| Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 3, Number 1, 2005
Contents
Editorial Pp.1-1
Ted M. Ross
[Full text article]
HIV-2 Infection and Chemokine Receptors Usage
– Clues to Reduced Virulence of HIV-2 Pp.3-16
Jose Miguel Azevedo-Pereira, Quirina Santos-Costa and
Jose Moniz-Pereira
[Abstract] [Full
text article]
HIV-1 Prophylactic Vaccine Trials in Thailand
Pp.17-30
Punnee Pitisuttithum
[Abstract] [Full
text article]
HIV-1 Infection In Children: A Clinical and Immunologic
Overview Pp.31-41
Rana Chakraborty
[Abstract] [Full
text article]
The Role of Vpr in HIV-1 Pathogenesis Pp.43-51
Joshua L. Andersen and Vicente Planelles
[Abstract] [Full
text article]
Pathogenesis of Macrophage Tropic HIV-1 Pp.53-60
Paul R. Gorry, Melissa Churchill, Suzanne M. Crowe, Anthony
L. Cunningham and Dana Gabuzda
[Abstract] [Full
text article]
HIV-1 TAR RNA: The Target of Molecular Interactions
Between the Virus and its Host Pp.61-71
Sylvie Bannwarth and Anne Gatignol
[Abstract] [Full
text article]
The Packaging and Maturation of the HIV-1 Pol
Proteins Pp.73-85
Melissa Hill, Gilda Tachedjian and Johnson Mak
[Abstract] [Full
text article]
Nef: "Necessary and Enforcing Factor"
in HIV Infection Pp.87-94
Ajith M. Joseph, Manish Kumar and Debashis Mitra
[Abstract] [Full
text article]
Syphilis and HIV Co-Infection: When is Lumbar
Puncture Indicated? Pp.95-98
Derek J. Chan
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial
Ted M. Ross
[Full text
article]
Current HIV Research begins its third volume providing
our readers with stimulating, timely, and in-depth articles
on current HIV and AIDS research. As the Editor-in-Chief,
I take this opportunity to thank the authors who contributed
their ideas and insights into each article. The manuscripts
published in volumes 1 and 2 highlight a wide array of innovative
scientific and medical research on HIV/AIDS.
Beginning with the January, 2005 issue (Volume 3, Number
1), Current HIV Research will begin publishing original
scientific articles on all areas of HIV and AIDS research.
The journal will continue providing in-depth review articles,
however, the journal is expanding to include primary scientific
research at the request of authors and readers. The journal
welcomes the submission of novel and pioneering work in the
basic and clinical fields of virus replication and gene expression,
HIV assembly, virus–cell interaction, viral pathogenesis,
epidemiology and transmission, anti-retroviral therapy and
adherence, drug discovery, the latest developments in HIV/AIDS
vaccines and animal models, and prevention of viral infection.
Current HIV Research aims to be the international
journal for both comprehensive review articles and cutting-edge
scientific findings on HIV research. The Editorial Advisory
Board reflects the international representation of scientists
and clinicians located in 14 different nations 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 fills a special void in the
existing biomedical literature in publishing manuscripts focused
on all areas of HIV/AIDS research including molecular biology,
biochemistry, immunology, pharmacology, epidemiology, prevention
of transmission, antiviral agents and vaccine development,
as well as clinical research, which should be of interest
to both basic and clinical investigators.
We will continue to be responsive to our readers in order
to build one of the leading research journal on HIV and AIDS
research and we welcome your comments.
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
[Back to top]
HIV-2 Infection and Chemokine Receptors Usage – Clues
to Reduced Virulence of HIV-2
Jose Miguel Azevedo-Pereira, Quirina Santos-Costa
and Jose Moniz-Pereira
[Full text
article]
Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)
are the causative agents of Acquired Immunodeficiency Syndrome
(AIDS). Without therapeutic intervention, HIV-1 or HIV-2 infections
in humans are characterized by a gradual and irreversible
immunologic failure that ultimately leads to the onset of
a severe immunodeficiency that constitutes the hallmark of
AIDS. In the last two decades AIDS has evolved into a global
epidemic affecting millions of persons worldwide.
Although sharing several identical properties, HIV-1 and
HIV-2 have shown some important differences in vivo.
In fact, a significant amount of epidemiologic, clinical and
virologic data suggest that HIV-2 is in general less virulent
than HIV-1. This reduced virulence is revealed by the longer
asymptomatic period and the smaller transmission rate that
characteristically are observed in HIV-2 infection. In this
context, studies using HIV-2 as a model of a naturally less
pathogenic infection could bring important new insights to
HIV pathogenesis opening to new strategies to vaccines or
therapeutic design.
The reasons underlying the reduced pathogenicity of HIV-2
are still essentially unknown and surely are the outcome of
a combination of distinct factors. In this review we will
discuss the importance and the possible implications in HIV-2
pathogenesis, particularly during the asymptomatic period,
of a less fitted interaction between viral envelope glycoproteins
and cellular receptors that have been described in the way
HIV-2 and HIV-1 use these receptors.
