Greater CD4 increases from 12 weeks with nevirapine could have caused more serious immune reconstitution inflammatory syndrome (IRIS) [20]. However, week 4 and 12 viral load

changes were similar in the two groups, and the clinical events diagnosed were not predominantly IRIS-type events. Furthermore, there was no clear association between developing clinical events and rapidity of viral load changes, nor did the difference between nevirapine and abacavir vary with pre-ART CD4 cell count, both strong predictors of IRIS [21,22], nor was there evidence that the differences between groups were restricted to the first 6 months on ART when IRIS events would be likely to predominate. Emergence of HIV resistance mutations is described separately [5] but, given that higher viral load suppression was substantially and significantly greater in the nevirapine group, it is unclear how any find more differences in resistance accumulation Z-VAD-FMK concentration or the relative fitness cost of NNRTI and NRTI mutations could have increased overall disease progression relative to the abacavir group. If suboptimal virological potency of abacavir was driving results, either

more ART modifications or more clinical events (or both) would be expected in the abacavir group – neither was observed. While patients initiating ART with advanced HIV disease and low CD4 cell counts may be at higher risk of opportunistic infections, it is unclear why their risk would be greater on nevirapine- than abacavir-containing regimens. Furthermore, we found no evidence to suggest that absolute levels of CD4 and HIV RNA had different prognostic values for clinical outcomes in the nevirapine and abacavir groups, Chloroambucil and after adjustment for time-updated CD4 cell count, haemoglobin and weight, differences between randomized groups were similar to those obtained in unadjusted analyses. Without stored cells, we are unable to explore whether the quality rather than the quantity of CD4 immune restoration differed between the abacavir and nevirapine groups. The only published data appear to be

those of a small study in children simplifying from boosted protease inhibitor to triple NRTI therapy, which demonstrated increased functionality [23]; whether this would be similar in ART-naïve adults in NORA is unclear. Nevertheless, our findings highlight the importance of close follow-up and high-quality clinical management (including primary and secondary prophylaxis/treatment for opportunistic infections) for patients initiating ART with advanced disease. The timescale for changes in prognostic markers to influence clinical outcome could differ; i.e. inferior 48-week immunological/virological response in the abacavir group might lead to poorer clinical outcome only later on. We noted a trend towards superior weight gain with nevirapine at 48 weeks but not before; and a nonsignificant (P=0.

Greater CD4 increases from 12 weeks with nevirapine could have caused more serious immune reconstitution inflammatory syndrome (IRIS) [20]. However, week 4 and 12 viral load

changes were similar in the two groups, and the clinical events diagnosed were not predominantly IRIS-type events. Furthermore, there was no clear association between developing clinical events and rapidity of viral load changes, nor did the difference between nevirapine and abacavir vary with pre-ART CD4 cell count, both strong predictors of IRIS [21,22], nor was there evidence that the differences between groups were restricted to the first 6 months on ART when IRIS events would be likely to predominate. Emergence of HIV resistance mutations is described separately [5] but, given that higher viral load suppression was substantially and significantly greater in the nevirapine group, it is unclear how any Inhibitor Library manufacturer differences in resistance accumulation Selleckchem CT99021 or the relative fitness cost of NNRTI and NRTI mutations could have increased overall disease progression relative to the abacavir group. If suboptimal virological potency of abacavir was driving results, either

more ART modifications or more clinical events (or both) would be expected in the abacavir group – neither was observed. While patients initiating ART with advanced HIV disease and low CD4 cell counts may be at higher risk of opportunistic infections, it is unclear why their risk would be greater on nevirapine- than abacavir-containing regimens. Furthermore, we found no evidence to suggest that absolute levels of CD4 and HIV RNA had different prognostic values for clinical outcomes in the nevirapine and abacavir groups, tuclazepam and after adjustment for time-updated CD4 cell count, haemoglobin and weight, differences between randomized groups were similar to those obtained in unadjusted analyses. Without stored cells, we are unable to explore whether the quality rather than the quantity of CD4 immune restoration differed between the abacavir and nevirapine groups. The only published data appear to be

