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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 5, Number 3, May 2007
Contents
Review Articles
Effects of Highly Active Antiretroviral Therapy on
HIV-1 Associated Oral Complications Pp. 281-292
Zahida Parveen, Edward Acheampong, Roger J. Pomerantz,
Jeffrey M. Jacobson, Brian Wigdahl and Muhammad Mukhtar
[Abstract]
HIV-1 Replication from After Cell Entry to the Nuclear
Periphery Pp. 293-299
David Warrilow and David Harrich
[Abstract]
Progress in Understanding Basal Ganglia Dysfunction
as a Common Target for Methamphetamine Abuse and HIV-1 Neurodegeneration
Pp. 301-313
Shaji Theodore, Wayne A. Cass, Avindra Nath and William
F. Maragos
[Abstract]
Original Research Papers
Association of Gag Multimers with Filamentous
Actin During Equine Infectious Anemia Virus Assembly
Pp. 315-323
Chaoping Chen, Jing Jin, Marc Rubin, Liangqun Huang, Timothy
Sturgeon, Kelly M. Weixel, Donna B. Stolz, Simon C. Watkins,
James R. Bamburg, Ora A. Weisz and Ronald C. Montelaro
[Abstract]
Abnormal Cytokine Production by Circulating Monocytes
and Dendritic Cells of Myeloid Origin in ART-Treated HIV-1+
Patients Relates to CD4+ T-Cell Recovery and HCV Co-Infection
Pp. 325-336
Maria Almeida, Miguel Cordero, Julia Almeida and Alberto
Orfao
[Abstract]
Effects of Structured Treatment Interruptions on Metabolic,
Anthropometric, Immunologic, and Quality of Life Outcomes
in HIV-Positive Adults on HAART Pp. 337-343
Renato Maserati, Andrea Foli, Lina Tomasoni, Laura Sighinolfi,
Franco Maggiolo, Daria Sacchini, Massimo Di Pietro, Davide
Bertelli, Carmine Tinelli and Franco Lori
[Abstract]
SV40 and HIV Sequences in the Cerebrospinal Fluid
of a Patient with AIDS Dementia Complex Pp. 345-347
Manola Comar, Pierlanfranco D’Agaro, Roberto Luzzati,
Fernanda Martini, Mauro Tognon and Cesare Campello
[Abstract]
Multiple-Dose Pharmacokinetics of Efavirenz with and
without the Use of Rifampicin in HIV-Positive Patients
Pp. 349-353
Alberto Matteelli, Mario Regazzi, Paola Villani, Giuseppina
De Iaco, Maria Cusato, Anna Cristina C. Carvalho, Silvio Caligaris,
Lina Tomasoni, Maria Manfrin, Susanna Capone and Giampiero
Carosi
[Abstract]
Impact of Antiretroviral Therapy on the Relapse of
Cryptococcosis and Survival of HIV-Infected Patients with
Cryptococcal Infection Pp. 355-360
Ubonvan Jongwutiwes, Sasisopin Kiertiburanakul and Somnuek
Sungkanuparph
[Abstract]
Correlations Between Carotid IMT, Factor VIII Activity
Level and Metabolic Disturbances: A Cardio-Vascular Risk Factor
in the HIV Positive Persons Pp. 361-364
Luc de Saint Martin, Elisabeth Pasquier, Olivier Vandhuick,
Bertrand Arnaud, Sophie Vallet, Jérôme Duchemin,
Véronique Bellein and Luc Bressollette
[Abstract]
Abstracts
[Back to top]
Effects of Highly Active Antiretroviral
Therapy on HIV-1 Associated Oral Complications
Zahida Parveen, Edward Acheampong, Roger J. Pomerantz,
Jeffrey M. Jacobson, Brian Wigdahl and Muhammad Mukhtar
The oral cavity of human immunodeficiency virus type I (HIV-1)
infected individuals is subjected to a series of opportunistic
infections which are usually considered as a prognostic marker
for the severity of infection as well as an indicator of immunodeficiency.
