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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 5, Number 4, July 2007
Contents
Review Articles
HIV-1 Integrase: From Biology to Chemotherapeutics
Pp. 365-388
Eriketi Zeinalipour-Loizidou, Christos Nicolaou, Athanasios
Nicolaides and Leondios G. Kostrikis
[Abstract]
Original Research Papers
Oral Glucose Loading for Detection of
Mitochondrial Toxicity During HAART in HIV-Infected Patients
Pp. 389-393
Hadewych J.M. ter Hofstede, George F. Borm and Peter P.
Koopmans
[Abstract]
Rev-Dependent Indicator T Cell Line Pp. 394-402
Yuntao Wu, Margaret H. Beddall and Jon W. Marsh
[Abstract]
Oncogenic Properties of HIV-Tat in Colorectal Cancer
Cells Pp. 403-409
Duy Huynh, Elizabeth Vincan, Theo Mantamadiotis, Damian
Purcell, Chee-Kai Chan and Robert Ramsay
[Abstract]
The Antimicrobial Peptide LL-37 Inhibits HIV-1 Replication
Pp. 410-415
Peter Bergman, Lilian Walter-Jallow, Kristina Broliden,
Birgitta Agerberth and Johan Söderlund
[Abstract]
HIV-1-Discordant Couples in Sub-Saharan Africa: Explanations
and Implications for High Rates of Discordancy Pp.
416-429
Brandon L. Guthrie, Guy de Bruyn and Carey Farquhar
[Abstract]
Lability of Antiretroviral Drug Resistance Mutations
- Correlates with Immunological and Virological Responses
Pp. 430-439
Ali Al Mazari, Albert Y. Zomaya, Michael Charleston, Hanan
Salem, AnnaMarie Maher and Roger J. Garsia
[Abstract]
Clinical Ritonavir and Lopinavir Hypersensitivity
Confirmed by a Specific In Vitro Cellular Allergen
Stimulation Test Pp. 440-442
Roberto Manfredi, Sergio Sabbatani and Sergio Bergonzi
[Abstract]
Abstracts
[Back to top]
HIV-1 Integrase: From Biology to Chemotherapeutics
Eriketi Zeinalipour-Loizidou, Christos Nicolaou, Athanasios
Nicolaides and Leondios G. Kostrikis
AIDS has claimed the lives of 25 million people worldwide,
an additional 40 million people are HIV-infected and new cases
are being diagnosed every year. Despite the fact that HAART
has moved AIDS from the category of terminal diseases to that
of treatable chronic illnesses, its long-term therapeutic
success may be compromised by the development of resistance
to the currently used drugs. Despite the availability of RT,
PR and fusion inhibitors, the development of further drugs
such as inhibitors that target the third enzyme IN is essential
for the clinical management of HIV-infected patients. The
absence of cellular homolgues to IN and the unique nature
of the reactions catalyzed by IN, make it an ideal target
for drug design. Considerable progress towards designing HIV-1
IN inhibitors has been made over the last years and several
lead compounds have been identified, synthesized and clinically
studied. This review focuses on the existing knowledge of
the biology of HIV-1 IN with emphasis on the mechanism of
integration, structure and function and the technologies for
measuring IN activity. This is followed by the current trends
on designing HIV-1 IN inhibitors with the aid of molecular
informatics and a review on the main classes of HIV-1 IN inhibitors
reported this far with special emphasis on the clinical candidates.
[Back to top]
Oral Glucose Loading for Detection of
Mitochondrial Toxicity During HAART in HIV-Infected Patients
Hadewych J.M. ter Hofstede, George F. Borm and Peter P.
Koopmans
Nucleoside reverse transcriptase inhibitors used in antiretroviral
therapy may cause mitochondrial toxicity. Mitochondrial dysfunction
leads to disturbance of the glucose metabolism, resulting
in an accumulation of L-lactate. We tested the hypothesis
that an oral glucose tolerance test (OGTT) can be used to
detect mitochondrial toxicity in patients on antiretroviral
nucleoside analogues. An OGTT was performed in 30 subjects:
16 HIV-infected treated patients without adverse events (group
1) and 14 HIV-infected patients with adverse events related
to nucleoside reverse transcriptase inhibitor-induced mitochondrial
toxicity (group 2). Lactate was measured at baseline and 60
and 120 min after glucose loading. At all time points the
lactate levels were higher in the adverse events group compared
to the other group, with the highest levels of lactate at
t = 60 min (mean 1912 µmol/L, SD ±
609); mean lactates in the group without adverse events was
1429 µmol/L (SD ±
464). When levels above the upper limit of normal of 1800
µmol/L were used as an indication for mitochondrial
toxicity, the sensitivity and specificity were 57% and 81%,
respectively. The area under the ROC curve was 0.75. For L-lactate
levels > 2000 μmol/L
the specificity was 90%. An OGTT with measurement of lactate
at baseline and one hour after glucose loading can detect
(occult) hyperlactataemia in patients with mitochondrial impairment.
