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Papers by patricia defechereux

Research paper thumbnail of Use of Drug-Level Testing and Single-Genome Sequencing to Unravel a Case of HIV Seroconversion on PrEP

Clinical Infectious Diseases

Cases of seroconversion on PrEP should be carefully investigated given their public health implic... more Cases of seroconversion on PrEP should be carefully investigated given their public health implications and rarity. We report a case of transmitted drug resistance causing seroconversion on PrEP in spite of high adherence, confirmed with dried blood spot and segmental hair drug-level testing and single-genome sequencing.

Research paper thumbnail of High Accuracy of a Real-Time Urine Antibody-Based Tenofovir Point-Of-Care Test Compared to Laboratory-Based Elisa in Diverse Populations

JAIDS Journal of Acquired Immune Deficiency Syndromes

Research paper thumbnail of HIV pre-exposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and changes in kidney function and tubular health

Research paper thumbnail of Impact of Estimated PrEP Adherence Patterns on Bone Mineral Density in a Large PrEP Demonstration Project

AIDS Research and Human Retroviruses

Bone mineral density (BMD) declines due to tenofovir-containing pre-exposure prophylaxis (PrEP) h... more Bone mineral density (BMD) declines due to tenofovir-containing pre-exposure prophylaxis (PrEP) have varied among PrEP demonstration projects, potentially related to variable adherence. Characterization of BMD changes in highly adherent individuals, estimated via tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS), can assist clinicians when counseling patients. Cisgender men who have sex with men and transwomen in the optional dual-energy X-ray absorptiometry (DXA) substudy of a large, international, openlabel PrEP demonstration project, the iPrEx-open-label extension (OLE) study underwent DXA scans and DBS collection every 24 weeks, with average weekly dosing adherence patterns (2, 4, and 7 doses/week) estimated from validated TFV-DP cut-offs. The mean percent BMD change was estimated in strata of average weekly adherence by using a linear mixed-effects model to calculate the BMD decline in highly adherent individuals on PrEP for the first time. DXA/DBS data were available for 254 individuals over a median of 24 weeks in iPrEx-OLE from June 2011 to December 2013. The percent decline in spine BMD was monotonically associated with strata of increasing average weekly adherence ( p < .001 trend); the p value for trends using hip BMD measurements was .07. Individuals with estimated daily adherence experienced a 1.2% decrease in spine BMD and a 0.5% drop in hip BMD. In highly adherent PrEP users, we found a lower-than-expected drop in BMD when compared with previous studies. This drop is likely not clinically significant for most PrEP users. However, for those at the highest risk of fracture who plan prolonged PrEP use, alternate PrEP strategies could be considered.

Research paper thumbnail of Cocaine Use and Pre-Exposure Prophylaxis

JAIDS Journal of Acquired Immune Deficiency Syndromes

Research paper thumbnail of Identification of hepatitis B virus genotype I in Thailand

Journal of Medical Virology

The rare hepatitis B virus genotype I (HBV-I) classification includes complex A/G/C/U recombinant... more The rare hepatitis B virus genotype I (HBV-I) classification includes complex A/G/C/U recombinants identified amongst the individuals from China, India, Laos, and Vietnam. Herein we report the first HBV-I specimen from Thailand, with detectable HBsAg despite a 10-amino-acid truncation. This HBV-I genome has a similar recombinant pattern to reference strains, including a C region that branches basal to references, suggesting a premodern era recombination event gave rise to HBV-I. With an average sequence divergence from other genotypes ranging from 7.66% (standard deviation [SD], 0.42%; C) to 14.27% (SD, 0.31%; H), this new genome supports the HBV-I classification as a unique genotype.

Research paper thumbnail of Pre-exposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine and Kidney Tubular Dysfunction in HIV-Uninfected Individuals

Journal of acquired immune deficiency syndromes (1999), 2018

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) ... more Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is becoming increasingly adopted for HIV prevention. Tenofovir can cause proximal tubular damage and chronic kidney disease in HIV-infected persons, but little is known regarding its nephrotoxic potential among HIV-uninfected persons. In this study, we evaluated the effects of PrEP on urine levels of the following: α1-microglobulin (α1m), a marker of impaired tubular reabsorption; albuminuria, a measure of glomerular injury; and total proteinuria. The Iniciativa Profilaxis Pre-Exposicion (iPrEx) study randomized HIV-seronegative men and transgender women who have sex with men to oral TDF/FTC or placebo. The iPrEx open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. A cross-sectional analysis compared urine biomarker levels by study arm in iPrEx (N = 100 treatment arm, N = 100 placebo arm). Then, urine biomarker levels were compared...

