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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 5, Number 1, January 2007
Contents
Review Articles
Editorial Pp. 1
Regulation of HIV-1 Transcription by Protein Phosphatase
1 Pp. 3-9
Sergei Nekhai, Marina Jerebtsova, Angela Jackson and William
Southerland
[Abstract] [Full
text article]
Exploiting Structurally Diverse Nucleoside Analogs
as Probes of Reverse Transcription Complexes Pp.
11-22
Jason W. Rausch and Stuart F.J. Le Grice
[Abstract] [Full
text article]
HIV Genetic Diversity: Biological and Public Health
Consequences Pp. 23-45
Isolde F. Butler, Ivona Pandrea, Preston A. Marx and Cristian
Apetrei
[Abstract] [Full
text article]
Immune Responses to HIV gp120 that Facilitate Viral
Escape Pp. 47-54
Liljana Stevceva, Victor Yoon, Daphne Anastasiades and
Mark C. Poznansky
[Abstract] [Full
text article]
Impact of Human Immune Deficiency Virus Infection
on Hepatitis C Virus Infection and Replication Pp.
55-67
Cecilia Parodi, Liliana Belmonte, Patricia Baré,
María M.E. de Bracco and Beatriz Ruibal-Ares
[Abstract] [Full
text article]
Original Research Papers
Alteration of the Proline at Position 7 of the HIV-1
Spacer Peptide p1 Suppresses Viral Infectivity in a Strain
Dependent Manner Pp. 69-78
Melissa K. Hill, Anna Bellamy-McIntyre, Laura J. Vella,
Shahan M. Campbel, John A. Marshall, Gilda Tachedjian and
Johnson Mak
[Abstract] [Full
text article]
Herpesvirus Saimiri Terminal Membrane Proteins Modulate
HIV-1 Replication by Altering Nef and Tat Functions
Pp. 79-86
Andrea D. Raymond, Muneer Hasham, Alexander Y. Tsygankov
and Earl E. Henderson
[Abstract] [Full
text article]
Identification of Cross-Neutralization Determinants
by GAP Analysis: A Mutational Behavior Approach Pp.
87-96
Fusheng Li, Peter B. Gilbert and Steve G. Self
[Abstract] [Full
text article]
HIV-1 CTL-Based Vaccine Immunogen Selection: Antigen
Diversity and Cellular Response Features Pp. 97-107
Fusheng Li, Helen Horton, Peter B. Gilbert, Juliana M.
McElrath, Lawrence Corey and Steve G. Self
[Abstract] [Full
text article]
Routine Collection of Patient-Reported Outcomes in
an HIV Clinic Setting: The First 100 Patients Pp.
109-118
Heidi M. Crane, William Lober, Eric Webster, Robert D.
Harrington, Paul K. Crane, Thomas E. Davis and Mari M. Kitahata
[Abstract] [Full
text article]
Identification of HLA-A11-Restricted HIV-1-Specific
Cytotoxic T-Lymphocyte Epitopes in China Pp. 119-128
Shaoyang Wang, Yongtao Sun Song Zhai, Yan Zhuang, Shuguang
Zhao, Whenzhen Kang, Xinhong Li, Dedong Huang,Xu G. Yu, Bruce
D. Walker and Marcus A. Altfeld
[Abstract] [Full
text article]
Prevalence of Dilated Cardiomyopathy in HIV-Infected
African Patients Not Receiving HAART: A Multicenter, Observational,
Prospective, Cohort Study in Rwanda Pp. 129-137
Marc Twagirumukiza, Emmanuel Nkeramihigo, Benoit Seminega,
Emmanuel Gasakure, Franck Boccara and Giusseppe Barbaro
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial
Current HIV Research begins its
fifth 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 in previously published volumes highlight
a wide array of innovative scientific and medical research
on HIV/AIDS.
In 2007, (Volume 5), Current HIV Research
will expand the number of published issues to 6. The journal
will continue to publish both original scientific articles
and in-depth reviews on all areas of HIV and AIDS research.
In 2006, Current HIV Research began publishing a
series of HOT TOPIC issues focusing on research
from leading HIV/AIDS researchers on a specialized area of
HIV research. Each issue is edited by a distinguished leader
in the HIV/AIDS field. In Volume 4, Dr. Jon Marsh from the
National Institute of Mental Health, in Bethesda, Maryland,
USA edited an outstanding issue (Volume 4-3) on NeuroAIDS.
This issue has been the most requested issue for reprints
from Current HIV Research. The success
of this issue has promoted me to continue this program to
include at least one HOT TOPIC issue in each
future volume of Current HIV Research.