The highly active antiretroviral therapy (HAART) has significantly
lessened the severity of HIV-associated oral infections although
this therapeutic regimen is considered to be responsible for
some of the oral lesions such as oral warts and salivary gland
disorders. In addition, the beneficial effects of HAART on
HIV associated oral lesions are stratified with age, with
the adult population showing improvements whereas the oral
lesions among children remain unchanged with this therapy.
The presence of HIV-1 in the saliva, and infectivity of oral
epithelial cells suggest that the oral cavity is a site of
HIV pathogenesis and potential reservoir for the disease in
the setting of virally suppressive HAART. Overall HIV associated
oral lesions are usually due to fungal, bacterial, and viral
infections as well as some of unknown etiology. This review
describes the current status of HIV associated oral lesions
by comparing historically available pre-HAART data. Future
directions envisioned by the National Institutes of Health
as well as novel avenues to be explored are also presented.
[Back to top]
HIV-1 Replication from After Cell Entry to the Nuclear
Periphery
David Warrilow and David Harrich
Productive infection with HIV-1 is mediated by fusion of the
HIV-1 envelope with the cell membrane and subsequent entry
of the virion core into the cytoplasm. The core is then rearranged
to form the reverse transcription complex which is responsible
for conversion of the genomic RNA to its double-stranded DNA
copy. Various genetic, biochemical and microscopy studies
have shed light on the role of viral proteins in the core
in this process; Gag cleavage products, in particular, are
crucial. It is also at this point that core is potentially
exposed to the action of restriction factors such as TRIM5α
and APOBEC3G, highlighting the vulnerability of this stage
of the retrovirus life-cycle to the cell’s defenses.
Rearrangement of the core may be an active process involving
host-cell activities, although this is not clear, but may
also be partly passive due to the instability of the structure.
What regulates this process is unknown. Several host-cell
kinase activities are important for replication and have been
shown to be incorporated in the virion. We speculate that
these kinases may regulate core rearrangement or the interaction
of the reverse transcription complex/pre-integration complex
with the cytoplasm. Recent real-time microscopy experiments
with fluorescent-labeled probes suggest a model in which the
virion utilizes the cytoskeleton for transport whilst in the
cytoplasm. After entering the cell, the virion interacts initially
with actin filaments which assist binding to microtubles enabling
transport to the nuclear periphery. An actin-transport process
may then facilitate the remaining short journey to the nuclear
membrane.
[Back to top]
Progress in Understanding Basal Ganglia Dysfunction
as a Common Target for Methamphetamine Abuse and HIV-1 Neurodegeneration
Shaji Theodore, Wayne A. Cass, Avindra Nath and William
F. Maragos
HIV-1 infection with concurrent methamphetamine (MA) abuse
results in exacerbated neurodegenerative changes and rapid
progression of a form of sub-cortical dementia termed HIV-1
associated dementia (HAD). A notable feature of HAD is the
involvement of the dopaminergic system manifested as parkinsonian
like movement abnormalities. The HIV-1 transactivator of transcription
(Tat) protein is very often used in experimental studies trying
to understand neurotoxic consequences of HIV-1 infection,
since the pathophysiological changes induced by Tat mirrors,
in part, the means by which HIV-1 infection of the nervous
system results in neuronal damage. Understanding the interaction
of Tat and MA in the basal ganglia and the resultant injury
to the dopaminergic system in rodent models as well as cell
culture will shed light on the dopaminergic pathology occurring
in HIV-1 infected-MA abusers. The aim of this review is to
update the reader on the current knowledge of MA and HIV-1
neurotoxicity, specifically Tat, and discuss the progress
in understanding how MA synergizes with the HIV-1 transactivator
protein Tat to damage the basal ganglia.