those of a small study in children simplifying from boosted protease inhibitor to triple NRTI therapy, which demonstrated increased functionality [23]; whether this would be similar in ART-naïve adults in NORA is unclear. Nevertheless, our findings highlight the importance of close follow-up and high-quality clinical management (including primary and secondary prophylaxis/treatment for opportunistic infections) for patients initiating ART with advanced disease. The timescale for changes in prognostic markers to influence clinical outcome could differ; i.e. inferior 48-week immunological/virological response in the abacavir group might lead to poorer clinical outcome only later on. We noted a trend towards superior weight gain with nevirapine at 48 weeks but not before; and a nonsignificant (P=0.

Instead, other members of the Proteobacteria, known for hosting many known hydrocarbon degraders (Widdel & Rabus, 2001), were identified (Fig. S2 in Appendix S1). One sequence was closely related to a clone identified at the Gullfaks and Tommeliten oil field methane seeps of the North Sea (Wegener et al., 2008). AOM rates were determined to assess potential methane losses

during incubation time. These rates were selleck chemical in good agreement with those observed typically in methane-fed environments (Knittel & Boetius, 2009). However, methane seepage was apparently not the major energy source of Zeebrugge sediments. Therefore, in situ AOM possibly depended on hydrocarbon-derived methane, as indicated by the growth of the AOM community in hexadecane-amended microcosms (Fig. 5). Based on the methane partial pressure-dependent and cell-specific AOM rate constant reported by Thauer & Shima (2008), we calculated a loss of no more than 12% of the produced methane in hydrocarbon-amended microcosms. To fully exploit exhausted oil reservoirs, the conversion of residual oil to methane seems to be a viable technique to recover energy that would otherwise be lost. As a possible contribution for this application, our experiments demonstrated that additional sulfate or trivalent iron accelerated methanogenesis in aliphatic and

aromatic hydrocarbon (e.g. BTEX)-degrading communities. In contrast, the inhibitory effect selleck kinase inhibitor of nitrate, commonly used to suppress sulfate reducers in oil fields, most likely prohibits its application for oil recovery as methane. Additionally, we present convincing evidence for the conversion of a PAH to methane. Consequently, our results also provide novel insights for bioremediation, where the conversion of hydrocarbon contaminants to

volatile methane PRKACG seems to be an option. Nevertheless, methane is a much more potent greenhouse gas than CO2. Therefore, the addition of high amounts of nitrate or sulfate may be preferred to stimulate biodegradation when methanogenesis is unwanted and oxygen treatment is impossible. Funding was partially provided by the Deutsche Forschungsgemeinschaft (grants KR 3311/5-1 & 6-1), the Bundesministerium für Bildung und Forschung (grant 03G0189A), the Landesanstalt für Altlastenfreistellung Magdeburg and the Flemish Environmental and Technology Innovation Platform (MIP, project ‘In situ conditioning of dredged and mineral sludge’). We thank Dr Axel Schippers for fruitful discussions and for improving the manuscript. Appendix S1. Eckernförde Bay. Please note: Wiley-Blackwell is not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. “
“Listeria monocytogenes is a food-borne pathogen that causes severe opportunistic infection in humans and animals.

