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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 5, Number 5, September 2007
Contents
Review Articles
The Presence of Antibodies Recognizing a Peptide Derived from
the Second Conserved Region of HIV-1 gp120 Correlates with
Non-Progressive HIV Infection Pp. 443-448
Ana Djordjevic, Milena Veljkovic, Sascha Antoni, Maria
Sakarellos-Daitsiotis, Dimitrios Krikorian, Stella Zevgiti,
Ursula Dietrich, Nevena Veljkovic and Donald R. Branch
[Abstract]
Original Research Papers
Electron-Topological Method of the Non-Nucleoside
HIV-1 RT Inhibitors Study: Structure-Activity Relationships
Pp. 449-458
Fatma Kandemirli, Vasyl Kovalishyn and Sedat Giray Kandemirli
[Abstract]
Ultrasonography and Anthropometry for Measuring Regional
Body Fat in HIV-Infected Patients Pp. 459-466
Sergio Padilla, Juan A. Gallego, Mar Masiá, Francisco
Ardoy, Ildefonso Hernández and Félix Gutiérrez
[Abstract]
HIV-1-Infected Long-Term Non-Progressors have Milder
Mitochondrial Impairment and Lower Mitochondrially-Driven
Apoptosis in Peripheral Blood Mononuclear Cells than Typical
Progressors Pp. 467-473
Joaquim Peraire, Òscar Miró, Maria Saumoy,
Pere Domingo, Enric Pedrol, Francesc Villarroya, Esteban Martínez,
Miguel López-Dupla, Glória Garrabou, Mª
Antònia Sambeat, Elisabet Deig, Joan Villarroya, Matilde
R. Chacón, Sònia López, Àngels
Fontanet, Maija Holmstrom, Marta Giralt, Josep Mª Gatell
and Francesc Vidal
[Abstract]
The HIV-1 Tat Protein Stimulates Reverse Transcription
In Vitro Pp. 474-483
Ann Apolloni, Luke W Meredith, Andreas Suhrbier, Rosemary
Kiernan and David Harrich
[Abstract]
AIDS-Defining Illnesses: A Comparison Between Before
and After Commencement of Highly Active Antiretroviral Therapy
(HAART) Pp. 484-489
Yvonne Lim Ai Lian, Benedict Sim Lim Heng, Veeranoot Nissapatorn
and Christopher Lee
[Abstract]
Steatohepatitis in HIV-Infected Subjects: Pathogenesis,
Clinical Impact and Implications in Clinical Management Pp.
490-498
Marco Bongiovanni and Federica Tordato
[Abstract]
Clinical Presentation, Treatment Outcome and Survival
Among the HIV Infected Children with Culture Confirmed Tuberculosis
Pp. 499-504
Alok Kumar, Sanjay Upadhyay and Geeta Kumari
[Abstract]
Abstracts
[Back to top]
The Presence of Antibodies Recognizing a Peptide Derived
from the Second Conserved Region of HIV-1 gp120 Correlates
with Non-Progressive HIV Infection
Ana Djordjevic, Milena Veljkovic, Sascha Antoni, Maria
Sakarellos-Daitsiotis, Dimitrios Krikorian, Stella Zevgiti,
Ursula Dietrich, Nevena Veljkovic and Donald R. Branch
The C-terminus of the second conserved region of HIV-1 gp120
represents a functionally important domain, as it encompasses
amino acids directly involved in the binding to the CD4 receptor
and in post-receptor binding events. Previous studies have
suggested that antibodies with specific affinity to a 23 amino
acids-long NTM polypeptide, derived from this HIV-1 gp120
domain, may be involved in the control of HIV disease progression.
In the current work, we searched for NTM-recognizing antibodies
in specific cohorts of HIV-1 infected individuals, including
long-term nonpro-gressors (LTNP) and progressors. For this
purpose, we employed a previously defined bioinformatics criterion
for design of an NTM peptide mimetic to select an octapeptide,
NTMs (FTDNAKTI), which is more suitable for use in a solid-state
enzyme-linked immunosorbent assay (ELISA). Our results show
that NTMs-reactive antibodies are significantly more prevalent
(p < 0.01) in LTNP as compared to progressors and healthy
control subjects, indicating their association with non-progressive
infection. The presence of antibodies recognizing the second
conserved region of the HIV-1 gp120 derived peptide, NTMs,
in LTNP sera suggest that these antibodies could be of considerable
interest for development of anti-HIV immune-based therapies
and vaccines.