In addition, the journal continues to welcome 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 16 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,
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)
Center for Vaccine Research
University of Pittsburgh
9047 Biomedical Science Tower 3
3501 Fifth Avenue
Pittsburgh
PA 15261
USA
E-mail: rosst@dom.pitt.edu
[Back to top]
Regulation of HIV-1 Transcription by Protein Phosphatase 1
Sergei Nekhai, Marina Jerebtsova, Angela Jackson and William
Southerland
[Full
text article]
The emergence of drug-resistant HIV-1 strains presents a challenge
for the design of new drugs. Targeting host cell factors involved
in the regulation of HIV-1 replication might be one way to
overcome the resistance of HIV-1 to anti-viral agents. Our
recent studies identified protein phosphatase-1 (PP1) as an
important regulator of HIV-1 transcription. Transcription
of HIV-1 genes is activated by HIV-1 Tat protein that induces
phosphorylation of the C-terminal domain of RNA polymerase-II
by CDK9/cyclin T1. We have shown that HIV-1 Tat binds PP1
in vitro; targets PP1 to the nucleus; and that Tat
interaction with PP1 is important for HIV-1 transcription.
In this review, we discuss two potential targets of PP1 in
Tat-induced HIV-1 transcription: the C-terminal domain of
RNA polymerase-II and CDK9. We also present a computer model
of Tat-PP1 complex that might be useful for future drug design
in anti-HIV-1 therapeutics.
[Back to top]
Exploiting Structurally Diverse Nucleoside Analogs
as Probes of Reverse Transcription Complexes
Jason W. Rausch and Stuart F.J. Le Grice
[Full
text article]
Crystal structures of HIV-1 reverse transcriptase (RT) in
complex with either duplex DNA or an RNA/DNA hybrid have provided
significant insights into the manner in which this highly
versatile enzyme accommodates the conformationally-distinct
nucleic acid substrates encountered during the reverse transcription
cycle. Biochemical data likewise suggest that unique structural
features of the nucleic acid substrates contribute towards
recognition by their cognate RT. While site-directed mutagenesis
of catalytically- and structurally-critical protein motifs
is relatively facile, understanding how nucleic acid structure
contributes to its recognition presents a greater challenge.
The relative ease with which large DNA and RNA fragments can
now be chemically synthesized, in conjunction with the increased
availability of ribo- and deoxyribonucleoside analogs, allows
nucleic acid structure to be examined with respect to the
role of hydrogen bonding, nucleobase stacking, sugar ring
geometry and charge of the phosphodiester backbone. This review
summarizes our use of nucleoside analogs to understand how
the structure of cis-acting regulatory signals mediates
their recognition by structurally diverse retroviral and retrotransposon
enzymes.
[Back to top]
HIV Genetic Diversity: Biological and Public Health
Consequences
Isolde F. Butler, Ivona Pandrea, Preston A. Marx and Cristian
Apetrei
[Full
text article]
The devastating consequences of AIDS pandemic will probably
only be controlled when a vaccine is developed that is safe,
effective, affordable, and simple enough to permit implementation
in developing countries where the impact of AIDS is most severe.
However, the major obstacle for the control of the spread
of AIDS lies in the diversity of HIV and its enormous evolutionary
potential. Numerous HIV forms contribute to the AIDS pandemic.
Two viral types (HIV-1 and HIV-2), numerous groups (M, N and
O for HIV-1 and A through H for HIV-2) and numerous subtypes,
sub-subtypes and circulating recombinant forms (CRF) have
emerged during the last 50 years. At least nine different
genetic HIV-1 sub-types and over 20 CRFs were defined within
group M, which accounts for the majority of cases in the AIDS
pandemic. Even though HIV-1 subtype C and A predominate globally,
the other viral forms co-circulate all over the world and
may have a major impact for the strategies of pandemic control.
Here we discuss the distribution of these divergent viral
forms worldwide and the potential consequences of such a tremendous
viral diversity for diagnostic, monitoring, treatment and
the development of an effective vaccine.
[Back to top]
Immune Responses to HIV gp120 that Facilitate Viral
Escape
Liljana Stevceva, Victor Yoon, Daphne Anastasiades and
Mark C. Poznansky
[Full
text article]
The gp160 complex of the envelope of the HIV virus and its
component gp120 are essential for viral entry into the host
cell. Gp120 binding to its receptor CD4 and co-receptor, CXCR4
or CCR5 is required for fusion of viral and cellular membranes.