Instead, other members of the Proteobacteria, known for hosting many known hydrocarbon degraders (Widdel & Rabus, 2001), were identified (Fig. S2 in Appendix S1). One sequence was closely related to a clone identified at the Gullfaks and Tommeliten oil field methane seeps of the North Sea (Wegener et al., 2008). AOM rates were determined to assess potential methane losses

during incubation time. These rates were CX 5461 in good agreement with those observed typically in methane-fed environments (Knittel & Boetius, 2009). However, methane seepage was apparently not the major energy source of Zeebrugge sediments. Therefore, in situ AOM possibly depended on hydrocarbon-derived methane, as indicated by the growth of the AOM community in hexadecane-amended microcosms (Fig. 5). Based on the methane partial pressure-dependent and cell-specific AOM rate constant reported by Thauer & Shima (2008), we calculated a loss of no more than 12% of the produced methane in hydrocarbon-amended microcosms. To fully exploit exhausted oil reservoirs, the conversion of residual oil to methane seems to be a viable technique to recover energy that would otherwise be lost. As a possible contribution for this application, our experiments demonstrated that additional sulfate or trivalent iron accelerated methanogenesis in aliphatic and

aromatic hydrocarbon (e.g. BTEX)-degrading communities. In contrast, the inhibitory effect learn more of nitrate, commonly used to suppress sulfate reducers in oil fields, most likely prohibits its application for oil recovery as methane. Additionally, we present convincing evidence for the conversion of a PAH to methane. Consequently, our results also provide novel insights for bioremediation, where the conversion of hydrocarbon contaminants to

volatile methane Fludarabine purchase seems to be an option. Nevertheless, methane is a much more potent greenhouse gas than CO2. Therefore, the addition of high amounts of nitrate or sulfate may be preferred to stimulate biodegradation when methanogenesis is unwanted and oxygen treatment is impossible. Funding was partially provided by the Deutsche Forschungsgemeinschaft (grants KR 3311/5-1 & 6-1), the Bundesministerium für Bildung und Forschung (grant 03G0189A), the Landesanstalt für Altlastenfreistellung Magdeburg and the Flemish Environmental and Technology Innovation Platform (MIP, project ‘In situ conditioning of dredged and mineral sludge’). We thank Dr Axel Schippers for fruitful discussions and for improving the manuscript. Appendix S1. Eckernförde Bay. Please note: Wiley-Blackwell is not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. “
“Listeria monocytogenes is a food-borne pathogen that causes severe opportunistic infection in humans and animals.

The cells for SEM observation were critical-point dried and applied to a silicon wafer slide. The cells were then examined using a JSM-6360 scanning electron microscope (JEOL) (Qu et al., 2008). The cells (grown at 42 °C for 144 h) for TEM observation were embedded in the Epon 812 embedding kit and cut into ultrathin sections. The sections were double-stained with uranyl acetate and lead nitrate and then examined using a JEM-2000EX TEM (JEOL). The lipopolysaccharides

prepared from MV501 (pYJ), MV501 (pYJ-1), MV501 (pYJ-2) and MV501 (pUC18) cells were analyzed by SDS-PAGE, followed by silver staining (Fig. 2). The lipopolysaccharides from MV501 (pYJ), MV501 (pYJ-1) and MV501 (pYJ-2) cells showed a ladder-like banding pattern selleck compound characteristic of O side-chain material. The results suggested that Rv1302 and MSMEG_4947 have the same function as E. coli WecA and both Rv1302 and MSMEG_4947 utilize C55-P and UDP-GlcNAc as substrates to buy NVP-LDE225 initiate the synthesis of the O7 polysaccharide that is covalently linked to the lipid A-core oligosaccharide of E. coli O7:K1 strain VW187 (Valvano & Crosa, 1989). The MSMEG_4947 in conditional replication plasmid pYJ-4 was disrupted by inserting a kanR cassette.