Research paper thumbnail of The Role of Social Relationships in PrEP Uptake and Use Among Transgender Women and Men Who Have Sex with Men

AIDS and behavior, Jan 12, 2018

Qualitative studies suggest that social relationships play an important role in HIV pre-exposure ... more Qualitative studies suggest that social relationships play an important role in HIV pre-exposure prophylaxis (PrEP) use, but there have been few quantitative assessments of the role of social relationships in PrEP uptake or adherence. We examined the association between disclosure of study participation or LGBT identity and PrEP use in the 1603 HIV-negative participants enrolled in the iPrEx OLE study. We also evaluated the association between LGBT social group involvement and PrEP use. Study participation disclosure to parents and LGBT identity disclosure to anyone in a participant's social network were associated with greater PrEP uptake. Study participation disclosure to partners was associated with higher probability of having protective PrEP drug concentrations compared [risk difference 0.15 95% CI (0.01, 0.30)]. For each additional type of LGBT organization a participant was involved in, the probability of PrEP uptake and having protective drug concentrations increased by ...

Research paper thumbnail of Gene activation by Varicella-zoster virus IE4 protein requires its diminution and involves both the arginine-rich sequence, the central part and the carboxy-terminal cycteine-rich region

Varicella-zoster virus (VZV) open reading frame 4-en-coded protein (IE4) possesses transactivatin... more Varicella-zoster virus (VZV) open reading frame 4-en-coded protein (IE4) possesses transactivating properties for VZV genes as well as for those of heterologous viruses. Since most transcription factors act as dimers, IE4 dimerization was studied using the mammalian two-hybrid system. Introduction of mutations in the IE4 open reading frame demonstrated that both the central region and the carboxylterminal cysteine-rich domain were important for efficient dimerization. Within the carboxyl-terminal domain, substitution of amino acids encompassing residues 443-447 totally abolished dimer-ization. Gene activation by IE4 was studied by transient transfection with an IE4 expression plasmid and a reporter gene under the control of either the human immunodeficiency virus, type 1, long terminal repeat or the VZV thymidine kinase promoter. Regions of IE4 important for dimerization were also shown to be crucial for transactivation. In addition, the arginine-rich domains Rb and Rc of the aminoterminal region were also demonstrated to be important for transactivation, whereas the Ra domain as well as an acidic and bZIP-containing regions were shown to be dispensable for gene transactivation. A nucleocytoplasmic shuttling of IE4 has also been characterized, involving a nuclear localization signal identified within the Rb domain and a nuclear export mechanism partially depending on Crm-1.

Research paper thumbnail of Regulation of Varicella-Zoster virus gene expression by the IE62 protein and mutational dissection of the IE62 protein

Research paper thumbnail of Depression and Oral FTC/TDF Pre-exposure Prophylaxis (PrEP) Among Men and Transgender Women Who Have Sex With Men (MSM/TGW)

AIDS and Behavior, 2015

We conducted a longitudinal and cross-sectional analysis of depressive symptomology in iPrEx, a r... more We conducted a longitudinal and cross-sectional analysis of depressive symptomology in iPrEx, a randomized, placebo-controlled trial of daily, oral FTC/TDF HIV pre-exposure prophylaxis (PrEP) in men and transgender women who have sex with men. Depression-related adverse events (AEs) were the most frequently reported severe or life-threatening AEs and were not associated with being randomized to the FTC/TDF arm (152 vs. 144 respectively OR 0.66 95 % CI 0.35-1.25). Center for Epidemiologic Studies Depression scale (CES-D) and a four questions suicidal ideation scale scores did not differ by arm. Participants reporting forced sex at anal sexual debut had higher CES-D scores (coeff: 3.23; 95 % CI 1.24-5.23) and were more likely to have suicidal ideation (OR 2.2; 95 % CI 1.09-4.26). CES-D scores were higher among people reporting non-condom

Research paper thumbnail of Concentrations of TFV-DP/FTC-TP in dried blood spots and TFV/FTC in hair are strongly correlated in iPrEx OLE: Implications for PrEP adherence monitoring

The Journal of infectious diseases, Jan 20, 2015

Self-reported adherence to PrEP has limitations, raising interest in pharmacologic monitoring. Dr... more Self-reported adherence to PrEP has limitations, raising interest in pharmacologic monitoring. Drug concentrations in hair and dried-blood-spots (DBS) assess long-term-exposure; hair shipment/storage occurs at room temperature. iPrEx Open-Label-Extension collected DBS routinely, with opt-in hair collection; concentrations were measured via liquid-chromatography/tandem-mass-spectrometry. In 806 hair-DBS pairs, tenofovir (TFV) hair levels and TFV-diphosphate in DBS were strongly correlated (Spearman's coefficient 0.734, p<0.001), as were hair TFV/DBS emtricitabine (FTC)-triphosphate (r 0.781, p<0.001); hair FTC/ DBS TFV-diphosphate (r 0.742, p<0.001); hair FTC/DBS FTC-triphosphate (r 0.587,…

