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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 4, Number 1, January 2006
Contents
Review Articles
Editorial Pp. 1
Affordable Antiretroviral Drugs for the Under-Served
Markets: How to Expand Equitable Access Against the Backdrop
of Challenging Scenarios? Pp. 3-20
Daniele Dionisio, Yunzhen Cao, Lu Hongzhou, Krisana Kraisintu
and Daniela Messeri
[Abstract]
Understanding Human Immunodeficiency Virus Type 1
and Hepatitis C Virus Coinfection Pp. 21-30
Yee-Joo Tan, Seng Gee Lim and Wanjin Hong
[Abstract]
Uracils as a Cellular Weapon Against Viruses and Mechanisms
of Viral Escape Pp. 31-42
StŽphane Priet, JosŽphine Sire and Gilles QuŽrat
[Abstract]
Role of Viral Splicing Elements and Cellular RNA Binding
Proteins in Regulation of HIV-1 Alternative RNA Splicing
Pp. 43-55
C. Martin Stoltzfus and Joshua M. Madsen
[Abstract]
Modelling Thymic HIV-1 Nef Effects Pp. 57-64
Veronique Stove and Bruno Verhasselt
[Abstract]
HIV-1 Fitness and Disease Progression: Insights from
the SIV-Macaque Model Pp. 65-77
Jason T. Kimata
[Abstract]
Metabolic and Cardiovascular Complications of
Highly Active Antiretroviral Therapy for HIV Infection
Pp. 79-85
Giuseppe Barbaro
[Abstract]
Intestinal Parasite Infestation in HIV Infected
Patients Pp. 87-96
Viroj Wiwanitkit
[Abstract]
Original Research Articles
Diabetes Case Identification Methods Applied to Electronic
Medical Record Systems: Their Use in HIV-Infected Patients
Pp. 97-106
Heidi M. Crane, Joseph B. Kadane, Paul K. Crane and Mari
M. Kitahata
[Abstract]
Thrombocytopenia in HIV Infection: Impairment of Platelet
Formation and Loss Correltes with Increased cMpl and Ligand
Thrombopoietin Expression Pp. 107-116
I. Birgitta Sundell and Prasad S. Koka
[Abstract]
Abstracts
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Editorial
Current HIV Research begins its fourth volume providing
our readers with stimulating, timely, and in-depth articles
on current HIV and AIDS research. I take this opportunity
to thank the authors for providing such insightful reviews
and original scientific findings. Current HIV Research
received its first Impact Factor (1.571) from the
2004 SCI Journal Citation Reports with each issue indexed
in Chemical Abstracts, BIOSIS, Science Citation Index Expanded,
ISI Alerting Services, MEDLINE/Index Medicus, EMBASE/Excerpta
Medica, and the National Library of Medicine/PubMed. In 2005,
four times as many articles were submitted to the journal
for review than in the previous year; most likely due to the
increased profile of the journal in the scientific community.
I would also like to thank the Editorial Advisory Board for
their assistance and advice. The Editorial Advisory Board
reflects the international representation of scientists and
clinicians from some of the leading institutions in the world.
We are proud that a similar diversity is reflected in the
published and submitted articles as well. The journal publishes
both comprehensive reviews and original research articles
focused on all areas of HIV/AIDS research including molecular
biology, biochemistry, immunology, pharmacology, epidemiology,
antiviral agents and vaccine development, as well as clinical
research, which should be of interest to both basic and clinical
investigators.
In 2006, we expect to continue publishing the high level
of quality articles in Current HIV Research.
Ted M. Ross
Editor-in-Chief
Current HIV Research
University of Pittsburgh
School of Medicine, Division of Infectious Diseases
Scaife Hall, Suite 871
3550 Terrace Street
Pittsburgh
PA 15261, USA
E-mail: rosst@dom.pitt.edu
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Affordable Antiretroviral Drugs for the Under-Served
Markets: How to Expand Equitable Access Against the Backdrop
of Challenging Scenarios?
Daniele Dionisio, Yunzhen Cao, Lu Hongzhou, Krisana Kraisintu
and Daniela Messeri
BACKGROUND: Threats by enforced Intellectual
Property (IP) rights to equitable HIV treatment access by
poor populations are impending. India and China’s policy
directions in the field will be crucial in ultimately affecting
the affordability and accessibility of antiretroviral (ARV)
therapy in the under-served markets. These directions, together
with the exploitation level of IP-bound flexibilities and
the evolutionary modelling in partnerships and trade agreements
between research-based and generic pharmaceutical industry,
will also affect the outcomes of self-sufficiency efforts
now at their beginning in the developing world as far as domestic
manufacturing of generic ARV drugs is concerned.