A two-step homologous recombination procedure (Li et al., 2006) was used to achieve the allelic replacement of the MSMEG_4947 gene by MSMEG_4947∷kanR. MSMEG_4947 (406 amino acids) shares 79% identity with Rv1302 (404 amino acids); therefore, the rescue plasmid pYJ-6 carrying Rv1302 was constructed for complementation studies. The MSMEG_4947 knockout mutant was confirmed by a Southern blot Sinomenine using MSMEG_4947 as a probe (Fig. 3). The growth of five MSMEG_4947 knockout mutants (nos 1–5) was investigated at both 30 and 42 °C. All five MSMEG_4947 knockout mutants had similar growth patterns and the growth curve of no. 2 mutant is shown in Fig. 4a. The results clearly showed that the MSMEG_4947 knockout mutant grew only at 30 °C and not at 42 °C. The rescue plasmid pYJ-6 was unable to replicate at 42 °C and, therefore, no more Rv1302 protein was generated. In contrast, wild-type mc2155 containing

pCG76 grew at both 30 and 42 °C, confirming that MSMEG_4947 was essential for the growth of M. smegmatis. To investigate whether a decrease in WecA has effects on the morphology of the MSMEG_4947 knockout mutant, a certain amount of cells was acquired by performing a temperature shift experiment. The MSMEG_4947 knockout mutant (no. 2) was grown at 30 °C for 24 h to produce Rv1302 protein, and then grown at 42 °C. A600 nm was measured at 24-h intervals (Fig. 4b) and the cells were harvested for observation of the morphological phenotype (Fig. 5). MSMEG_4947 knockout cells grown at 30 °C for 72 (Fig. 5a) and 144 h (Fig. 5c) had a smooth cell surface and exhibited the normal rod-like shape seen in the wild-type mc2155 cells (Qu et al., 2008).

This research was supported Dasatinib supplier by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0003256). “
“Both ThyA and ThyX proteins catalyze the transfer of the methyl group from methylenetetrahydrofolate (CH2H4-folate) to dUMP, forming dTMP. To estimate the relative steady state expression levels of ThyA and ThyX, Western blot analysis was performed using ThyA or ThyX antiserum on total protein from the wild-type, ΔthyX, and thyX-complemented strains of Corynebacterium glutamicum.

The level of ThyA decreased gradually during the stationary growth phase but that of ThyX was maintained steadily. Whereas the expression level of ThyA in a ΔsigB strain was comparable to that of the wild-type,

the level of ThyX was significantly diminished in the deletion mutant and was restored to that of the wild-type in the complemented strain, indicating that the level of ThyX was regulated by SigB. Growth of the C. glutamicum ΔsigB strain was dependent upon coupling activity of dihydrofolate reductase (DHFR) with ThyA for the synthesis of thymidine, and thus showed sensitivity to the inhibition of DHFR by the experimental inhibitor, WR99210-HCl. These results suggested that the relative levels of ThyA and ThyX differ in response to different growth phases and that SigB is necessary for maintenance Vorinostat solubility dmso of the level of ThyX during transition into the stationary growth phase. dTMP is a key metabolite required for the biosynthesis of dTTP, a building block of DNA. The enzymes thymidylate synthase ThyA (EC 2.1.1.45) and ThyX (EC 2.1.1.148) can each catalyze the de novo formation

of dTMP in vivo. Both ThyA and ThyX proteins catalyze Resveratrol the transfer of the methyl group from CH2H4-folate to dUMP, forming dTMP. The homodimeric ThyA protein carries out reductive methylation of dUMP, using CH2H4-folate as a reductant and the source of a methylene group, generating dTMP and dihydrofolate (H2-folate). As reduced folates are essential for many biochemical processes, H2-folate is reduced to tetrahydrofolate (H4-folate) by dihydrofolate reductase (DHFR) with subsequent regeneration of CH2H4-folate, catalyzed by serine hydroxymethyltransferase. In contrast, the homotetrameric ThyX protein utilizes CH2H4-folate solely as a one-carbon donor and uses Flavin Adenine Dinucleotide (FAD)-mediated hydride transfer for the reduction of the methylene to form dTMP and H4-folate (Giladi et al., 2002; Graziani et al., 2004; Griffin et al., 2005; Koehn et al., 2009; Leduc et al., 2003, 2007; Liu & Yang, 2004; Myllykallio et al., 2002, 2003; Sampathkumar et al., 2005; Zhong et al., 2006). Corynebacterium glutamicum ATCC 13032 is a non-sporulating and non-pathogenic soil bacterium belonging to the group of high G + C Gram-positive Actinobacteria (Hecht & Causey, 1976; Stackebrandt et al., 1997). A blast search has revealed that C.