Research paper thumbnail of Characterization of regulatory functions of the varicella-zoster virus gene 63-encoded protein

Journal of virology, 1992

Varicella-zoster virus (VZV) gene 63 encodes a protein (IE63) with a predicted molecular mass of ... more Varicella-zoster virus (VZV) gene 63 encodes a protein (IE63) with a predicted molecular mass of 30.5 kDa which has amino acid similarities to the immediate-early (IE) protein 22 (ICP22) of herpes simplex virus type 1. ICP22 is a polypeptide synthesized in herpes simplex virus type 1-infected cells, and as is the case for its VZV counterpart, its regulatory functions are unknown. On the basis of the VZV DNA sequence, it has been shown that IE63 exhibits hydrophilic and acidic properties, suggesting that this protein could play a regulatory role during the infectious cycle. We report in this article cotransfection experiments which demonstrate that the VZV gene 63 protein strongly represses, in a dose-dependent manner, the expression of VZV gene 62. On the other hand, transient expression of the VZV gene 63 protein can promote activation of the thymidine kinase gene but cannot affect the expression of the genes encoding glycoproteins I and II. The results of transient expression expe...

Research paper thumbnail of Gene Activation by Varicella-Zoster Virus IE4 Protein Requires Its Dimerization and Involves Both the Arginine-rich Sequence, the Central Part, and the Carboxyl-terminal Cysteine-rich Region

Journal of Biological Chemistry, 2000

Varicella-zoster virus (VZV) open reading frame 4-en-coded protein (IE4) possesses transactivatin... more Varicella-zoster virus (VZV) open reading frame 4-en-coded protein (IE4) possesses transactivating properties for VZV genes as well as for those of heterologous viruses. Since most transcription factors act as dimers, IE4 dimerization was studied using the mammalian two-hybrid system. Introduction of mutations in the IE4 open reading frame demonstrated that both the central region and the carboxylterminal cysteine-rich domain were important for efficient dimerization. Within the carboxyl-terminal domain, substitution of amino acids encompassing residues 443-447 totally abolished dimer-ization. Gene activation by IE4 was studied by transient transfection with an IE4 expression plasmid and a reporter gene under the control of either the human immunodeficiency virus, type 1, long terminal repeat or the VZV thymidine kinase promoter. Regions of IE4 important for dimerization were also shown to be crucial for transactivation. In addition, the arginine-rich domains Rb and Rc of the aminoterminal region were also demonstrated to be important for transactivation, whereas the Ra domain as well as an acidic and bZIP-containing regions were shown to be dispensable for gene transactivation. A nucleocytoplasmic shuttling of IE4 has also been characterized, involving a nuclear localization signal identified within the Rb domain and a nuclear export mechanism partially depending on Crm-1.

Research paper thumbnail of Overview of the Replication Cycle of Varicella-Zoster Virus

Contributions to Microbiology, 1999

... Overview of the Replication Cycle of Varicella-Zoster Virus Catherine Sadzot-Delvaux, Laurenc... more ... Overview of the Replication Cycle of Varicella-Zoster Virus Catherine Sadzot-Delvaux, Laurence Baudoux, Patricia ... 21 Debrus S, Sadzot-Delvaux C, Nikkels AF, Piette J, Rentier B: Varicella-zoster ... 33 McGeoch DJ, Dolan A, Donald S, Brauer DH: Complete DNA sequence of the ...

Research paper thumbnail of Drug resistance and plasma viral RNA level after ineffective use of oral pre-exposure prophylaxis in women

AIDS, 2015

Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine (FTC)/tenofovir disoproxil fumarate... more Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine (FTC)/tenofovir disoproxil fumarate may select for drug resistance if there is low adherence. Plasma viral HIV-1 RNA level, CD4 T-cell counts, and drug resistance were evaluated among seroconverting women in the FEM-PrEP trial (clinicaltrials.gov NCT00625404) using standard clinical tests, allele-specific PCR (ASPCR), and by deep sequencing. Tenofovir, FTC, and their intracellular metabolites were measured in plasma and cells. There was no difference in plasma HIV-1 RNA level or CD4 cell count among seroconverters in the active arm versus those receiving placebo. Tenofovir resistance was not observed. FTC resistance was detected using clinical assays in five seroconverters (four in the active arm and one in the placebo arm); two in the active arm occurred among women having moderate concentrations of PrEP drugs in the blood. The first evidence of infection occurred at the first postenrollment visit in three of the four with FTC resistance, although none had detectable viral nucleic acids at enrollment. FTC-resistant minor variants were detected in an additional four seroconverters (one in the active arm and three in the placebo arm). Drug resistance detected during ineffective PrEP use had characteristics suggesting transmitted infection or incubating infection prior to starting PrEP.