From our study we suggest to perform an OGTT as an additional
test in patients with symptoms suspect for adverse events
to discern mitochondrial toxicity.
[Back to top]
Rev-Dependent Indicator T Cell Line
Yuntao Wu, Margaret H. Beddall and Jon W. Marsh
Measuring virion infectivity is critical for studying and
monitoring the process of HIV-1 infection. The easiest and
the most common method utilizes reporter cell lines based
on the HIV LTR promoter. The early HIV gene product Tat amplifies
expression from the LTR; however, there is a background transcriptional
activity that is independent of Tat. Furthermore, LTR activity
can be influenced by cellular activation states. We have recently
constructed a Rev-dependent expression vector, and as a test
of this construct's functionality, we have integrated this
vector into a continuous T cell line. This novel indicator
cell has no measurable background signal, is not affected
by elevated metabolic states, and yet responds robustly to
the presence of HIV. The line is able to complete TCID50 assays
in 3-5 days, and appears sensitive to both CCR5- and CXCR4-utilizing
viruses.
[Back to top]
Oncogenic Properties of HIV-Tat in Colorectal Cancer
Cells
Duy Huynh, Elizabeth Vincan, Theo Mantamadiotis, Damian
Purcell, Chee-Kai Chan and Robert Ramsay
With the advent of Highly-Active-Anti-Retroviral-Therapy (HAART),
HIV patients can expect to live beyond 10-15 years following
diagnosis. An unexpected result of increased survival is the
emergence of opportunistic, oncogenic virus-associated cancers
such as Burkitt’s lymphoma (Epstein-Barr Virus), cervical
cancer (Human Papilloma Virus) and Kaposi’s sarcoma
(Kaposi’s sarcoma-associated herpesvirus) in this immuno-compromised
population. Furthermore, there are reports of colorectal cancers
(CRC) in long-term HIV-AIDS survivors. Compared to the general,
non-immuno-compromised population, long-term AIDS patients
have 4 and 3.3-fold increased risk of developing colorectal
and anorectal cancer respectively. Unlike oncogenic virus-associated
cancers, CRC is not known to have a viral etiology. Our study
aimed to investigate one aspect of HIV infection and colorectal
carcinogenesis. We proposed that the HIV transactivator protein
Tat; a protein with known oncogenic properties that is secreted
and can re-enter non-infected cells may have a role in CRC.
Using two CRC cell lines, LIM1215 and LIM2537 we found that
Tat inhibits epithelial cyto-differentiation, blocks apoptosis
in vitro and accelerates tumour formation in
vivo. In addition, Tat significantly increases in
vitro migration in the absence of foetal calf serum.
These properties underpin CRC, and as HIV infection is initiated
in the gut lymphoid system, these data provide a basis for
the increased incidence of CRC in long term AIDS patients.
[Back to top]
The Antimicrobial Peptide LL-37 Inhibits HIV-1 Replication
Peter Bergman, Lilian Walter-Jallow, Kristina Broliden,
Birgitta Agerberth and Johan Söderlund
The antimicrobial peptide LL-37 is the only cathelicidin that
has been described in humans. LL-37 exerts chemotactic, immunomodulatory
and angiogenic effects; activities that are mediated through
binding to the formyl peptide receptor like (FPRL)-1 receptor.
Agonistic ligation of FPRL-1 can also induce down-regulation
of HIV-1 chemokine receptors and reduce susceptibility to
HIV-1 infection in vitro. Therefore, we have evaluated
the capacity of LL-37 to inhibit HIV-1 infection in vitro.
Here we demonstrate that LL-37 inhibits HIV-1 replication
in PBMC, including primary CD4+ T cells. This inhibition
was readily reproduced using various HIV-1 isolates without
detectable changes in the target cell expression of HIV-1
chemokine receptors. Accordingly, the HIV-1 inhibitory effect
was shown to be independent of FPRL-1 signalling. Given the
epithelial expression of LL-37, it may contribute to the local
protection against HIV-1 infection.
[Back to top]
HIV-1-Discordant Couples in Sub-Saharan Africa: Explanations
and Implications for High Rates of Discordancy
Brandon L. Guthrie, Guy de Bruyn and Carey Farquhar
In sub-Saharan Africa, approximately 1 in 2 HIV-1-infected
persons living in a couple have a serodiscordant partner.
Recent data suggest a large proportion of new HIV-1 infections
in mature epidemics occur within discordant couples, making
discordancy a major contributor to the spread of HIV/AIDS
in Africa. What accounts for high rates of HIV-1 discordance
and why some individuals remain uninfected despite repeated
sexual exposure to HIV-1 is unknown. Studying HIV-1-discordant
couples may contribute to understanding correlates of HIV-1
immunity and acute infection. Additionally, HIV-1-discordant
couples are an important population for prevention efforts.