[Back to top]
Association of Gag Multimers with Filamentous
Actin During Equine Infectious Anemia Virus Assembly
Chaoping Chen, Jing Jin, Marc Rubin, Liangqun Huang, Timothy
Sturgeon, Kelly M. Weixel, Donna B. Stolz, Simon C. Watkins,
James R. Bamburg, Ora A. Weisz and Ronald C. Montelaro
Materials/movie1
Materials/movie2
A role for the actin cytoskeleton in retrovirus assembly has
long been speculated. However, specific mechanisms by which
actin facilitates the assembly process remain elusive. We
previously demonstrated differential effects of experimentally
modified actin dynamics on virion production of equine infectious
anemia virus (EIAV), a lentivirus related to HIV-1, suggesting
an involvement of actin dynamics in retrovirus production.
In the current study, we used bimolecular fluorescence complementation
(BiFC) to reveal intimate (<15nm) and specific associations
between EIAV Gag and actin, but not tubulin. Specific interaction
between Gag and filamentous actin was also demonstrated by
co-immunoprecipitation experiments combined with the actin
severing protein gelsolin to solubilize F-actin. Deletion
of capsid (CA) or nucleocapsid (NC) genes reduced Gag association
with F-actin by 40% and 95%, respectively. Interestingly,
GCN4, a leucine zipper motif, could substitute for the NC
domain in mediating F-actin association. Furthermore, deficiency
of the ΔNC Gag in F-actin interaction was restored upon
co-expression of Gag constructs containing both CA and NC
or the GCN4, suggesting a requirement for Gag polyprotein
multimerization prior to F-actin association. The observed
Gag-F-actin association appeared to correlate with viral budding,
as enhanced budding of the ΔNC mutant was evident upon
restoration of F-actin association. Intracellular association
of Gag complexes with F-actin was also detected by immunoscanning
electron microscopy of Triton-extracted EIAV-infected cells.
Together, these data suggest that Gag multimers induced by
CA and NC domains interact with F-actin and that this association
is important for efficient virion production.
[Back to top]
Abnormal Cytokine Production by Circulating Monocytes
and Dendritic Cells of Myeloid Origin in ART-Treated HIV-1+
Patients Relates to CD4+ T-Cell Recovery and HCV Co-Infection
Maria Almeida, Miguel Cordero, Julia Almeida and Alberto
Orfao
HIV-1 infection is associated with dysregulation of cytokine
production by peripheral blood (PB) monocytes and dendritic
cells (DC), but controversial results have been reported.
We aimed to analyze the effect of antiretroviral therapy (ART)
on the in vitro production of inflammatory cytokines
by PB-stimulated monocytes and DC of myeloid origin –CD33high+
myeloid DC (mDC) and CD33+/CD14-/dim+/CD16high+
DC– from HIV-1+ patients and its relationship with CD4+
T-cell recovery and co-infection with hepatitis C virus (HCV).
In vitro cytokine production was analyzed at the
single cell level in 32 HIV-1+ patients, grouped according
to the number of CD4+ T-cells/μl
in PB (<200 CD4 versus >200
CD4). Patients were tested prior to therapy and at weeks +2,
+4, +8, +12 and +52 after ART. Prior to ART, production of
IL-6, TNF-α
and IL-12 by mDC and of IL-8 and IL-12 by CD16+ DC was significantly
increased among >200 CD4 patients. After one year of ART,
increased production of IL-8 by monocytes, of TNF-α
by mDC and of IL-1β,
IL-6 and TNF-α
by CD16+ DC was specifically observed among <200 CD4 HIV-1+
individuals showing a high recovery of PB CD4+ T-cell counts.
In turn, we found that the significantly reduced percentage
of IL-1β,
IL-6, IL-8 and TNF-α-producing
monocytes and of IL-6 and IL-8-producing mDC and CD16+ DC,
as well as the significantly diminished mean amount of IL-6
produced per monocyte, mDC and CD16+ DC and of IL-12 produced
per CD16+ DC observed at week +52 for the >200 CD4 patients,
were related to the presence of co-infection with HCV. In
summary, HIV-1+ individuals show abnormal production of inflammatory
cytokines by PB-stimulated monocytes and DC of myeloid origin
even after one year of ART, such abnormalities being associated
with the degree of recovery of PB CD4+ T-cell counts in more
immunocompromised patients and HCV co-infection in more immunocompetent
HIV-1+ individuals.