Research paper thumbnail of Lessons to be learned from varicella-zoster virus

Veterinary Microbiology, 1996

Varicella-zoster virus (VZV) is an alphaherpesvirus responsible for two human diseases: chicken p... more Varicella-zoster virus (VZV) is an alphaherpesvirus responsible for two human diseases: chicken pox and shingles. The virus has a respiratory port of entry. After two successive viremias, it reaches the skin where it causes typical lesions. There, it penetrates the peripheral nervous system and it remains latent in dorsal root ganglia. It is still debatable whether VZV persists in neurons or in satellite cells. During latency, VZV expresses a limited set of transcripts of its immediate early (IE) and early (E) genes but no protein has been detected. Mechanisms of reactivation from ganglia have not been identified. However, dysfunction of the cellular immune system appears to be involved in this process. The cell-associated nature of VZV has made it difficult to identify a temporal order of gene expression, but there appears to be a cascade mechanism as for HSV-1. The lack of high titre cell-free virions or recombination mutants has hindered so far the understanding of VZV gene functions. Five genes, ORFs 4, 10, 61, 62, and 63 that encode regulatory proteins could be involved in VZV latency. ORF4p activates gene promoters with basal activities. ORF10p seems to activate the ORF 62 promoter. ORF61p has trans-activating and trans-repressing activities. The major IE protein ORF62p, a virion component, has DNA-binding and regulatory functions, transactivates many VZV promoters and even regulates its own expression. ORF63p is a nuclear IE protein of yet unclear regulatory functions, abundantly expressed very early in infection. We have established an animal model of VZV latency in the rat nervous system, enabling us to study the expression of viral mRNA and protein expression during latency, and yielding results similar to those found in humans. This model is beginning to shed light on the molecular events in VZV persistent infection and on the regulator mechanisms that maintain the virus in a latent stage in nerve cells.

Research paper thumbnail of The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation

The EMBO Journal, 2001

Because of the heterogeneity of chromatin, the site of integration of human immunode®ciency virus... more Because of the heterogeneity of chromatin, the site of integration of human immunode®ciency virus (HIV) in the genome could have dramatic effects on its transcriptional activity. We have used an HIV-1-derived retroviral vector, in which the green¯uorescent protein is under the control of the HIV promoter, to generate by infection 34 Jurkat clonal cell lines each containing a single integration of the HIV-1 vector. In the absence of Tat, a 75-fold difference in expression level between the highest and lowest expressing clones was observed. Basal promoter activity was low in 80% of the clones and moderate to high in the remaining 20% of clones. We found that differences in expression levels are due to the integration site and are not controlled by DNA methylation or histone acetylation. Tat activated transcription in each clone, and an inverse correlation was observed between basal transcriptional activity and inducibility by Tat. These observations demonstrate that the chromatin environment in¯uences basal HIV gene expression and that the HIV Tat protein activates transcription independently of the chromatin environment.

Research paper thumbnail of Enhancement of varicella-zoster virus infection in cell lines expressing ORF4- or ORF62-encoded proteins

Journal of Medical Virology, 1996

Varicella-Zoster virus (VZV) open reading frames 4 (ORF4) and 62 (ORF62) encode putative immediat... more Varicella-Zoster virus (VZV) open reading frames 4 (ORF4) and 62 (ORF62) encode putative immediate early proteins (ORF4p and ORF62p, respectively) which are strong transactivators of other VZV genes and are involved in the very early stages of viral infection. ORF4p and ORF62p transactivate immediate-early and early gene promoters but have little or no effect on late gene promoters. To investigate the effect of ORF4p or ORF62p overexpression on the viral replication cycle, we constructed Vero cell lines expressing those genes under the control of the human cytomegalovirus major immediate-early promoter. VZV OKA infection of these stably transformed cell lines was followed-up using VZV glycoprotein E (gE) antigen quantification and virus titration. Upon serial passaging of infection in these cell lines expressing functionally active ORF4p or ORF62p, a 5- to 10-fold increase in viral gE antigen production was observed. Viral titers also demonstrated a 2- to 5-fold increase in viral production in these transformed cell lines. These results emphasize the role that both ORF4p and ORF62p play in enhancing the VZV replicative cycle.

Research paper thumbnail of Antibody Responses to Hepatitis A Virus Vaccine in HIV‐Infected Children with Evidence of Immunologic Reconstitution while Receiving Highly Active Antiretroviral Therapy

The Journal of Infectious Diseases, 2006

Background. Human immunodeficiency virus (HIV)-infected patients have weak responses to vaccines ... more Background. Human immunodeficiency virus (HIV)-infected patients have weak responses to vaccines and may require revised immunization regimens. We investigated the safety and immunogenicity of 2 doses of hepatitis A virus (HAV) vaccine followed by a booster dose in HIV-infected children receiving stable highly active antiretroviral therapy.

