new insights into P. vivax transmission dynamics and population structure in these border areas of the GMS. Coordinated and integrated control efforts on both sides of international borders are essential to reach the goal of regional malaria elimination. [ABSTRACT FROM AUTHOR]

Background: The malaria elimination plan of the Greater Mekong Subregion (GMS) is jeopardized by the increasing number of Plasmodium vivax infections and emergence of parasite strains with reduced susceptibility to the frontline drug treatment chloroquine/primaquine. This study aimed to determine the evolution of the P. vivax multidrug resistance 1 (Pvmdr1) gene in P. vivax parasites isolated from the China–Myanmar border area during the major phase of elimination. Methods: Clinical isolates were collected from 275 P. vivax patients in 2008, 2012–2013 and 2015 in the China–Myanmar border area and from 55 patients in central China. Comparison was made with parasites from three border regions of Thailand. Results: Overall, genetic diversity of the Pvmdr1 was relatively high in all border regions, and over the seven years in the China–Myanmar border, though slight temporal fluctuation was observed. Single nucleotide polymorphisms previously implicated in reduced chloroquine sensitivity were detected. In particular, M908L approached fixation in the China–Myanmar border area. The Y976F mutation sharply decreased from 18.5% in 2008 to 1.5% in 2012–2013 and disappeared in 2015, whereas F1076L steadily increased from 33.3% in 2008 to 77.8% in 2015. While neutrality tests suggested the action of purifying selection on the pvmdr1 gene, several likelihood-based algorithms detected positive as well as purifying selections operating on specific amino acids including M908L, T958M and F1076L. Fixation and selection of the nonsynonymous mutations are differently distributed across the three border regions and central China. Comparison with the global P. vivax populations clearly indicated clustering of haplotypes according to geographic locations. It is noteworthy that the temperate-zone parasites from central China were completely separated from the parasites from other parts of the GMS. Conclusions: This study showed that P. vivax populations in the China–Myanmar border has experienced major changes in the Pvmdr1 residues proposed to be associated with chloroquine resistance, suggesting that drug selection may play an important role in the evolution of this gene in the parasite populations. [ABSTRACT FROM AUTHOR]

HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and antiretroviral therapies (ART). Since stavudine was removed from recommended treatment schedules, the prevalence of HIV-SN has declined and associated risk factors have changed. With stavudine, rs1799964*C (TNF-1031) associated with HIV-SN in Caucasians and Indonesians but not in South Africans. Here, we investigate associations between HIV-SN and rs1799964*C and 12 other polymorphisms spanning TNF and seven neighboring genes (the TNF-block) in Indonesians (n = 202; 34/168 cases) and South Africans (n = 75; 29/75 cases) treated without stavudine. Haplotypes were derived using fastPHASE and haplotype networks built with PopART. There were no associations with rs1799964*C in either population. However, rs9281523*C in intron 10 of BAT1 (alternatively DDX39B) independently associated with HIV-SN in Indonesians after correcting for lower CD4 T-cell counts and >500 copies of HIV RNA/mL (model p = 0.0011, Pseudo R² = 0.09). rs4947324*T (between NFKBIL1 and LTA) independently associated with reduced risk of HIV-SN and shared haplotype 1 (containing no minor alleles) associated with increased risk of HIV-SN after correcting for greater body weight, a history of tuberculosis and nadir CD4 T-cell counts (model: p = 0.0003, Pseudo R² = 0.22). These results confirm TNF-block genotypes influence susceptibility of HIV-SN. However, critical genotypes differ between ethnicities and with stavudine use. [ABSTRACT FROM AUTHOR]

The malaria parasite Plasmodium vivax is known to be majorly endemic to Asian and Latin American countries with no or very few reports of Africans infected with this parasite. Since the human Duffy antigens act as receptors for P. vivax to invade human RBCs and Africans are generally Duffy-negative, non-endemicity of P. vivax in Africa has been attributed to this fact. However, recent reports describing P. vivax infections in Duffy-negative Africans from West and Central parts of Africa have been surfaced including a recent report on P. vivax infection in native Cameroonians. In order to know if Cameroonians living in the southern regions are also susceptible to P. vivax infection, we collected finger-prick blood samples from 485 malarial symptomatic patients in five locations and followed PCR diagnostic assays with DNA sequencing of the 18S ribosomal RNA gene. Out of the 201 malaria positive cases detected, 193 were pure P. falciparum, six pure P. vivax and two mixed parasite infections (P. falciparum + P. vivax). The eight P. vivax infected samples (six single + two mixed) were further subjected to DNA sequencing of the P. vivax multidrug resistance 1 (pvmdr1) and the P.vivax circumsporozoite (pvcsp) genes. Alignment of the eight Cameroonian pvmdr1 sequences with the reference sequence showed high sequence similarities, reconfirming P. vivax infection in all the eight patients. DNA sequencing of the pvcsp gene indicated all the eight P. vivax to be of VK247 type. Interestingly, DNA sequencing of a part of the human Duffy gene covering the promoter region in the eight P. vivax-infected Cameroonians to identify the T-33C mutation revealed all these patients as Duffy-negative. The results provide evidence of single P. vivax as well as mixed malaria parasite infection in native Cameroonians and add knowledge to the growing evidences of P. vivax infection in Duffy-negative Africans. [ABSTRACT FROM AUTHOR]

Objectives The main objective of this study was to unravel the distribution of different Pfcrt genotypes in the central, littoral, eastern and southern regions of Cameroon and also in locations bordering Gabon and Equatorial Guinea. This is because (i) the chloroquine-resistant malaria parasite Plasmodium falciparum shows a wide occurrence in Cameroon, (ii) mutations in the 72nd to 76th amino acid positions of the Pfcrt gene are known to confer resistance to chloroquine, and (iii) only a single chloroquine-resistant haplotype (C72V73I74E75T76) has so far been reported in Cameroon. Methods We followed a molecular approach with DNA sequencing of the second exon of the Pfcrt gene to identify single nucleotide polymorphisms in 180 P. falciparum field isolates sampled in five different locations in Cameroon. Results The chloroquine-resistant Pfcrt CVIET haplotype was most abundant, followed by the wild-type CVMNK haplotype. Five hitherto unreported chloroquine-resistant Pfcrt haplotypes were detected for the first time in Cameroonian P. falciparum, including the surprise appearance of the S(agt)VMNT haplotype. Conclusions The high observed haplotype diversity of the chloroquine-resistant Pfcrt gene and the appearance of the S(agt)VMNT haplotype are daunting and can be attributed to drug pressure and/or the misuse of chloroquine and/or amodiaquine in Cameroon. [ABSTRACT FROM PUBLISHER]