[Back to top]
Effects of Structured Treatment Interruptions on Metabolic,
Anthropometric, Immunologic, and Quality of Life Outcomes
in HIV-Positive Adults on HAART
Renato Maserati, Andrea Foli, Lina Tomasoni, Laura Sighinolfi,
Franco Maggiolo, Daria Sacchini, Massimo Di Pietro, Davide
Bertelli, Carmine Tinelli and Franco Lori
Structured treatment interruptions may have beneficial effects
on metabolic parameters, while data on anthropometric parameters
and on the quality of life are scanty. This study was designed
to evaluate the effects of structured treatment interruptions
on plasma cholesterol, triglycerides, anthropometric, immunologic,
virologic changes and quality of life. A total of 112 HIV-infected
patients under HAART with undetectable viremia for longer
than 6 months were randomized to undergo 6 cycles of 1-month
off and 1-month on therapy or to continue HAART. Patients
treated with structured treatment interruptions (STI group)
were evaluated monthly, patients in the control group (CTRL
group) were evaluated every two months. Anthropometric and
quality of life data were collected every four months. The
study was designed as a two-arm, prospective, multicentred,
controlled trial.
Results on the primary endpoints showed a significant decrease
in the cholesterol levels in the STI group compared to the
CTRL group (total cholesterol median AUC [IQR] was 193.5 mg/dL/month
[173.4-209.4], and 210.8 mg/dL/month [194-242.4], respectively,
p=0.0009). Although the triglyceride levels were
lower in the STI group, the results did not reach statistical
significance (triglyceride median AUC [IQR] was 166.8 mg/dL/month
[IQR: 112.5-234.9] in the CTRL group, and 169 [IR: 124.7-256.7]
in the STI group; p=0.37). As for the secondary endpoints
no major differences among groups were noted.
Cyclic structured treatment interruptions may have a favorable,
although limited, impact on plasma total cholesterol levels
in HIV-infected subjects. No modifications of anthropometric
and quality of life values were noted.
[Back to top]
SV40 and HIV Sequences in the Cerebrospinal Fluid
of a Patient with AIDS Dementia Complex
Manola Comar, Pierlanfranco D’Agaro, Roberto Luzzati,
Fernanda Martini, Mauro Tognon and Cesare Campello
Central Nervous System (CNS) diseases that occur in HIV-positive
patients are mainly due to HIV itself or to opportunistic
microorganisms. Polyomavirus JCV, BKV and SV40 have been associated
with encephalopathies in both HIV-positive and HIV-negative
patients. To investigate the presence of Polyomavirus DNA
sequences in patients affected by CNS disorders, 82 CSF samples
from 70 HIV-positive and 12 HIV-negative patients were analyzed
by PCR. A double HIV and SV40 infection was found in one patient
suffering with AIDS dementia complex. SV40 DNA sequence analysis
showed the homology with wild type SV40 strain. SV40 should
be considered as a potential causal agent of CNS disorders
in AIDS patients.
[Back to top]
Multiple-Dose Pharmacokinetics of Efavirenz with and
without the Use of Rifampicin in HIV-Positive Patients
Alberto Matteelli, Mario Regazzi, Paola Villani, Giuseppina
De Iaco, Maria Cusato, Anna Cristina C. Carvalho, Silvio Caligaris,
Lina Tomasoni, Maria Manfrin, Susanna Capone and Giampiero
Carosi
Rifampicin (RIF) decreases serum concentrations of several
antiretroviral drugs. We carried out a prospective, comparative
study to define efavirenz (EFV) pharmacokinetics in 16 cases
and 13 controls. Cases were HIV and tuberculosis (TB) co-infected
adults assuming RIF 600 mg once daily and EFV 800 mg once
daily. Patients on EFV at standard 600 mg dose without RIF
were taken as controls. EFV levels in plasma were assayed
by high-performance liquid chromatography (HLPC) predose (Ctrough)
and at 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 16, 18, 22
and 24 hours post-dose, and pharmacokinetic parameters were
determined by non-compartmental methods. Among cases, 81%
were males, mean age was 37 years, 50% were Caucasians, mean
weight was 64 kg, mean CD4 cell counts and log HIV RNA copies
were 160/μl
and 5.2 /μl,
respectively. Cases had a significantly higher Cl/F/kg if
compared with controls (0.269 ±
0.12 versus 0.167 + 0.05 L/h/kg,
p<0.01). Otherwise, dose-dependent pharmacokinetic parameters
of EFV were similar between cases and controls. Interindividual
variability was consistently higher among TB cases compared
to controls for all considered parameters. All cases completed
combined treatment and no increased EFV toxicity was observed.