AIMS: This paper explores key issues, implications
and interaction dynamics across these challenging scenarios
while attempting to provide equitable solution glimpses into
the near future.
RESULTS: Access-oriented long-term drug
policy strategies entitled to pass muster of governments,
research-based as well as generic industries in both developed
and developing countries are needed if equitable access to
affordable ARV treatments by poor people has to be achieved
despite enforced IP rights.
Predictable dynamics between western multinationals and transitional
country generic corporations let regard IP-bound Voluntary
License flexibilities as a fitting measure into just mentioned
needs especially if substantial incentives to generic corporations
are concurrently secured.
Efforts to equitably expand ARV drug access through exploiting
IP opportunities should encompass attainment of self-sufficiency
in domestic drug manufacturing whenever basic requirements
are in place in the developing world as a whole. A credible
industrial potential would act, indeed, as a boosting factor
for drawing branded drug producers into technology transfer
agreements, the terms of which would let all contractors enjoy
substantial advantages.
These perspectives consistently bind up with the foreseeable
long-term trade and drug policy directions of India and China
according to frontier crossing implications of their key IP
management trends as well as their multifaceted penetration
strategies of both the wealthy and under-served markets worldwide
As coherent with these perspectives, more disbursement by
wealthy country governments and donors to basic infrastructure
development in sub-Saharan African nations with stable governments
in place is urged both as a priority for improving Africa’s
economy and a prerequisite for allowing domestic industrial
plants to take off.
Aiming at the targets just underscored, WHO’s brokering
role in negotiated agreements between wealthy and developing
country-based firms as well as its technical guidance in setting
international standards have always to be sought if equitable
and appropriate end results are to be attained.
CONCLUSION: Overall insights in this paper
would mean that, while research-based corporations are to
be praised whenever waiving, on humanitarian purposes, part
of their profits, the trade and profit rules cannot basically
be given up if long-term sustainable results are the goal
to look for. Only negotiated agreements securing all contracting
parties lasting advantages may ensure shifting of such a goal
from mere vision to a really sustainable attainment.
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Understanding Human Immunodeficiency Virus Type 1
and Hepatitis C Virus Coinfection
Yee-Joo Tan, Seng Gee Lim and Wanjin Hong
In recent years, there has been an alarming increase in
the number of cases of coinfection with the human immunodeficiency
virus type 1 (HIV-1) and the hepatitis C virus (HCV). It is
now known that coinfection of HIV-1 patients by HCV can complicate
the treatment of these patients with highly active antiretroviral
therapy and the interactions between anti-HIV-1 and anti-HCV
medications can also affect treatment efficacy and efficiency.
Equally concerning, the bidirectional interferences between
the two viruses are complex and can modify the natural history
of both infections. This review aims to summarize the findings
of numerous scientific investigations in the area of HIV/HCV
coinfection. These investigations can be broadly classified
into 3 groups; (a) immune evasion mechanisms (b) viral evolution
and quasispecies diversity and (c) functions of viral proteins
and their interactions with host factors. Our cumulative knowledge
in this area and future research on the interplay between
these two viruses will be important to the development of
better antiviral therapeutics.
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Uracils as a Cellular Weapon Against Viruses and Mechanisms
of Viral Escape
StŽphane Priet, JosŽphine Sire and Gilles QuŽrat
Uracil in DNA is a deleterious event that may arise either
by cytosine deamination or misincorporation of dUTP. Consequently,
cells from all free-living organisms have developed strategies
to protect their genome against the presence of uracils, by
using uracil DNA glycosylase (UNG) and deoxyuridine triphosphatase
(dUTPase) enzymatic activities. In the viral kingdom, some
(namely poxviruses and herpesviruses) but not all of the DNA
viruses encode their own UNG and dUTPase to control uracilation
of their genome. Some retroviruses, which are RNA viruses
using DNA as an intermediate of replication, also encode dUTPase.
Surprisingly, though most of nonprimate lentiviruses encode
dUTPase, primate lentiviruses such as HIV-1, HIV-2 or SIV
do not. Because these latter viruses also replicate in nondividing
cells where the dUTP/dTTP ratio is high, it is probable that
they have found other ways to fight against the emergence
of uracilated-viral transcripts. Indeed, recent studies showed
that HIV-1 efficiently controls both the cytosine deamination
and the dUTP misincorporation. The viral Vif protein acts
in preventing the packaging into viral particles of the host-derived
cytosine deaminase APOBEC3G enzyme, while the viral integrase
domain of the Gag-Pol precursor mediates the packaging of
the host-derived uracil DNA glycosylase UNG2 enzyme. In the
absence of Vif or UNG2, HIV-1 viral transcripts are heavily
charged in uracil bases leading to inactivation of the virus.