This research was supported Alectinib by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0003256). “
“Both ThyA and ThyX proteins catalyze the transfer of the methyl group from methylenetetrahydrofolate (CH2H4-folate) to dUMP, forming dTMP. To estimate the relative steady state expression levels of ThyA and ThyX, Western blot analysis was performed using ThyA or ThyX antiserum on total protein from the wild-type, ΔthyX, and thyX-complemented strains of Corynebacterium glutamicum.

The level of ThyA decreased gradually during the stationary growth phase but that of ThyX was maintained steadily. Whereas the expression level of ThyA in a ΔsigB strain was comparable to that of the wild-type,

the level of ThyX was significantly diminished in the deletion mutant and was restored to that of the wild-type in the complemented strain, indicating that the level of ThyX was regulated by SigB. Growth of the C. glutamicum ΔsigB strain was dependent upon coupling activity of dihydrofolate reductase (DHFR) with ThyA for the synthesis of thymidine, and thus showed sensitivity to the inhibition of DHFR by the experimental inhibitor, WR99210-HCl. These results suggested that the relative levels of ThyA and ThyX differ in response to different growth phases and that SigB is necessary for maintenance http://www.selleckchem.com/products/U0126.html of the level of ThyX during transition into the stationary growth phase. dTMP is a key metabolite required for the biosynthesis of dTTP, a building block of DNA. The enzymes thymidylate synthase ThyA (EC 2.1.1.45) and ThyX (EC 2.1.1.148) can each catalyze the de novo formation

of dTMP in vivo. Both ThyA and ThyX proteins catalyze Dapagliflozin the transfer of the methyl group from CH2H4-folate to dUMP, forming dTMP. The homodimeric ThyA protein carries out reductive methylation of dUMP, using CH2H4-folate as a reductant and the source of a methylene group, generating dTMP and dihydrofolate (H2-folate). As reduced folates are essential for many biochemical processes, H2-folate is reduced to tetrahydrofolate (H4-folate) by dihydrofolate reductase (DHFR) with subsequent regeneration of CH2H4-folate, catalyzed by serine hydroxymethyltransferase. In contrast, the homotetrameric ThyX protein utilizes CH2H4-folate solely as a one-carbon donor and uses Flavin Adenine Dinucleotide (FAD)-mediated hydride transfer for the reduction of the methylene to form dTMP and H4-folate (Giladi et al., 2002; Graziani et al., 2004; Griffin et al., 2005; Koehn et al., 2009; Leduc et al., 2003, 2007; Liu & Yang, 2004; Myllykallio et al., 2002, 2003; Sampathkumar et al., 2005; Zhong et al., 2006). Corynebacterium glutamicum ATCC 13032 is a non-sporulating and non-pathogenic soil bacterium belonging to the group of high G + C Gram-positive Actinobacteria (Hecht & Causey, 1976; Stackebrandt et al., 1997). A blast search has revealed that C.

“
“Streptococcal histidine triad protein was identified recently as a cell surface-associated protein family. Five members of this family (PhtA, PhtB, PhtD, PhtE and HtpA), derived from Streptococcus pneumoniae and Streptococcus pyogenes, have been shown as antigens that confer protection to the host on infection. In this report, a gene sequence highly homologous to htpA and phtD (designated htpS, the histidine triad protein of Streptococcus suis) was identified from S. suis 2 Chinese strain 05ZYH33. Our data revealed that htpS is extremely conserved in S. suis 2 and widely distributed in 83% (29/35)

of 35 S. suis serotypes. It was also demonstrated by Western blot and flow cytometry that HtpS is a cell surface-associated protein that was expressed during S. suis 2 infection. An antibody against HtpS could increase the deposition of human find more complement 3 on S. suis 2 and also enhance the clearance of S. suis 2 in whole blood. In addition, www.selleckchem.com/products/AG-014699.html mice could be immunized against S. suis 2 infection and were well protected after immunization with recombinant HtpS.