[Back to top]
Electron-Topological Method of the Non-Nucleoside
HIV-1 RT Inhibitors Study: Structure-Activity Relationships
Fatma Kandemirli, Vasyl Kovalishyn and Sedat Giray Kandemirli
Structure activity relationships for a series of TIBO (4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-j,k][1,4]
benzodiazepin-2(1H)-one) derivatives, which significantly
inhibit HIV-1 replication are analyzed by the Electron-Topological
Method (ETM) and Artificial Neural Networks (ANNs). Activities
of the TIBO series including 91 compounds are given as IC50.
Conformational analysis and quantum-chemical calculations
are carried out for each TIBO derivatives, and then molecular
fragments being specific for active compounds and non-active
compounds are revealed by using ETM. In this study, we used
optimized geometry data and electronic characteristics to
form Electron-Topological Matrices of Contiguity (ETMCs) for
all compounds in the series of TIBO derivatives. Effective
charges on atoms are taken as diagonal elements, bond characteristics
and optimized distances represent non-diagonal elements. To
obtain the algorithmic base for the activity prediction, ANNs
were used after the ETM (the so-called combined ETM-ANN method).
As the result, 6 pharmacophores and anti-pharmacophores were
chosen as the most important ones. The statistical coefficients
calculated by the proposed algorithm were q2=0.82,
for training set and q2=
0.72, for external test set respectively Thus, the found results
showed that ETM-ANNs approach is a good convenient tool for
QSAR studies.
[Back to top]
Ultrasonography and Anthropometry for Measuring Regional
Body Fat in HIV-Infected Patients
Sergio Padilla, Juan A. Gallego, Mar Masiá, Francisco
Ardoy, Ildefonso Hernández and Félix Gutiérrez
To evaluate ultrasonography and anthropometry for the measurement
of regional body fat in HIV infected patients. In a cross-sectional
study, 61 patients receiving antiretroviral therapy underwent
ultrasonography and anthropometry for measuring body fat at
abdominal, peripheral and facial levels. Reproducibility and
accuracy of the measurements at the different compartments
were determined using quantitative computed tomography (CT)
and clinical evaluation of li-podystrophy as reference standard.
Intrabdominal and subcutaneous abdominal fat assessed by ultrasonography
correlated with visceral and subcutaneous abdominal fat quantified
by CT (r=0.74, P<0.001, and r=0.84, P<0.001, respectively).
Ultrasound-determined subcutaneous fat at mid-thigh level
correlated with adipose tissue area measured by CT (r = 0.84,
P<0.001). Waist-to-hip ratio (r=0.69, P<0.001), suprailiac
skinfold (r=0.78, P<0.001) and mid-thigh skinfold thickness
(r=0.83, P<0.001) were also significantly correlated with
visceral abdominal fat, subcutaneous abdominal fat, and with
subcutaneous leg fat quantified by CT, respectively. Poorer
correlations were found between ultrasonographic and anthropometric
assessments of facial fat, and adipose tissue measured by
CT (r=0.15, P=0.25, and r=0.58; P<0.001; respectively).
Reproducibility was higher for anthropometry than for ultrasonography
in most body regions. The highest variability was observed
for ultrasonographic assessment of facial fat (median inter-observer
coefficient of variation, 32.10%). Using the clinical diagnosis
of lipodystrophy as reference, the best accuracy was observed
for ultrasound-determined intrabdominal fat, waist-to-hip
ratio and subcutaneous crural fat measured by ultrasonography.
Ultrasonography and anthropometry are fairly accurate and
reproducible methods for the evaluation of intrabdominal and
peripheral fat. Its role for assessing facial fat seems to
be more limited.