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Role of Viral Splicing Elements and Cellular RNA Binding
Proteins in Regulation of HIV-1 Alternative RNA Splicing
C. Martin Stoltzfus and Joshua M. Madsen
In HIV-1 infected cells, over 40 different mRNA species
are produced by alternative splicing of the single HIV-1 primary
RNA transcript. In addition, approximately half of the HIV-1
primary RNA transcripts are not spliced and are exported to
the cytoplasm where they serve as mRNA and as genomic RNA.
In this article, we will review current knowledge of the mechanisms
by which the HIV-1 alternative splicing is regulated. Several
negatively and positively-acting cis-acting elements
have been detected within the viral genome that repress or
facilitate viral RNA splicing by binding to cellular proteins.
These include exonic splicing silencers (ESS) and an intronic
splicing silencer (ISS) that are selectively bound either
by members of the hnRNP A/B family (hnRNPs A1, A1B,
A2, and B1) or by hnRNP H. Exonic splicing enhancers (ESE)
are also present within the HIV-1 genome and are selectively
bound by members of the SR protein family. ESS and ISS repression
mediated by hnRNP A/B proteins occurs at early steps of splicing,
prior to formation of pre-spliceosome complexes. Current models
propose that ESS elements promote cooperative binding of hnRNP
A/B proteins to the exon and prevent efficient binding of
essential cellular splicing factors to the 3’ splice
site. SR proteins bound to ESE elements that are juxtaposed
or overlapping ESS elements may counteract this inhibition.
We will review data indicating the importance of the HIV-1
splicing elements and their cognate binding proteins for efficient
virus replication. Differences in cis-acting splicing
elements between the group M (major) and group O (outlier)
HIV-1 strains will also be discussed. Finally we will review
evidence suggesting the possibility that there may be changes
in regulation of HIV-1 alternative splicing in infected human
T cells, human macrophages and rodent cells.
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Modelling Thymic HIV-1 Nef Effects
Veronique Stove and Bruno Verhasselt
The nef gene is conserved among primate lentiviruses
and is one of the first viral genes that is transcribed following
infection. This suggests a critical role for Nef in the virus
life cycle and in the pathogenesis of lentiviral infections.
In vitro, several functions have been described,
including down regulation of CD4 and MHC class I surface expression,
altered T-cell signaling and activation, and enhanced viral
infectivity. However, the impact of these individual functions
on viral pathogenicity in general, and thymic T cell production
in particular, remains elusive. Here, we review the observations
from experimental models that have been used to study the
pathogenic effect of HIV-1 Nef on the thymus. These in
vitro and in vivo studies have led to a better
understanding of Nef’s mechanism of action, although
there still exists discord as to the contribution of Nef-mediated
disturbance of thymopoiesis in the pathogenesis of AIDS.
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HIV-1 Fitness and Disease Progression: Insights from
the SIV-Macaque Model
Jason T. Kimata
Within the initial weeks following transmission, HIV-1 becomes
well established in the lymphatic tissue reservoir. Replication
of the virus occurs throughout the course of infection despite
the induction of a vigorous adaptive immune response by the
host. The emergence of variants with particular characteristics
correlates with increased viral burden and disease progression,
indicating that the fitness of the infecting virus and selected
variants plays a significant role in persistent viral replication
and disease progression. This article reviews studies of HIV-1
variants and pathogenicity. It focuses mainly on experimental
SIV infection of macaques as a model system to decipher the
significance of viral variants for infection, persistence,
and disease because it is difficult to systematically examine
transmission and pathogenesis of HIV-1 in humans.
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Metabolic and Cardiovascular Complications of Highly
Active Antiretroviral Therapy for HIV Infection
Giuseppe Barbaro
Highly active antiretroviral therapy (HAART) regimens, especially
those including protease inhibitors have been shown to cause,
in a high proportion of HIV-infected patients, a metabolic
syndrome (lipodystrophy/lipoatrophy, dyslipidemia, type 2
diabetes mellitus, insulin resistance) that may be associated
with an increased risk of cardiovascular disease. A careful
stratification of the cardiovascular risk of HIV-infected
patients under HAART is needed according to the most recent
clinical guidelines.