[Back to top]
HIV-1 Prophylactic Vaccine Trials in Thailand
Punnee Pitisuttithum
[Full text
article]
The HIV epidemic has resulted in medical, social and economic
consequences. There is general agreement that a safe, effective
and affordable preventive HIV vaccine is urgently needed to
control the epidemic. To date, over 60 phase I/II trials of
about 30 candidate vaccines have been conducted worldwide.
In 1991, Thailand was selected by WHO, UNAIDS as one of the
countries for potential HIV vaccine evaluation sites, and
10 projects with HIV phase I, II and III trials have been
conducted since 1994. Strong national commitment, collaboration
both at national and international levels together with infrastructure
strengthening and capacity building, are very important for
success. The vaccine designs pursued included synthetic peptides,
recombinant protein and recombinant viral vectors followed
by or with boosting doses of recombinant proteins. All phase
I/II trials indicated that the candidate vaccines were safe
and produced binding and a certain level of neutralizing antibodies.
The recombinant vector vaccines produced both humoral and
cell-mediated responses. The AIDSVAX phase III trial conducted
in 1999 was the first efficacy trial of HIV vaccine in Thailand
that brought valuable information for further HIV vaccine
development. Recently, a phase III trial of ALVAC-HIV priming
with AIDSVAX®
B/E boosting was launched in 2003, and the findings
of this trial will be shared with the international community.
With committed parties in medical science, government, industry
and the community, we hope that we can achieve success in
developing a safe and effective HIV vaccine in the near future.
[Back to top]
HIV-1 Infection In Children: A Clinical and Immunologic Overview
Rana Chakraborty
[Full text
article]
Globally, HIV-1 is most often transmitted heterosexually
so that nearly half of all infected adults are women of child-bearing
age. Infants may acquire infection from vertical transmission.
Without treatment most HIV-1 infected children in Africa die
before their third birthday; as a result child mortality has
increased overall by 35-50%, and by greater than 100% in areas
of high seroprevalence.
HIV-1 infection has a heterogeneous spectrum of clinical
course. Compared to HIV-1-infected adults, survival times
are considerably shorter for children who acquire the virus
perinatally or during infancy. Factors contributing to accelerated
disease progression in infants and children are poorly understood
but may include relative immunological immaturity, thymic
HIV-1-mediated destruction at a time of active thymopoiesis,
and HLA class I sharing between mother and infant.
This review will initially discuss clinical and biological
determinants of mother-to-child transmission and disease progression
in HIV-infected infants and children. Our current knowledge
of the mechanisms of T cell depletion is summarised and the
host immune response to HIV-1 (innate and adaptive) described
in the context of Pediatric HIV-1 infection.
[Back to top]
The Role of Vpr in HIV-1 Pathogenesis
Joshua L. Andersen and Vicente Planelles
[Full text
article]
The HIV-1 vpr gene is conserved among the human
(HIV-1, HIV-2) and simian immunodeficiency viruses (SIV).
HIV-1 vpr encodes a 96-amino acid, 14 kDa protein
(Vpr). Research from a number of laboratories in the last
decade has shown that Vpr performs multiple functions, including
the induction of cell cycle arrest in the G2 phase, transactivation
of the viral promoter, nuclear import of preintegration complexes,
and induction of apoptosis in the infected cell. More recent
studies have attempted to elucidate the cellular targets that
Vpr utilizes in order to perform the above functions. This
review presents the latest findings about the pathogenic events
triggered by Vpr, the cellular pathways involved, and the
molecular and cellular consequences of the action of Vpr in
the context of HIV-1 infection.
[Back to top]
Pathogenesis of Macrophage Tropic HIV-1
Paul R. Gorry, Melissa Churchill, Suzanne M.
Crowe, Anthony L. Cunningham and Dana Gabuzda
[Full text
article]
Despite numerous studies on the impact of viral diversity,
human immunodeficiency virus type 1 (HIV-1)-specific immune
responses and host factors on disease progression, we still
do not have a firm understanding of the pathogenesis of HIV-1
infection. Rapid depletion of CD4+ T-lymphocytes has been
associated with a switch in viral coreceptor usage from CCR5
to CXCR4 in approximately 40 to 50% of infected individuals.
However, the majority of infected individuals who progress
to AIDS harbor only CCR5- dependent (R5) viral strains. HIV-1
disease progression is associated with an enhanced tropism
of R5 viral strains for cells of the monocyte/macrophage lineage
(enhanced M-tropism). However, the underlying molecular mechanisms
contributing to enhanced M-tropism by R5 HIV-1 strains, and
how HIV-1 variants with enhanced M-tropism cause CD4+ T-cell
depletion in vivo are unknown. This review examines
the relationship between viral coreceptor usage, M-tropism,
and pathogenicity of HIV-1. We highlight evidence supporting
the hypothesis that enhanced M-tropism of R5 HIV-1 results
from adaptive viral evolution, resulting in HIV-1 variants
that have increased ability to utilize relatively low levels
of CD4 and CCR5 expressed on macrophages. The evidence also
suggests that these late-emerging, R5 viral strains have reduced
sensitivity to entry inhibitors, and increased ability to
cause CD4+ T-lymphocyte loss. These variants are likely to
impact HIV-1 disease progression, particularly in patients
who persistently harbor only R5 viral strains.