[Back to top]
HIV-1-Infected Long-Term Non-Progressors have Milder
Mitochondrial Impairment and Lower Mitochondrially-Driven
Apoptosis in Peripheral Blood Mononuclear Cells than Typical
Progressors
Joaquim Peraire, Òscar Miró, Maria Saumoy,
Pere Domingo, Enric Pedrol, Francesc Villarroya, Esteban Martínez,
Miguel López-Dupla, Glória Garrabou, Mª
Antònia Sambeat, Elisabet Deig, Joan Villarroya, Matilde
R. Chacón, Sònia López, Àngels
Fontanet, Maija Holmstrom, Marta Giralt, Josep Mª Gatell
and Francesc Vidal
Mitochondrial parameters in peripheral blood mononuclear cells
(PBMC) and their relationship with mitochondrially-driven
PBMC apoptosis were investigated in a group of HIV-1-infected
long-term nonprogressors (LTNP) and compared with untreated
asymptomatic HIV-1 infected typical progressors (TP) and uninfected
healthy controls (HC). Twenty-six LTNP, 27 TP and 31 HC were
evaluated. Studies were performed in PBMCs. Mitochondrial
DNA content (mtDNA) was assessed by quantitative real-time
PCR. Activities of mitochondrial respiratory chain complexes
(MRC) II, III and IV were determined by spectrophotometry.
Caspase-3 activity was assessed by fluorimetry, and caspase-9
activation and Bcl-2 levels were assessed by immunoblotting.
mtDNA abundance (p<0.05), MRC complex II (p<0.001),
complex III (p<0.01) and complex IV (p=0.01) were lower
in the TP group than in the HC group. In the LTNP group these
parameters were similar to those of the HC group except for
complex II, which was decreased (p<0.01). The PBMC of TP
showed the highest overall apoptotic activation, since their
caspase-3 activity was greater than that of HC (p<0.05)
and LTNP. In the case of LTNP, however, the difference was
non-significant. Caspase-9 and the caspase-9/Bcl-2 ratio were
both over-expressed in TP compared to HC (p<0.01) and LTNP
(p<0.05). Both of these measurements indicate that mitochondrially-driven
apoptosis in TP is greater than in LTNP and HC. A relationship
between mitochondrial damage and apoptotic activation was
found in TP. Mitochondrial damage is associated with increased
PBMC apoptosis in patients with active HIV-1 replication (TP).
These abnormalities are slight or not present in LTNP.
[Back to top]
The HIV-1 Tat Protein Stimulates Reverse Transcription
In Vitro
Ann Apolloni, Luke W Meredith, Andreas Suhrbier, Rosemary
Kiernan and David Harrich
The role of Tat in HIV-1 reverse transcription has been controversial
largely because different studies have observed disparate
effects of the Tat protein on reverse transcription. Studies
of HIV-1 lacking a functional tat gene demonstrated
a decrease in reverse transcription efficiency following infection
of T-cells however, in vitro recombinant Tat1-86
has been shown to inhibit RT activity. Here we show that 20-200
nM of both N-terminally histidine-tagged recombinant Tat1-72
and Tat1-86 stimulated reverse
transcription by HIV-1 reverse transcriptase (RT) in vitro
by 2-3 fold. However, both Tat species were efficient inhibitors
of RT activity at 400 nM. The lower concentrations of Tat
increased reverse transcription efficiency by facilitating
multiple rounds of DNA synthesis, and this increase was either
not seen or reduced when Tat proteins with multiply-mutated
cysteine or basic domains were used. Tat-enhanced reverse
transcription occurred in a RNA-independent manner, and required
formation of a Tat-RT complex. Pull-down and immunoprecipitation
experiments confirmed that Tat could interact with the RT
p51 subunit, and mammalian two-hybrid experiments showed interaction
between Tat and both the p51 and p66 subunits. Together these
results provide evidence that Tat can stimulate reverse transcription
through an interaction with RT.
[Back to top]
AIDS-Defining Illnesses: A Comparison Between Before
and After Commencement of Highly Active Antiretroviral Therapy
(HAART)
Yvonne Lim Ai Lian, Benedict Sim Lim Heng, Veeranoot Nissapatorn
and Christopher Lee
Attempts to address the significant impact of HAART on medical
variables on the Malaysian HIV/AIDS population have yet to
be evaluated. This study aims to analyze the proportions of
AIDS-defining illnesses (ADIs) before and after HAART. A retrospective
study was carried out on 128 new cases of HIV infected patients
who first commenced HAART in 2004 at the national HIV reference
center. Before commencement of HAART, 76 clinical episodes
of ADIs were recorded in 52 patients. Most common being pulmonary
Mycobacterium tuberculosis (28.9%), PCP (27.6%) and
disseminated and extrapulmonary Mycobacterium tuberculosis
(11.8%). During HAART, 8 clinical episodes of ADIs were documented
in 7 patients with a median time of onset of 10 weeks after
initiation of HAART (range, 4-36 weeks). The median CD4 count
at the time of the commencement of HAART for these patients
was 11 cells/mm3. ADIs reported include PCP (2 episodes),
disseminated and extrapulmonary Mycobacterium tuberculosis
(2 episodes), extrapulmonary cryptococcosis (1 episode), esophageal
candidiasis (1 episode), recurrent pneumonia (1 episode) and
disseminated or extrapulmonary histoplasmosis (1 episode).