Research paper thumbnail of Use of Drug-Level Testing and Single-Genome Sequencing to Unravel a Case of HIV Seroconversion on PrEP

Clinical Infectious Diseases

Cases of seroconversion on PrEP should be carefully investigated given their public health implic... more Cases of seroconversion on PrEP should be carefully investigated given their public health implications and rarity. We report a case of transmitted drug resistance causing seroconversion on PrEP in spite of high adherence, confirmed with dried blood spot and segmental hair drug-level testing and single-genome sequencing.

Research paper thumbnail of High Accuracy of a Real-Time Urine Antibody-Based Tenofovir Point-Of-Care Test Compared to Laboratory-Based Elisa in Diverse Populations

JAIDS Journal of Acquired Immune Deficiency Syndromes

Research paper thumbnail of HIV pre-exposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and changes in kidney function and tubular health

Research paper thumbnail of Impact of Estimated PrEP Adherence Patterns on Bone Mineral Density in a Large PrEP Demonstration Project

AIDS Research and Human Retroviruses

Bone mineral density (BMD) declines due to tenofovir-containing pre-exposure prophylaxis (PrEP) h... more Bone mineral density (BMD) declines due to tenofovir-containing pre-exposure prophylaxis (PrEP) have varied among PrEP demonstration projects, potentially related to variable adherence. Characterization of BMD changes in highly adherent individuals, estimated via tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS), can assist clinicians when counseling patients. Cisgender men who have sex with men and transwomen in the optional dual-energy X-ray absorptiometry (DXA) substudy of a large, international, openlabel PrEP demonstration project, the iPrEx-open-label extension (OLE) study underwent DXA scans and DBS collection every 24 weeks, with average weekly dosing adherence patterns (2, 4, and 7 doses/week) estimated from validated TFV-DP cut-offs. The mean percent BMD change was estimated in strata of average weekly adherence by using a linear mixed-effects model to calculate the BMD decline in highly adherent individuals on PrEP for the first time. DXA/DBS data were available for 254 individuals over a median of 24 weeks in iPrEx-OLE from June 2011 to December 2013. The percent decline in spine BMD was monotonically associated with strata of increasing average weekly adherence ( p < .001 trend); the p value for trends using hip BMD measurements was .07. Individuals with estimated daily adherence experienced a 1.2% decrease in spine BMD and a 0.5% drop in hip BMD. In highly adherent PrEP users, we found a lower-than-expected drop in BMD when compared with previous studies. This drop is likely not clinically significant for most PrEP users. However, for those at the highest risk of fracture who plan prolonged PrEP use, alternate PrEP strategies could be considered.

Research paper thumbnail of Cocaine Use and Pre-Exposure Prophylaxis

JAIDS Journal of Acquired Immune Deficiency Syndromes

Research paper thumbnail of Identification of hepatitis B virus genotype I in Thailand

Journal of Medical Virology

The rare hepatitis B virus genotype I (HBV-I) classification includes complex A/G/C/U recombinant... more The rare hepatitis B virus genotype I (HBV-I) classification includes complex A/G/C/U recombinants identified amongst the individuals from China, India, Laos, and Vietnam. Herein we report the first HBV-I specimen from Thailand, with detectable HBsAg despite a 10-amino-acid truncation. This HBV-I genome has a similar recombinant pattern to reference strains, including a C region that branches basal to references, suggesting a premodern era recombination event gave rise to HBV-I. With an average sequence divergence from other genotypes ranging from 7.66% (standard deviation [SD], 0.42%; C) to 14.27% (SD, 0.31%; H), this new genome supports the HBV-I classification as a unique genotype.

Research paper thumbnail of Pre-exposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine and Kidney Tubular Dysfunction in HIV-Uninfected Individuals

Journal of acquired immune deficiency syndromes (1999), 2018

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) ... more Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is becoming increasingly adopted for HIV prevention. Tenofovir can cause proximal tubular damage and chronic kidney disease in HIV-infected persons, but little is known regarding its nephrotoxic potential among HIV-uninfected persons. In this study, we evaluated the effects of PrEP on urine levels of the following: α1-microglobulin (α1m), a marker of impaired tubular reabsorption; albuminuria, a measure of glomerular injury; and total proteinuria. The Iniciativa Profilaxis Pre-Exposicion (iPrEx) study randomized HIV-seronegative men and transgender women who have sex with men to oral TDF/FTC or placebo. The iPrEx open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. A cross-sectional analysis compared urine biomarker levels by study arm in iPrEx (N = 100 treatment arm, N = 100 placebo arm). Then, urine biomarker levels were compared...