[Back to top]
HIV-1 TAR RNA: The Target of Molecular Interactions Between
the Virus and its Host
Sylvie Bannwarth and Anne Gatignol
[Full text
article]
HIV-1 TAR RNA is the binding site of the viral protein Tat,
the trans-activator of the HIV-1 LTR. It is present at the
5' end of all HIV-1 spliced and unspliced mRNAs in the nucleus
as well as in the cytoplasm. It has a highly folded stem-bulge-loop
structure, which also binds cellular proteins to form ribonucleoprotein
complexes. The Tat-Cyclin T1-CDK9 complex is the main component
in the trans-activation of HIV-1 and its affinity for TAR
is regulated through Tat acetylation by histone acetyl transferases.
Recent studies show that this complex is able to recruit other
cellular partners to mediate efficient transcriptional elongation.
TRBP, PKR and La bind directly to the TAR RNA structure and
influence translation of HIV-1 in either positive or negative
manners. Some mutations in TAR RNA severely impair HIV-1 trans-activation,
translation and viral production, showing its functional importance.
The overexpression or suppression of several TAR RNAbinding
proteins has a strong impact on viral replication pointing
out their major role in the viral life cycle. TAR RNA has
been the target of drug development to inhibit viral replication.
Recent data using small molecules or RNA-based technologies
show that acting on the TAR RNA or on its viral and cellular
binding factors effectively decreases virion production.
[Back to top]
The Packaging and Maturation of the HIV-1 Pol Proteins
Melissa Hill, Gilda Tachedjian and Johnson Mak
[Full text
article]
The Pol protein of human immunodeficiency virus type 1 (HIV-1)
harbours the viral enzymes critical for viral replication;
protease (PR), reverse transcriptase (RT), and integrase (IN).
PR, RT and IN are not functional in their monomeric forms
and must come together as either dimers (PR), heterodimers
(RT) or tetramers (IN) to be catalytically active. Our knowledge
of the tertiary structures of the functional enzymes is well
advanced, and substantial progress has recently been made
towards understanding the precise steps leading from Pol protein
synthesis through viral assembly to the release of active
viral enzymes. This review will summarise our current understanding
of how the Pol proteins, which are initially expressed as
a Gag-Pol fusion product, are packaged into the assembling
virion and discuss the maturation process that results in
the release of the viral enzymes in their active forms. Our
discussion will focus on the relationship between structure
and function for each of the viral enzymes. This review will
also provide an overview of the current status of inhibitors
against the HIV-1 Pol proteins. Effective inhibitors of PR
and RT are well established and we will discuss the next generation
inhibitors of these enzymes as well recent investigations
that have highlighted the potential of IN and RNase H as antiretroviral
targets.
[Back to top]
Nef: "Necessary and Enforcing Factor" in HIV Infection
Ajith M. Joseph, Manish Kumar and Debashis Mitra
[Full text
article]
The Human Immunodeficiency Virus -1 (HIV-1) Nef protein that
was originally identified as a viral negative factor is a
27kDa myristoylated protein. However, this so called dispensable
viral protein has emerged as one of the most important proteins
for viral life cycle. Nef not only establishes the host cell
environment suitable for viral replication and pathogenesis
but also facilitates the progression of the infection into
disease. Previous efforts have been focussed to explain how
Nef down modulates host cell receptors like CD4 and MHC-1
molecules, thereby helping the virus to evade host defense
and to increase viral infectivity. Nef also ably modulates
specific processes like apoptosis in favour of viral life
cycle other than being the stimulus for cell activation and
signal transduction pathways. After much maligning over its
reported positive or negative functions on the HIV-1 Long
Terminal Repeat (LTR) promoter, the Nef protein is now perceived
to enhance viral replication and infection through a combination
of different effector functions. Recent reports emphasize
a role for Nef in viral gene expression and place it in a
prime position to oversee and optimize viral replication.
Nef may do so by enhancing Tat mediated gene expression from
the LTR by activating signalling pathways that result in a
concomitant increase in the activation of general transcription
factors, and also by mediating translocation of repression
factors from the nucleus. Thus, Nef not only enhances infection
but also plays an important role in viral replication and
pathogenesis.
[Back to top]
Syphilis and HIV Co-Infection: When is Lumbar Puncture Indicated?
Derek J. Chan
[Full text
article]
The rate of syphilis/HIV co-infection amongst men who have
sex with men (MSM) in large urban regions ranges from 20 to
70% [7]. Concurrent HIV infection can alter the clinical presentation
of syphilis, the response to treatment, and complicate the
diagnosis and clinical course of neurosyphilis [18]. Therefore
whether to perform a lumbar puncture (LP) on every co-infected
patient in order to diagnose neurosyphilis is controversial.
Current clinical guidelines specify the indications for LP,
but fall short of recommending LP in certain clinical situations
such as early syphilis without neurological involvement. This
article reviews the current literature on the relative utility
and indications for LP in syphilis/HIV co-infected patients
and new research in this area.
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