Streptococcus suis is an important Gram-positive pathogenic bacterium that can infect piglets and cause many serious diseases such as arthritis, meningitis and septicemia (Lun et al., 2007). It is also an important zoonotic agent for individuals who are in contact with infected swine or healthy carriers (Wertheim et al., 2009). To date, 35 serotypes (types 1/2 and 1–34) of S. suis have been described. Streptococcus suis serotype 2 (S. suis 2) is the most frequently isolated and associated with disease (Higgins & Gottschalk, 1995; Messier et al., 2008). Two outbreaks of severe human S. suis 2 infections in China were characterized by streptococcal toxic shock syndrome in 1998 and 2005, which caused mortality of up to 62.7% and 81.3%, respectively (Tang et al., 2006). This suggested that the prevention and Sulfite dehydrogenase control of the S. suis 2 infection has become an urgent task in such a grim situation. However, effective control of S. suis 2 infection

was lacking due to the absence of safe and effective vaccines (Haesebrouck et al., 2004). It is well recognized that sequence-conserved, surface-exposed bacterial proteins could be considered as vaccine candidates for subunit vaccine development (Etz et al., 2002; Hamel et al., 2004; Timoney et al., 2007). Based on the sequencing of two virulent S. suis 2 genomes (Chen et al., 2007), a collection of structural and enzymatic proteins that are associated with the bacterial cell wall have been identified from the highly pathogenic isolates (Feng et al., 2007, 2009; Li et al., 2007; Esgleas et al., 2008; Ge et al., 2009; Wang et al., 2009; Zhang et al., 2009). Recently, a study of the divalent-cation-regulated cell surface-associated proteins of S. suis 2 identified several immunogenic proteins in the adcR mutation of S.

, 2009). Four additional MtrB homologs were subsequently identified in the GKT137831 chemical structure MtrAB modules of Fe(II)-oxidizing α- and β-proteobacteria (Shi et al., 2012a, b). The rapid expansion of sequenced bacterial genomes has resulted in a sharp increase in the number of proteins displaying similarity to S. oneidensis MtrB. As of July 2013, the list of MtrB homologs identified outside the Shewanella genus numbered 52 (Table S3, Fig. S3), including one each from the phyla Acidobacteria and

NC10 group, and 50 from the α-, β-, γ-, and δ-proteobacteria. The 52 MtrB homologs facilitated amino acid sequence analysis of MtrB homologs in bacteria that cross phylogenetic and phenotypic lines, including metal- and nonmetal-reducing strains. Literature searches were conducted to determine the dissimilatory metal reduction capability of the host strains harboring each of the 52 MtrB homologs (Table S3). Correlations

between the similarity of the 52 MtrB homologs and the ability of the corresponding host strains to catalyze dissimilatory metal reduction were not observed. The 52 MtrB homologs found outside the Shewanella genus were subsequently ranked according to e-value, ranging from the MtrB homolog of the metal-reducing γ-proteobacterium Ferrimonas balearica (e-value of 7.00e-145) to the MtrB homolog of the metal-reducing δ-proteobacterium Geobacter metallireducens (e-value of 0.28). clustalw analyses of the 52 MtrB homologs (Table S3) indicated that Fossariinae N-terminal length varied from 4 to 132 this website amino acids,