Three (37.5%) of these occurred despite a reduction of viral
load by at least 2 log10
and an increased in the CD4 cell count. In conclusion, ADIs
can still present after the initiation of successful HAART
especially in those with CD4 counts below 100 cells/mm3.
In Malaysia, ADIs are the major causes of HIV/AIDS associated
morbidity and mortality, thus increased awareness on the management
of these illnesses is warranted especially in the months following
HAART.
[Back to top]
Steatohepatitis in HIV-Infected Subjects: Pathogenesis,
Clinical Impact and Implications in Clinical Management
Marco Bongiovanni and Federica Tordato
Antiretroviral medications have significantly improved the
prognosis of subjects infected by human immunodeficiency virus
(HIV). However, long-term complications of these drugs are
increasingly recognized as significant causes of morbidity
and mortality. Non-alcoholic fatty liver disease (NAFLD),
which can evolve into non-alcoholic steato-hepatitis (NASH),
cirrhosis and ultimately hepatic failure is one of the more
often observed complications in the current clinical practice
and the correlation with liver enzyme elevations is controversial.
Multiple factors have been considered as possibly correlated
to this event in the HIV-infected population, including metabolic
abnormalities (such as hyperlipi-daemia, hyperglycaemia and
being overweight), chronic inflammation, concurrent infection
with hepatitis C and B viruses, and treatment with certain
nucleoside reverse transcriptase inhibitors (NRTI). HIV-associated
syndromes such as lactic acidosis and lypodystrophy are frequently
associated with fatty liver disease and a mitochondrial injury
has been considered as its possible pathogenetic factor. In
particular, treatment containing stavudine and didanosine
have proven to be the most commonly implicated in the occurrence
of mitochondrial abnormalities. Epidemiologic data to better
define the role of predictive factors and drugs associated
with the development of NAFLD are still lacking. Furthermore,
it remains unclear the better therapeutic management for this
condition, even if the current best therapeutic option for
NAFLD is the treatment of the underlying disease. Other studies
are mandatory to better elucidate the pathogenesis of NAFLD
and the optimal therapeutic strategy for the underlying conditions.
[Back to top]
Clinical Presentation, Treatment Outcome and Survival
Among the HIV Infected Children with Culture Confirmed Tuberculosis
Alok Kumar, Sanjay Upadhyay and Geeta Kumari
Background: We studied the clinical
presentation, diagnosis, treatment outcome and survival in
children with HIV and Tuberculosis (TB) co-infection.
Methods: All HIV infected children with symptoms
or signs consistent with tuberculosis were screened. We studied
24 cases of culture confirmed TB from among a cohort of 213
HIV infected children. All these children were on HAART for
their HIV infection. Information on TB was collected by retrospective
chart review of these children.
Results: In a cohort of 213 children with vertically
transmitted HIV infection, a total of 76 (36%) children suspected
to have tuberculosis based on their clinical presentation
together with either a positive Mantoux test or AFB positivity
and treated for TB. Twenty four children had culture positive
TB. The median age at diagnosis of TB was 16 months. Over
half of these children had some immunodeficiency. Common presentations
were fever (87%), history of contact with an open case of
TB (79%), cough for more than 2 weeks (75%), malnutrition
(71%), hepatosplenomegaly (71%), chronic diarrhea (67%) and
generalized lymphadenopathy (58%). Mantoux test result was
positive in 12 (50%) patients. Chest ro-entgenograms were
abnormal in all the children, with hilar and/or Para tracheal
node (62%) and lobar or segmental opacification (57%). Twenty
one (87%) children had pulmonary TB at the time of their diagnosis.
One or more sites of Extrapulmonary TB were confirmed in 10
(41%) patients. After six months of ATT, the cure rate was
64%. Three patients had documented drug-resistant. Five children
(20%) died.
Conclusion: TB is a common co-infection in HIV infected
children and children often present with un-resolving pneumonia.
It carries significant mortality despite the HAART and adequate
anti-tuberculosis treatment in these children.
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