The presence of gp120 facilitates immune escape of the virus
through its profound effect on the immune cells. It is a polyclonal
activator of B cells, causing them to differentiate into immunoglobulin
producing cells while activating the complement cascade. This
results in the formation of immune complexes that are unable
to kill the virus but instead shield it from the attack of
other immune cells. Such HIV-1 virus that is trapped within
immune complexes and is bound to the B cells via
CD21 is more infectious than the free virion. In addition,
HIV virions are trapped on the membrane of follicular dendritic
cells (FDC) processes in immune complexes or through complement
receptors. Thus, FDC can serve as a ‘Trojan horse’
and transmit the trapped virus to CD4+ T lymphocytes as they
migrate through the germinal centre to the follicular mantle
and paracortical areas. It was demonstrated that CXCR4-binding
HIV-1 X4 gp120 causes the movement of T cells, including HIV-specific
CTL, away from high concentrations of the viral protein and
its expression by target cells reduces CTL efficacy in
vitro. Therefore, apart from the essential role in viral
attachment and infection of cells, gp120 possesses several
properties that affect the behavior of immune cells and skew
the immune response to the virus facilitating viral escape.
[Back to top]
Impact of Human Immune Deficiency Virus Infection
on Hepatitis C Virus Infection and Replication
Cecilia Parodi, Liliana Belmonte, Patricia Baré,
María M.E. de Bracco and Beatriz Ruibal-Ares
[Full
text article]
Human immune deficiency virus (HIV) and human hepatitis C
virus (HCV) infection are frequent in patients who have been
exposed to blood or blood-derived products. It has been suggested
that HIV infection increases HCV replication altering the
course of HCV-related disease. However, it is not known if
HIV directly enhances HCV replication or if its effect is
the consequence of HIV infection of other cell types that
control HCV replication (lymphocytes, macrophages). While
the main cell targets for HIV infection are mononuclear leukocytes
bearing CD4 and the chemokine receptors CCR5 and CXCR4, HCV
was originally thought to be strictly hepatotropic, but it
is now known that HCV can also replicate in peripheral blood
mononuclear cells (PBMC). Therefore, in co-infected individuals,
these two different viruses could share cell targets and interact
either directly or indirectly. Some membrane receptors can
be used by both HCV and HIV for entry into target cells, but
the intracellular mechanisms shared by these viruses are not
known. Lack of experimental systems providing suitable methods
for the study of HCV replication in the presence or absence
of HIV co-infection has hampered advances in this research
area, but recent investigations are currently going on in
order to answer these questions. This is an important issue,
as knowledge of HIV/HCV interactions is required for the design
of effective antiviral therapies.
[Back to top]
Alteration of the Proline at Position 7 of the HIV-1
Spacer Peptide p1 Suppresses Viral Infectivity in a Strain
Dependent Manner
Melissa K. Hill, Anna Bellamy-McIntyre, Laura J. Vella,
Shahan M. Campbel, John A. Marshall, Gilda Tachedjian and
Johnson Mak
[Full
text article]
The HIV-1 spacer peptide p1 is located in the C-terminus of
the Gag polyprotein and separates the nucleocapsid (NC) and
p6Gag. Research centered on p1 has been limited
and as yet no function has been ascribed to this spacer peptide.
We have previously found that the conserved p1 proline residues
(position 7 and 13) are critical for replication in the HIV-1
strain HXB2-BH10. In this study we have focused on the proline
rich p1-p6Gag C-terminus of HIV-1. We individually
examined the role of p1 proline’s in multiple strains
of HIV-1 and investigated the role of three proline residues
in p6Gag (P24, P25 and P30). Assessment of the
HXB2-BH10 based mutants revealed that Gag-Pol incorporation
relative to Gag decreased in the p1 mutant virions, with the
double proline mutant the most impaired. Mutating both p1
proline residues was found to abolish infectivity in multiple
strains of HIV-1. Independent mutation of the p1 proline at
position 7 resulted in a strain-dependent suppression of viral
infectivity. This defect correlates with the presence of a
tyrosine residue at position 9 of p1 and occurs in the early
phase of the HIV-1 replication cycle. The p1 proline residues
were found to be functionally distinct from P24, P25 and P30
in p6Gag. This work affords novel insights into
our understanding of the role of p1 in HIV-1 replication.