while the number of C-terminal β-sheets varied from 22 to 32 sheets. MtrB homologs of the γ-proteobacteria Ferrimonas, Aeromonas, and Vibrio were represented in 20 of the top 21 MtrB homologs, and each of the 20 Ferrimonas, Aeromonas, and Vibrio homologs contained an N-terminal CXXC motif (Fig. 1, Table S3). The threshold e-value for MtrB homologs containing an N-terminal CXXC motif was 4.00e-43 displayed by the MtrB homolog of V. vulnificus YJ016. Ferrimonas and Aeromonas species are facultatively anaerobic γ-proteobacteria capable of dissimilatory metal reduction (Knight & Blakemore, 1998; Martin-Carnahan & Joseph, 2005; Nolan et al., 2010), while Vibrio species have not been previously examined for dissimilatory metal reduction activity. Of the top 21 MtrB homologs, only the MtrB homolog of the γ-proteobacterium Nitrosococcus halophilus Tc4 lacked an N-terminal CXXC motif (Table S3). N. halophilus Tc4 is a nitrifying chemolithotroph that obligately respires oxygen as terminal electron acceptor (Campbell et al., 2011). These results indicate that N-terminal CXXC motifs are found in MtrB homologs of γ-proteobacteria capable of dissimilatory metal reduction, while N-terminal CXXC motifs are missing from the MtrB homolog of an obligately aerobic, nonmetal-reducing γ-proteobacterium.

The strategy

has shown efficacy in HIV-seronegative individuals [71–73], though specific data from HIV-seropositive individuals is more limited. Antiviral therapy should be initiated during the prodrome or early in an attack and aciclovir 200–400 mg orally five times daily for 5 days is recommended [47]. Alternative regimens are aciclovir 400 mg orally three times a day for 5 days; valaciclovir 500 mg orally twice daily for 3–5 days; valaciclovir 1 g orally, twice daily for 5 days; famciclovir 500 mg orally twice daily Inhibitor Library order for 5 days. There is no evidence of clear superiority of the alternative regimens over standard doses of aciclovir. In more immunocompromised HIV-seropositive persons, episodes may be prolonged and more severe, requiring a longer duration of antiviral treatment. In HIV negative individuals, discontinuation of suppressive or episodic antiviral therapy after 12 months is recommended in order to assess the ongoing frequency of recurrences. In an HIV-seropositive individual with a low CD4 cell count, the interruption may be delayed. The timing of this treatment

interruption should be agreed with the patient and they should be given a supply of antiviral therapy to enable prompt administration of episodic treatment if recurrences recur. 6.3.5.3 Non-mucosal (or systemic) herpes. There is limited data on the treatment TSA HDAC cell line of systemic HSV disease in HIV-seropositive individuals. Recommendations

are based on evidence from studies in both immunocompetent and immunocompromised patient populations. Systemic infection should be treated with intravenous aciclovir 5–10 mg/kg every 8 h for 10–21 days. HSV meningitis can be treated with 10 mg/kg every 8 h [74]. For HSV encephalitis, aciclovir 10 mg/kg every 8 h for 14–21 days is recommended [75] and quantitative PCR in the CSF may be helpful in monitoring response to treatment. Mortality and morbidity is high. Joint care with a neurologist is essential and there should be a low threshold for referral to a brain ITU. Patients with HSV keratoconjunctivitis or acute retinal necrosis should be seen urgently by an ophthalmologist and managed jointly. 6.3.5.4 Antiviral-resistant HSV infection. DOK2 In prospective studies, aciclovir-resistant HSV variants have been described in up to 7% of isolates from HIV-seropositive patients [76,77]. The threshold for resistance is a greater than 1–3 mg/mL aciclovir concentration for viral inhibition. This is most usually due to a mutation affecting the gene encoding viral thymidine kinase (TK), the enzyme that phosphorylates aciclovir in HSV-infected cells. TK-deficient strains are of reduced pathogenesis in immunocompetent individuals but cause significant clinical disease in immunosuppressed patients. Although partial resistance can occur, most TK mutants are resistant to aciclovir, valaciclovir and ganciclovir and the majority to famciclovir.