Etiology of Genital Ulcer Disease and Association With HIV Infection in Malawi

Phiri, Sam; Zadrozny, Sabrina; Weiss, Helen A.; Martinson, Francis; Nyirenda, Naomi; Chen, Cheng Yen; Miller, William C.; Cohen, Myron S.; Mayaud, Philippe; Hoffman, Irving

doi:10.1097/olq.0000000000000051

Cited by 36 publications

(53 citation statements)

References 18 publications

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“…2 The effects of syphilis infection on markers of HIV infection have not yet been sufficiently clarified; the few studies on this issue in the medical literature have been contradictory about the severity of the impact of early syphilis on markers of HIV infection. 1,2 Our study aims to establish the effect of early syphilis on CD4 T cell count and HIV viral load (VL) in HIV-infected patients for the following reasons: first, because early syphilis presents with severe immune disorders; second, because it is easy to determine the time of occurrence of early syphilis. 1,2 On the other hand, latent syphilis does not present the above characteristics.…”

Section: Introductionmentioning

confidence: 98%

“…1,2 Our study aims to establish the effect of early syphilis on CD4 T cell count and HIV viral load (VL) in HIV-infected patients for the following reasons: first, because early syphilis presents with severe immune disorders; second, because it is easy to determine the time of occurrence of early syphilis. 1,2 On the other hand, latent syphilis does not present the above characteristics. This study focuses on a homogenous sample of HIV-infected MSM for whom we have detailed clinical information on their antiretroviral treatment (ART), which enabled us to determine if there is a differential effect between those who are taking ART and those who are not.…”

Section: Introductionmentioning

confidence: 99%

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Early syphilis affects markers of HIV infection

et al. 2016

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The objective of this study was to investigate if early syphilis infection affects markers of HIV infection; CD4 T cells and viral load (VL). A retrospective study was performed on 160 HIV-positive patients (111 receiving antiretroviral therapy [ART] and 49 without ART). Early syphilis diagnosis was made in HIV patients during their follow-up at the HIV/AIDS Unit at a Greek Dermatology and Venereology Unit. The patients' blood tests were available at the time of diagnosis, as well as before and 12 weeks after early syphilis diagnosis. CD4 T cell counts and VL levels were measured. It was found that syphilis infection had a negative impact on the CD4 T cell counts in both groups, with reduced CD4 T cell counts observed in 84.6% (99/111) and 79.5% (39/49) of patients receiving and not receiving ART, respectively. After treatment for syphilis, CD4 T cell counts returned to pre-treatment levels in most patients, especially those receiving ART. There was a slight and transient VL increase. Patients receiving ART had a 27% increase in VL, compared to 71.4% among patients not receiving ART. Although the VL increase was slight (41-14,000 copies/ml) in the group under treatment, 4-5% (5/111) patients did not return to pre-treatment levels. Moreover, viral mutations associated with treatment resistance were identified in these patients. Early syphilis accelerates and complicates the progression of HIV infection. Early diagnosis and treatment of syphilis may prevent infection-associated complications in most instances. Consequently, prevention of syphilis and other sexually transmitted infections is of great importance for patients infected with HIV.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Early syphilis affects markers of HIV infection

et al. 2016

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“…As a result of syndromic management of genital ulcers, chancroid prevalence has declined in many areas of endemicity and the overall global prevalence of chancroid is now undefined (2). However, reports of chancroid persist from Africa and Asia, implying that these regions have reservoirs of infected sex workers (3)(4)(5)(6)(7)(8).…”

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confidence: 99%

A (p)ppGpp-Null Mutant of Haemophilus ducreyi Is Partially Attenuated in Humans Due to Multiple Conflicting Phenotypes

Holley

Gangaiah

et al. 2014

Infect Immun

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f (p)ppGpp responds to nutrient limitation through a global change in gene regulation patterns to increase survival. The stringent response has been implicated in the virulence of several pathogenic bacterial species. Haemophilus ducreyi, the causative agent of chancroid, has homologs of both relA and spoT, which primarily synthesize and hydrolyze (p)ppGpp in Escherichia coli. We constructed relA and relA spoT deletion mutants to assess the contribution of (p)ppGpp to H. ducreyi pathogenesis. Both the relA single mutant and the relA spoT double mutant failed to synthesize (p)ppGpp, suggesting that relA is the primary synthetase of (p)ppGpp in H. ducreyi. Compared to the parent strain, the double mutant was partially attenuated for pustule formation in human volunteers. The double mutant had several phenotypes that favored attenuation, including increased sensitivity to oxidative stress. The increased sensitivity to oxidative stress could be complemented in trans. However, the double mutant also exhibited phenotypes that favored virulence. When grown to the mid-log phase, the double mutant was significantly more resistant than its parent to being taken up by human macrophages and exhibited increased transcription of lspB, which is involved in resistance to phagocytosis. Additionally, compared to the parent, the double mutant also exhibited prolonged survival in the stationary phase. In E. coli, overexpression of DksA compensates for the loss of (p)ppGpp; the H. ducreyi double mutant expressed higher transcript levels of dksA than the parent strain. These data suggest that the partial attenuation of the double mutant is likely the net result of multiple conflicting phenotypes.