Research paper thumbnail of The Role of Social Relationships in PrEP Uptake and Use Among Transgender Women and Men Who Have Sex with Men

AIDS and behavior, Jan 12, 2018

Qualitative studies suggest that social relationships play an important role in HIV pre-exposure ... more Qualitative studies suggest that social relationships play an important role in HIV pre-exposure prophylaxis (PrEP) use, but there have been few quantitative assessments of the role of social relationships in PrEP uptake or adherence. We examined the association between disclosure of study participation or LGBT identity and PrEP use in the 1603 HIV-negative participants enrolled in the iPrEx OLE study. We also evaluated the association between LGBT social group involvement and PrEP use. Study participation disclosure to parents and LGBT identity disclosure to anyone in a participant's social network were associated with greater PrEP uptake. Study participation disclosure to partners was associated with higher probability of having protective PrEP drug concentrations compared [risk difference 0.15 95% CI (0.01, 0.30)]. For each additional type of LGBT organization a participant was involved in, the probability of PrEP uptake and having protective drug concentrations increased by ...

Research paper thumbnail of Gene activation by Varicella-zoster virus IE4 protein requires its diminution and involves both the arginine-rich sequence, the central part and the carboxy-terminal cycteine-rich region

Varicella-zoster virus (VZV) open reading frame 4-en-coded protein (IE4) possesses transactivatin... more Varicella-zoster virus (VZV) open reading frame 4-en-coded protein (IE4) possesses transactivating properties for VZV genes as well as for those of heterologous viruses. Since most transcription factors act as dimers, IE4 dimerization was studied using the mammalian two-hybrid system. Introduction of mutations in the IE4 open reading frame demonstrated that both the central region and the carboxylterminal cysteine-rich domain were important for efficient dimerization. Within the carboxyl-terminal domain, substitution of amino acids encompassing residues 443-447 totally abolished dimer-ization. Gene activation by IE4 was studied by transient transfection with an IE4 expression plasmid and a reporter gene under the control of either the human immunodeficiency virus, type 1, long terminal repeat or the VZV thymidine kinase promoter. Regions of IE4 important for dimerization were also shown to be crucial for transactivation. In addition, the arginine-rich domains Rb and Rc of the aminoterminal region were also demonstrated to be important for transactivation, whereas the Ra domain as well as an acidic and bZIP-containing regions were shown to be dispensable for gene transactivation. A nucleocytoplasmic shuttling of IE4 has also been characterized, involving a nuclear localization signal identified within the Rb domain and a nuclear export mechanism partially depending on Crm-1.

Research paper thumbnail of Regulation of Varicella-Zoster virus gene expression by the IE62 protein and mutational dissection of the IE62 protein

Research paper thumbnail of Depression and Oral FTC/TDF Pre-exposure Prophylaxis (PrEP) Among Men and Transgender Women Who Have Sex With Men (MSM/TGW)

AIDS and Behavior, 2015

We conducted a longitudinal and cross-sectional analysis of depressive symptomology in iPrEx, a r... more We conducted a longitudinal and cross-sectional analysis of depressive symptomology in iPrEx, a randomized, placebo-controlled trial of daily, oral FTC/TDF HIV pre-exposure prophylaxis (PrEP) in men and transgender women who have sex with men. Depression-related adverse events (AEs) were the most frequently reported severe or life-threatening AEs and were not associated with being randomized to the FTC/TDF arm (152 vs. 144 respectively OR 0.66 95 % CI 0.35-1.25). Center for Epidemiologic Studies Depression scale (CES-D) and a four questions suicidal ideation scale scores did not differ by arm. Participants reporting forced sex at anal sexual debut had higher CES-D scores (coeff: 3.23; 95 % CI 1.24-5.23) and were more likely to have suicidal ideation (OR 2.2; 95 % CI 1.09-4.26). CES-D scores were higher among people reporting non-condom

Research paper thumbnail of Concentrations of TFV-DP/FTC-TP in dried blood spots and TFV/FTC in hair are strongly correlated in iPrEx OLE: Implications for PrEP adherence monitoring

The Journal of infectious diseases, Jan 20, 2015

Self-reported adherence to PrEP has limitations, raising interest in pharmacologic monitoring. Dr... more Self-reported adherence to PrEP has limitations, raising interest in pharmacologic monitoring. Drug concentrations in hair and dried-blood-spots (DBS) assess long-term-exposure; hair shipment/storage occurs at room temperature. iPrEx Open-Label-Extension collected DBS routinely, with opt-in hair collection; concentrations were measured via liquid-chromatography/tandem-mass-spectrometry. In 806 hair-DBS pairs, tenofovir (TFV) hair levels and TFV-diphosphate in DBS were strongly correlated (Spearman's coefficient 0.734, p<0.001), as were hair TFV/DBS emtricitabine (FTC)-triphosphate (r 0.781, p<0.001); hair FTC/ DBS TFV-diphosphate (r 0.742, p<0.001); hair FTC/DBS FTC-triphosphate (r 0.587,…