Consequently, HIV-1-discordant couples are increasingly viewed
as a valuable source of participants for HIV vaccine and prevention
trials. This review summarizes and critiques existing data
on HIV-1-discordant couples in developing countries, including
an analysis of transmission rates within discordant couples,
description of biological and behavioral characteristics important
in planning HIV-1 vaccine and prevention trials, and challenges
faced when carrying out such studies.
[Back to top]
Lability of Antiretroviral Drug Resistance Mutations
- Correlates with Immunological and Virological Responses
Ali Al Mazari, Albert Y. Zomaya, Michael Charleston, Hanan
Salem, AnnaMarie Maher and Roger J. Garsia
This study assessed the relationship between changes in CD4
T-cell count, HIV Viral Load (VL) level and evolutionary patterns
in Antiretroviral (ARV) resistance mutations of circulating
HIV in those with persistent viraemia despite treatment. The
study examined the dynamics of change in resistance mutations
to explore potential predictors of evolution in the circulating
virus over a prolonged period. Four longitudinal blood samples
from 29 HIV-infected Australian patients at RPAH are analysed
for the presence of genotypically resistant HIV virus. The
subjects had CD4 cells counts (40-670 cells/mm3),
VL levels (1.7-5.7 log10
copies/ml), drug resistance mutations, and had been treated
with ARV regimens for varying periods between February 1998
and June 2005 (i.e., 88 months). Parametric and nonparametric
tests were used to examine changes in CD4 T-cell counts and
VL levels, and in frequencies of mutations at different sample
points. Nonparametric LOESS fitting curves were used to analyse
changes in CD4 T-cell counts and VL levels. During the study
period, changes in mean values of CD4 cell counts and VL levels
in patients displaying an evolving genotypic resistance profile
differed from those without evidence of an evolving mutational
pattern; applied for both Reverse-Transcriptase (RT) and Protease
(PR) gene profiles. In patients with Evolution-of-Resistance
(EoR) at the RT site, there was a significant decrease in
mean CD4 cell count during the first 36 months (-194 cells/mm3,
P=0.0466) but no significant change in the last 52 months
or thereafter (-10 cells/mm3,
P=0.8464). Conversely, in patients with EoR at the PR site,
there was no significant change in mean CD4 cell count during
the first 36 months (-30 cells/mm3,
P=0.6187) but a significant decrease (-155 cells/mm³,
P=0.0348) thereafter. In patients without EoR at the RT site,
there was no significant change in mean CD4 count during the
first 36 months (-12 cells/mm3,
P=0.8371), however, a significant increase in mean CD4 cell
count occurred thereafter (+242 cells/mm³, P=0.0077).
Similarly, in patients without EoR at the PR site there was
no significant change in mean CD4 count during the first 36
months (-19 cells/mm3, P=0.6647)
and there was a significant increase in the last 52 months
(+145 cells/mm3, P=0.0348).
The only significant decrease in mean value of VL levels occurred
in patients without EoR associated with NRTIs thereafter (-1.33
log10 copies/ml, P=0.0477),
while no significant changes in mean value of VL levels in
patients with/without EoR associated with any ARV drugs at
any other time points (-0.65 to +0.15 log10
copies/ml, P=0.1855 to 0.7958). Low CD4 cell counts (<250
cells/mm3) and high VL levels
(>4.50 log10 copies/ml)
in the early stage of HIV infection, a significant decrease
in CD4 cell counts during the first 36 months (-50 or more
cells/mm3), and high frequencies
of mutations during the first 36 months of antiretroviral
regimen (>3 mutations) emerged as potential predictive
factors of EoR associated with NRTI/PRI agents thereafter.
Stable VL in the first 36 months correlated with lack of lability
of resistance mutations thereafter.
[Back to top]
Clinical Ritonavir and Lopinavir Hypersensitivity
Confirmed by a Specific In Vitro Cellular Allergen
Stimulation Test
Roberto Manfredi, Sergio Sabbatani and Sergio Bergonzi
A HIV-infected patient treated since eight years with all
antiretroviral classes save boosted protease inhibitors, at
the time of changing therapy due to an emerging genotyping
resistance to non-nucleoside reverse transcriptase inhibitors,
experienced repeated episodes of hypersensitivity reactions
to all available boosted protease inhibitors. After documenting
a combined ritonavir and lopinavir hypersensitivity by means
of a specific in vitro cellular antigen stimulation
test (CAST), antiretroviral therapy was safely continued with
unboosted atazanavir. According to our knowledge, we report
the first case of application of the in vitro CAST
assay to antiretroviral intolerance, and the subsequent, specific
regimen selection in a HIV-infected subject who showed multiple
allergy to all boosted protease inhibitors. Further, controlled
investigation is strongly needed to implement in vitro
allergometric testing in patients with HIV infection and related
diseases, who are prone to show unpredictable drug intolerance
reactions. In fact, HIV-infected patients may suffer from
frequent allergic drug reactions which may be difficult to
be systematically recognized (due to the frequent, multiple
concurrent pharmacotherapy), while eventual drug rechallenges
are expected to be potentially dangerous.
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