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“…Due to widespread implementation of syndromic management of genital ulcers, the epidemiology of chancroid is poorly defined, but its prevalence has declined in many areas where chancroid formerly was endemic (2). However, reports of chancroid persist from several countries in Africa and Asia, implying that these regions have clinical reservoirs of infected sex workers (3)(4)(5)(6)(7)(8).…”

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DksA and (p)ppGpp Have Unique and Overlapping Contributions to Haemophilus ducreyi Pathogenesis in Humans

et al. 2015

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jThe (p)ppGpp-mediated stringent response is important for bacterial survival in nutrient limiting conditions. For maximal effect, (p)ppGpp interacts with the cofactor DksA, which stabilizes (p)ppGpp's interaction with RNA polymerase. We previously demonstrated that (p)ppGpp was required for the virulence of Haemophilus ducreyi in humans. Here, we constructed an H. ducreyi dksA mutant and showed it was also partially attenuated for pustule formation in human volunteers. To understand the roles of (p)ppGpp and DksA in gene regulation in H. ducreyi, we defined genes potentially altered by (p)ppGpp and DksA deficiency using transcriptome sequencing (RNA-seq). In bacteria collected at stationary phase, lack of (p)ppGpp and DksA altered expression of 28% and 17% of H. ducreyi open reading frames, respectively, including genes involved in transcription, translation, and metabolism. There was significant overlap in genes differentially expressed in the (p)ppGpp mutant relative to the dksA mutant. Loss of (p)ppGpp or DksA resulted in the dysregulation of several known virulence determinants. Deletion of dksA downregulated lspB and rendered the organism less resistant to phagocytosis and increased its sensitivity to oxidative stress. Both mutants had reduced ability to attach to human foreskin fibroblasts; the defect correlated with reduced expression of the Flp adhesin proteins in the (p)ppGpp mutant but not in the dksA mutant, suggesting that DksA regulates the expression of an unknown cofactor(s) required for Flp-mediated adherence. We conclude that both (p)ppGpp and DksA serve as major regulators of H. ducreyi gene expression in stationary phase and have both overlapping and unique contributions to pathogenesis. Haemophilus ducreyi is the causative agent of chancroid, a sexually transmitted genital ulcer disease that facilitates both the transmission and acquisition of HIV-1 (1). Chancroid has a short duration of infectivity and is maintained only in populations with high sex partner change rates, such as commercial sex workers (2). Due to widespread implementation of syndromic management of genital ulcers, the epidemiology of chancroid is poorly defined, but its prevalence has declined in many areas where chancroid formerly was endemic (2). However, reports of chancroid persist from several countries in Africa and Asia, implying that these regions have clinical reservoirs of infected sex workers (3-8).Although non-sexually-transmitted cutaneous ulcers in children in the South Pacific islands and equatorial Africa are usually attributed to Treponema pallidum subsp. pertenue, recent studies performed as part of a World Health Organization-directed yaws eradication campaign suggest that H. ducreyi is a major cause of this syndrome. In three large cross-sectional community surveys, the proportion of ulcers in which H. ducreyi DNA was detected greatly exceeded that of T. pallidum DNA (9-11). Considering the global prevalence of yaws, infections due to H. ducreyi may be much more common than was previously recognized. Thu...

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Etiology of Genital Ulcer Disease and Association With HIV Infection in Malawi

Abstract: Herpes simplex virus type 2 ulcers are highly prevalent in this symptomatic population and strongly associated with HIV. Unlike most locations in sub-Saharan Africa, H. ducreyi remains prevalent in this population and requires periodic monitoring and an appropriate treatment regimen.

Cited by 36 publications

References 18 publications

Early syphilis affects markers of HIV infection

Early syphilis affects markers of HIV infection

A (p)ppGpp-Null Mutant of Haemophilus ducreyi Is Partially Attenuated in Humans Due to Multiple Conflicting Phenotypes

DksA and (p)ppGpp Have Unique and Overlapping Contributions to Haemophilus ducreyi Pathogenesis in Humans

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