These results suggest that a dose of 800 mg of EFV in association
with rifampicin may be appropriate for patients of weight
> 60 kg in Europe. Therapeutic drug monitoring may be beneficial
for patients on combination therapy with RIF.
[Back to top]
Impact of Antiretroviral Therapy on the Relapse of
Cryptococcosis and Survival of HIV-Infected Patients with
Cryptococcal Infection
Ubonvan Jongwutiwes, Sasisopin Kiertiburanakul and Somnuek
Sungkanuparph
Background: Cryptococcosis is an opportunistic infection
with morbidity and mortality in HIV-infected patients. Impact
of antiretroviral therapy (ART) on the relapse of cryptococcosis
and survival of HIV-infected patients with cryptococcosis
has not been well established.
Methods: A retrospective cohort study of HIV-infected
patients with cryptococcosis during 1997-2005 was conducted.
Relapse and survival rates with corresponding risk factors
were determined.
Results: There were 149 patients with a mean age
of 33.5±7.4 years and 57% were male. Median CD4 cell
count was 22 cells/mm3. After exclusion of patients
who died or were lost to follow-up during the first two weeks,
127 patients were eligible for the analysis of the effect
of ART on relapse and survival rates. Of 127 patients, 52
received ART. The demographic data between the two groups
were similar. Median time of ART initiation after cryptococcal
diagnosis was 2.6 months. The most frequent ART used was NNRTI-based
regimen (88.4%). Median CD4 change at six months of ART was
97 cells/mm3 and 87.9% achieved undetectable HIV-RNA.
The cumulative 75% survival (free) from relapse duration was
10.4 months in no-ART group and 41.9 months in ART group (P<0.01).
The 75% survival from cryptococcal-related mortality in no-ART
group was 6.4 months whereas >54 months for ART group (P<0.01).
In Cox proportional hazards model, ART was the only factor
that associated with lower relapse and mortality rate (P<0.01).
Conclusions: ART significantly reduced relapse and
mortality rate from cryptococcosis in HIV-infected patients.
ART is strongly recommended in this population and should
not be delayed.
[Back to top]
Correlations Between Carotid IMT, Factor VIII Activity
Level and Metabolic Disturbances: A Cardio-Vascular Risk Factor
in the HIV Positive Persons
Luc de Saint Martin, Elisabeth Pasquier, Olivier Vandhuick,
Bertrand Arnaud, Sophie Vallet, Jérôme Duchemin,
Véronique Bellein and Luc Bressollette
In the HIV infection, the short time-scale between the
HIV-induced cardiovascular events and the onset of antiretroviral
therapy elicits a thrombophilic co-factor that worsens the
induced atherosclerosis. We compared the factor VIII plasma
activity, previously implicated in arterial and venous thrombosis,
with a surrogate marker of atherosclerosis, the carotid intima-media
thickness, and with the usual atherosclerosis risk factors
in 154 HIV infected outpatients. The FVIII plasma activity
is significantly associated with the carotid intima-media
thickness and, strongly, with blood glucose and triglycerides
levels. A raised FVIII plasma activity is an important feature
of the metabolic syndrome and a putative co-factor of HAART
induced cardiovascular events. Thus the prevention of the
HAART-induced cardio-vascular events should probably not be
exclusively focused on atherosclerosis but likewise on the
thrombus formation process.
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