Research paper thumbnail of Characterization of regulatory functions of the varicella-zoster virus gene 63-encoded protein

Journal of virology, 1992

Varicella-zoster virus (VZV) gene 63 encodes a protein (IE63) with a predicted molecular mass of ... more Varicella-zoster virus (VZV) gene 63 encodes a protein (IE63) with a predicted molecular mass of 30.5 kDa which has amino acid similarities to the immediate-early (IE) protein 22 (ICP22) of herpes simplex virus type 1. ICP22 is a polypeptide synthesized in herpes simplex virus type 1-infected cells, and as is the case for its VZV counterpart, its regulatory functions are unknown. On the basis of the VZV DNA sequence, it has been shown that IE63 exhibits hydrophilic and acidic properties, suggesting that this protein could play a regulatory role during the infectious cycle. We report in this article cotransfection experiments which demonstrate that the VZV gene 63 protein strongly represses, in a dose-dependent manner, the expression of VZV gene 62. On the other hand, transient expression of the VZV gene 63 protein can promote activation of the thymidine kinase gene but cannot affect the expression of the genes encoding glycoproteins I and II. The results of transient expression expe...

Research paper thumbnail of Gene Activation by Varicella-Zoster Virus IE4 Protein Requires Its Dimerization and Involves Both the Arginine-rich Sequence, the Central Part, and the Carboxyl-terminal Cysteine-rich Region

Journal of Biological Chemistry, 2000

Varicella-zoster virus (VZV) open reading frame 4-en-coded protein (IE4) possesses transactivatin... more Varicella-zoster virus (VZV) open reading frame 4-en-coded protein (IE4) possesses transactivating properties for VZV genes as well as for those of heterologous viruses. Since most transcription factors act as dimers, IE4 dimerization was studied using the mammalian two-hybrid system. Introduction of mutations in the IE4 open reading frame demonstrated that both the central region and the carboxylterminal cysteine-rich domain were important for efficient dimerization. Within the carboxyl-terminal domain, substitution of amino acids encompassing residues 443-447 totally abolished dimer-ization. Gene activation by IE4 was studied by transient transfection with an IE4 expression plasmid and a reporter gene under the control of either the human immunodeficiency virus, type 1, long terminal repeat or the VZV thymidine kinase promoter. Regions of IE4 important for dimerization were also shown to be crucial for transactivation. In addition, the arginine-rich domains Rb and Rc of the aminoterminal region were also demonstrated to be important for transactivation, whereas the Ra domain as well as an acidic and bZIP-containing regions were shown to be dispensable for gene transactivation. A nucleocytoplasmic shuttling of IE4 has also been characterized, involving a nuclear localization signal identified within the Rb domain and a nuclear export mechanism partially depending on Crm-1.

Research paper thumbnail of Overview of the Replication Cycle of Varicella-Zoster Virus

Contributions to Microbiology, 1999

... Overview of the Replication Cycle of Varicella-Zoster Virus Catherine Sadzot-Delvaux, Laurenc... more ... Overview of the Replication Cycle of Varicella-Zoster Virus Catherine Sadzot-Delvaux, Laurence Baudoux, Patricia ... 21 Debrus S, Sadzot-Delvaux C, Nikkels AF, Piette J, Rentier B: Varicella-zoster ... 33 McGeoch DJ, Dolan A, Donald S, Brauer DH: Complete DNA sequence of the ...

Research paper thumbnail of Drug resistance and plasma viral RNA level after ineffective use of oral pre-exposure prophylaxis in women

AIDS, 2015

Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine (FTC)/tenofovir disoproxil fumarate... more Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine (FTC)/tenofovir disoproxil fumarate may select for drug resistance if there is low adherence. Plasma viral HIV-1 RNA level, CD4 T-cell counts, and drug resistance were evaluated among seroconverting women in the FEM-PrEP trial (clinicaltrials.gov NCT00625404) using standard clinical tests, allele-specific PCR (ASPCR), and by deep sequencing. Tenofovir, FTC, and their intracellular metabolites were measured in plasma and cells. There was no difference in plasma HIV-1 RNA level or CD4 cell count among seroconverters in the active arm versus those receiving placebo. Tenofovir resistance was not observed. FTC resistance was detected using clinical assays in five seroconverters (four in the active arm and one in the placebo arm); two in the active arm occurred among women having moderate concentrations of PrEP drugs in the blood. The first evidence of infection occurred at the first postenrollment visit in three of the four with FTC resistance, although none had detectable viral nucleic acids at enrollment. FTC-resistant minor variants were detected in an additional four seroconverters (one in the active arm and three in the placebo arm). Drug resistance detected during ineffective PrEP use had characteristics suggesting transmitted infection or incubating infection prior to starting PrEP.