[Back to top]
Herpesvirus Saimiri Terminal Membrane Proteins Modulate
HIV-1 Replication by Altering Nef and Tat Functions
Andrea D. Raymond, Muneer Hasham, Alexander Y. Tsygankov
and Earl E. Henderson
[Full
text article]
Herpesvirus saimiri (HVS)-transformed human T cells expressing
terminal membrane proteins (TMPs) tyrosine kinase interacting
protein (Tip) and saimiri transformation associated protein
strain C (StpC) are highly permissive for R5 and X4 strains
of HIV-1. StpC expression enhances replication of R5 and X4
strains of HIV-1 and induces latent reservoirs of replication
competent HIV-1 in cell lines derived from T cells or monocytes.
Paradoxically Tip expression restricts replication and cytopathic
effects of R5 and X4 strains of HIV-1 in T cells and monocytes
post-retrotransposition. Understanding the canonical pathways
whereby Tip and StpC alter HIV-1 replication may uncover novel
therapeutic approaches to HIV-1 infection. Here we show Tip
inhibits Tat-mediated transcriptional activation of the long
terminal repeat (LTR). Tip mediated inhibition of Tat transactivation
is reversed by Nef. Tip also mediates restriction of late-stage
replication of HIV-1 by disrupting Nef interaction with lymphocyte-specific
protein-tyrosine kinase (Lck) in lipid rafts. Specifically,
in the presence of Tip, Lck does not localize to lipid rafts
reducing Nef interaction with Lck within the lipid rafts.
Finally, the permissive phenotype conferred by StpC is the
result of synergy with Tat during transcriptional activation
of the HIV-1 LTR. This transcriptional synergy between StpC
and Tat requires Lck and NF-κB
consensus binding sequences. These findings demonstrate that
the HVS TMPs influence transcriptional and post-transcriptional
stages in HIV-1 replication. We propose that HVS-encoded TMPs
associated with T cell transformation have evolved ability
to modulate the replication of competing retroviruses. Gene
based approaches utilizing Tip and StpC may provide therapeutic
models for treating acute and latent HIV-1 infections, respectively.
[Back to top]
Identification of Cross-Neutralization Determinants
by GAP Analysis: A Mutational Behavior Approach
Fusheng Li, Peter B. Gilbert and Steve G. Self
[Full
text article]
Antigenic variation, which is the result of amino acid substitution
and genetic evolution, poses a major challenge in the development
of vaccines against pathogens with unstable genomes, such
as HIV-1 and Influenza. Thus, it is highly important to characterize
the relationship of genetic evolution, antigenic variation
and positional mutation (GAP) from the perspective of vaccine
development. For this purpose, we introduce an automatic and
simple GAP analysis approach, which is based on the fundamental
concept of “mutational behavior” in genomic research,
to predict the specificity-determining positions in protein
families. This approach identifies cross-neutralization determinants
by mutational behavior correlation to antigenic and genetic
changes. Correlated mutation analysis and structure mapping
further refine the cross-neutralization determinants. The
usability of this approach is confirmed by analysis of an
Influenza H3N2 cross-reactive dataset.
[Back to top]
HIV-1 CTL-Based Vaccine Immunogen Selection: Antigen
Diversity and Cellular Response Features
Fusheng Li, Helen Horton, Peter B. Gilbert, Juliana M.
McElrath, Lawrence Corey and Steve G. Self
[Full
text article]
Much of the current effort in HIV-1 vaccine design is directed
at achieving T-cell immunity that will result in enough immunological
memory to contain HIV-1 infection after acquisition. However,
antigenic diversity, plus a lack of understanding of HIV-1
vaccine immunology, have hindered the development of a globally
effective cytotoxic T-lymphocyte (CTL)-based vaccine. Cellular
response, in using a finite immune system to recognize an
infinite number of potential pathogens, exhibits a series
of parsimonious features. These features are considered critical
in modulating HIV-1 vaccine multiple specificities. We took
the features into consideration when the potential epitope
coverage (Ec) to circulating
strains by current vaccine strategies was analyzed. Based
on these analyses, several approaches are proposed to enhance
the breadth of vaccine responses and, hence, the potential
protective efficacy.
[Back to top]
Routine Collection of Patient-Reported Outcomes in
an HIV Clinic Setting: The First 100 Patients
Heidi M. Crane, William Lober, Eric Webster, Robert D.
Harrington, Paul K. Crane, Thomas E. Davis and Mari M. Kitahata
[Full
text article]
Background: Information from patient-reported outcomes
(PROs) can enhance patient-provider communication and facilitate
clinical research. However, there are barriers to collecting
PROs within a clinic. Recent technological advances may help
overcome these barriers. We examined the feasibility of using
a web-based application on tablet PCs with touch screens to
collect PROs in a busy, multi-provider, outpatient HIV clinical
care setting.