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Intestinal Parasite Infestation in HIV Infected Patients
Viroj Wiwanitkit
One of the major health problems among HIV - infected patients
is the intestinal parasite infestations. It can be seen that
intestinal helminth infestation in HIV - infected patients
is common. However, the reported prevalence is usually similar
to those of non HIV-infected patients in the same setting.
The infestations are ordinary not opportunistic, hence, thus
usually show no correlation to immune status of the patients.
The suppression of immunity due to HIV infection shows no
significant role in increasing the intestinal helminth infestations.
On the other hand, having occult intestinal helminth infestations
does also not worsen the outcome of HIV infection. Concerning
the clinical manifestation, most of the helminth infestations
are asymptomatic and the diagnosis is usually based on the
stool examination. Treatments of the infestations as well
as the outcomes are usually similar to immunocompetent host.
Intestinal protozoa infestations are also important problems
for HIV-infected patients. Some infections are ordinary, while
the others are opportunistic infection. The important opportunistic
intestinal parasites including C. parvum, I. belli, Cyclospora
and the Microsporidia are found at high prevalence
among the HIV-infected patients, especially in low immune
cases with persistent diarrhea. Concerning the clinical manifestation,
most of the infestations bring diarrhea and the diagnosis
is usually based on the stool examination with special stains.
The treatment of the opportunistic infection can usually get
control of the present illness but not prevent the re-infection.
Luckily, with the present wide distribution of HAART, the
prevalence of the opportunistic intestinal protozoa infections
is significantly decreased.
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Diabetes Case Identification Methods Applied to Electronic
Medical Record Systems: Their Use in HIV-Infected Patients
Pp. 97-106
Heidi M. Crane, Joseph B. Kadane, Paul K. Crane and Mari
M. Kitahata
Objective: New onset diabetes mellitus
type 2 is increasing among HIV-infected patients in the era
of potent antiretroviral therapy. Accurately identifying HIV-infected
patients with a diagnosis of diabetes in electronic medical
record systems will facilitate the study of patients with
this disease.
Study Design And Setting: We examined
electronic medical record data for all patients who initiated
care at an HIV clinic between 1/1/1997 and 12/31/2001 to identify
potential cases of diabetes. Case identification methods included
clinician-coded diagnoses, medications, and HbA1c and glucose
levels. Diabetes diagnoses were verified by clinician documentation
in an electronic medical record progress note. Test characteristics
of each case identification method were calculated.
Results: 53 cases of diabetes were
identified among the cohort of 1441 patients. Use of clinician-coded
diagnoses alone or combined with other methods was the most
sensitive method for identifying diabetes cases. Clinician-coded
diagnoses were also the best method as assessed by standard
receiver operator characteristic plots. A significant attenuation
of odds ratios for associations with diabetes were found for
case identification methods with imperfect specificity such
as serum glucose levels.
Conclusions: This study demonstrates
that electronic medical record data can be used to accurately
identify HIV-infected patients with diabetes. The optimal
method applied will depend on the goals of a particular study.
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Thrombocytopenia in HIV Infection: Impairment of Platelet
Formation and Loss Correltes with Increased cMpl and Ligand
Thrombopoietin Expression
I. Birgitta Sundell and Prasad S. Koka
Thrombocytopenia is a common hematologic disorder in patients
infected with the human immunodeficiency virus (HIV) and represents
a risk for bleeding which is further deleterious during surgery.
The major causes of the thrombocytopenia include accelerated
peripheral platelet destruction by antiplatelet antibodies
and insufficient production of platelets from the infected
megakaryocytes. Additionally, at an earlier stage of platelet
development, HIV may inhibit megakaryopoiesis at multiple
stages of pluripotent CD34+ progenitor stem cell differentiation
possibly contributing to decreased levels of platelets in
circulation. In HIV infected patients, both the serum thrombopoietin
(TPO) levels and theTPO-c-Mpl complexes on the platelet surface
were significantly elevated. Therapeutic infusion of HIV infected
patients with pegylated recombinant human megakaryocyte growth
development factor (PEG-rHu-MGDF) restores platelet counts
to normal levels and reduces the c-Mpl expression per platelet.
In vitro aggregation of platelets treated with TPO
and agonist, adenosine diphosphate (ADP), decrease the dose
of ADP that is required for half-maximum aggregation.
In vivo dosing does not effect platelet aggregation showing
that the metabolism of TPO following its internalization through
TPO-c-Mpl complex is rapid and that dosing within the therapeutic
range does not constitute increased risk of thrombotic disease.
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