Research paper thumbnail of Lessons to be learned from varicella-zoster virus

Veterinary Microbiology, 1996

Varicella-zoster virus (VZV) is an alphaherpesvirus responsible for two human diseases: chicken p... more Varicella-zoster virus (VZV) is an alphaherpesvirus responsible for two human diseases: chicken pox and shingles. The virus has a respiratory port of entry. After two successive viremias, it reaches the skin where it causes typical lesions. There, it penetrates the peripheral nervous system and it remains latent in dorsal root ganglia. It is still debatable whether VZV persists in neurons or in satellite cells. During latency, VZV expresses a limited set of transcripts of its immediate early (IE) and early (E) genes but no protein has been detected. Mechanisms of reactivation from ganglia have not been identified. However, dysfunction of the cellular immune system appears to be involved in this process. The cell-associated nature of VZV has made it difficult to identify a temporal order of gene expression, but there appears to be a cascade mechanism as for HSV-1. The lack of high titre cell-free virions or recombination mutants has hindered so far the understanding of VZV gene functions. Five genes, ORFs 4, 10, 61, 62, and 63 that encode regulatory proteins could be involved in VZV latency. ORF4p activates gene promoters with basal activities. ORF10p seems to activate the ORF 62 promoter. ORF61p has trans-activating and trans-repressing activities. The major IE protein ORF62p, a virion component, has DNA-binding and regulatory functions, transactivates many VZV promoters and even regulates its own expression. ORF63p is a nuclear IE protein of yet unclear regulatory functions, abundantly expressed very early in infection. We have established an animal model of VZV latency in the rat nervous system, enabling us to study the expression of viral mRNA and protein expression during latency, and yielding results similar to those found in humans. This model is beginning to shed light on the molecular events in VZV persistent infection and on the regulator mechanisms that maintain the virus in a latent stage in nerve cells.

Research paper thumbnail of The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation

The EMBO Journal, 2001

Because of the heterogeneity of chromatin, the site of integration of human immunode®ciency virus... more Because of the heterogeneity of chromatin, the site of integration of human immunode®ciency virus (HIV) in the genome could have dramatic effects on its transcriptional activity. We have used an HIV-1-derived retroviral vector, in which the green¯uorescent protein is under the control of the HIV promoter, to generate by infection 34 Jurkat clonal cell lines each containing a single integration of the HIV-1 vector. In the absence of Tat, a 75-fold difference in expression level between the highest and lowest expressing clones was observed. Basal promoter activity was low in 80% of the clones and moderate to high in the remaining 20% of clones. We found that differences in expression levels are due to the integration site and are not controlled by DNA methylation or histone acetylation. Tat activated transcription in each clone, and an inverse correlation was observed between basal transcriptional activity and inducibility by Tat. These observations demonstrate that the chromatin environment in¯uences basal HIV gene expression and that the HIV Tat protein activates transcription independently of the chromatin environment.

Research paper thumbnail of Enhancement of varicella-zoster virus infection in cell lines expressing ORF4- or ORF62-encoded proteins

Journal of Medical Virology, 1996

Varicella-Zoster virus (VZV) open reading frames 4 (ORF4) and 62 (ORF62) encode putative immediat... more Varicella-Zoster virus (VZV) open reading frames 4 (ORF4) and 62 (ORF62) encode putative immediate early proteins (ORF4p and ORF62p, respectively) which are strong transactivators of other VZV genes and are involved in the very early stages of viral infection. ORF4p and ORF62p transactivate immediate-early and early gene promoters but have little or no effect on late gene promoters. To investigate the effect of ORF4p or ORF62p overexpression on the viral replication cycle, we constructed Vero cell lines expressing those genes under the control of the human cytomegalovirus major immediate-early promoter. VZV OKA infection of these stably transformed cell lines was followed-up using VZV glycoprotein E (gE) antigen quantification and virus titration. Upon serial passaging of infection in these cell lines expressing functionally active ORF4p or ORF62p, a 5- to 10-fold increase in viral gE antigen production was observed. Viral titers also demonstrated a 2- to 5-fold increase in viral production in these transformed cell lines. These results emphasize the role that both ORF4p and ORF62p play in enhancing the VZV replicative cycle.

Research paper thumbnail of Antibody Responses to Hepatitis A Virus Vaccine in HIV‐Infected Children with Evidence of Immunologic Reconstitution while Receiving Highly Active Antiretroviral Therapy

The Journal of Infectious Diseases, 2006

Background. Human immunodeficiency virus (HIV)-infected patients have weak responses to vaccines ... more Background. Human immunodeficiency virus (HIV)-infected patients have weak responses to vaccines and may require revised immunization regimens. We investigated the safety and immunogenicity of 2 doses of hepatitis A virus (HAV) vaccine followed by a booster dose in HIV-infected children receiving stable highly active antiretroviral therapy.