Methods: Patients presenting for routine care were
asked to complete a touch-screen-based assessment containing
62 to 111 items depending on patient responses. The assessment
included instruments measuring body morphology abnormalities,
depression, symptom burden, medication adherence, drug/alcohol/tobacco
use, and health-related quality of life.
Results: Of 136 patients approached to participate
in the study, 106 patients (78%) completed the assessment,
6 (4%) started but did not complete it, and 24 (18%) refused.
Of those who completed the assessment, the mean age was 48
years, and 29% reported a history of injection drug use. The
median time to complete the assessment was 12 minutes. The
prevalence of lipoatrophy was 51%, the prevalence of lipohypertrophy
was 69%, and the prevalence of moderate or severe depression
was 51%. We found that 25% of those receiving highly active
antiretroviral therapy noted missing a dose of their antiretroviral
medications in the prior 4 days.
Conclusions: Collection of PROs using touch-screen-based,
internet technology was feasible in a busy HIV clinic. We
found a high prevalence of body morphology abnormalities,
depression, and poor adherence. Touch-screen-based collec-tion
of PROs is a promising tool to facilitate research and clinical
care.
[Back to top]
Identification of HLA-A11-Restricted HIV-1-Specific
Cytotoxic T-Lymphocyte Epitopes in China
Shaoyang Wang, Yongtao Sun Song Zhai, Yan Zhuang, Shuguang
Zhao, Whenzhen Kang, Xinhong Li, Dedong Huang,Xu G. Yu, Bruce
D. Walker and Marcus A. Altfeld
[Full
text article]
To fully define HLA-A11- restricted HIV-1- specific cytotoxic
T-lymphocyte epitopes in China, a method combining the enzyme-linked
immunospot (ELISPOT) assay with intracellular gamma interferon
staining (ICS) of peripheral blood mononuclear cells (PBMC)
was used to map the optimal epitopes targeted by ELISPOT and
then to define the HLA restriction of epitopes by ICS. A novel
HLA-A11-restricted CTL epitope and five other published HLA-A11-restricted
epitopes previously identified by reverse immunogenetics or
other methods were defined. The approach of integrating ELISPOT
with ICS is both convenient and useful for the characterization
of CTL responses to HIV-1 infection; this method is practical
for defining novel epitopes and facilitates in developing
new strategies for future vaccine design in China and other
Asian countries.
[Back to top]
Prevalence of Dilated Cardiomyopathy in HIV-Infected
African Patients Not Receiving HAART: A Multicenter, Observational,
Prospective, Cohort Study in Rwanda
Marc Twagirumukiza, Emmanuel Nkeramihigo, Benoit Seminega,
Emmanuel Gasakure, Franck Boccara and Giusseppe Barbaro
[Full
text article]
Introduction: Several studies performed before the
introduction of highly active antiretroviral therapy (HAART)
have shown that HIV-1 infection is an important cause of dilated
cardiomyopathy. However, factors associated with the development
of HIV-associated cardiomyopathy in developing countries are
still debated.
Objectives: To assess the prevalence of dilated cardiomyopathy,
diagnosed by echocardiography, in HIV-infected Rwandese patients
not receiving HAART and the risk factors associated with its
development.
Methods: A sample of 416 HIV-infected african patients,
without a previous definite history of cardiovascular disease,
attending University hospitals in Rwanda, from January to
December 2005, were included in a multicenter, observational,
prospective, cohort study, with the collaboration of two European
Clinical Centers (in France and in Italy). Clinical and laboratory
tests along with echocardiographic examination were performed
in all patients included in the study.
Results: Out of 416 patients included in the study,
dilated cardiomyopathy was documented by echocardiography
in 71 (17.7%). By both univariate and multivariate univariate
analysis, low socio-economic status, estimated duration of
HIV-1 infection, CD4 count, HIV-1 viral load, CDC stage B
and C of HIV disease and low plasmatic level of selenium were
factors significantly associated with the development of cardiomyopathy.
Alcohol consumption and smoking were factors associated with
the development of cardiomyopathy only by univariate analysis.
Conclusions: HIV-associated cardiomyopathy is a significant
clinical problem in HIV-infected patients not receiving HAART
in Rwanda. Early tracking of cardiomyopathy in african HIV-infected
patients is therefore recommended. Before administering HAART,
clinicians should be aware of a possible existing cardiomyopathy
to ensure appropriate, comprehensive, and rational patient
care.
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