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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 6, Number 4, July 2008
Contents
Letters
Proven Intra and Interobserver Reliability
in the Echographic Assessments of Body Fat Changes Related
to HIV Associated Adipose Redistribution Syndrome (HARS)
Pp. 276-278
Rosario Gulizia, Alessia Uglietti, Antonella
Grisolia, Cristina Gervasoni, Massimo Galli and Carlo
Filice
[Abstract]
Review Articles
A Careful Look at “A Re-Look at Recent Statistics
on Mortality in the Context of HIV/AIDS with Particular Reference
to South Africa” Pp. 279-285
Rob Dorrington and Tom A. Moultrie
[Abstract]
Factors Controlling Chromatin Organization and Nucleosome
Positioning for Establishment and Maintenance of HIV Latency
Pp. 286-295
Ivan Sadowski, Pedro Lourenco and Tom
Malcolm
[Abstract]
Original Research Papers
Levels of N-linked Glycosylation on
the V1 Loop of HIV-1 Env Proteins and their Relationship to
the Antigenicity of Env from Primary Viral Isolates Pp.
296-305
Zuhu Huang, Arthur Chou, Jonathan Tanguay,
Siyuan Shen, Innocent Mboudjeka, Te-Hui Chou, Shan Lu and
Shixia Wang
[Abstract]
Response of Feline Immunodeficiency Virus (FIV) to
Tipranavir may Provide New Clues for Development of Broad-Based
Inhibitors of Retroviral Proteases Acting on Drug-Resistant
HIV-1 Pp. 306-317
Sandro Norelli, Sary El Daker, Daniela D’Ostilio,
Federico Mele, Fabiola Mancini, Fabiana Taglia, Anna Ruggieri,
Massimo Ciccozzi, Roberto Cauda, Alessandra Ciervo, Maria
Letizia Barreca, Mauro Pistello, Mauro Bendinelli and
Andrea Savarino
[Abstract]
Detection of the Active Components of Calf Thymus
Nuclear Proteins (TNP), Histones that are Binding with High
Affinity to HIV-1 Envelope Proteins and CD4 Molecules
Pp. 318-326
Grigor Mamikonyan, Anatoly Kiyatkin, Nina
Movsesyan, Mikayel Mkrtichyan, Anahit Ghochikyan, Irina Petrushina,
Jimmy Hwang, Thomas E. Ichim, Haig Keledjian and Michael
G. Agadjanyan
[Abstract]
Increase of Non-B Subtypes and Recombinants Among
Newly Diagnosed HIV-1 Native Spaniards and Immigrants in Spain
Pp. 327-334
Africa Holguín, Miguel de Mulder,
Gonzalo Yebra, Marisa López and Vincent Soriano
[Abstract]
HIV-1-Specific Cytotoxic T Lymphocyte (CTL) Responses
Against Immunodominant Optimal Epitopes Slow the Progression
of AIDS in China Pp. 335-350
Song Zhai, Yan Zhuang, Yang Song, Shu Li,
Dedong Huang, Wenzhen Kang, Xinhong Li, Qi Liao, Yanhou Liu,
Zhongfang Zhao, Yichen Lu and Yongtao Sun
[Abstract]
The Unique Features of Pediatric HIV-1
in Sub-Saharan Africa Pp. 351-362
Anniek J. De Baets, Jose Ramet, Philippe
Msellati and Philippe Lepage
[Abstract]
Evaluation of HIV-1 and CD4+
T Cell Dynamic Parameters in Patients Treated with Genotypic
Resistance Testing-Guided HAART Pp. 363-369
Antonio Cappuccio, Filippo Castiglione,
Benedetto Piccoli and Valerio Tozzi
[Abstract]
Systematic Analysis of Host Immunological Pressure
on the Envelope Gene of Human Immunodeficiency Virus Type
1 by an Immunobioinformatics Approach Pp.
370-379
Binhua Liang, Ma Luo, T. Blake Ball, Xiaojian
Yao, Gary Van Domselaar, Wilfred R. Cuff, Mary Cheang, Steven
J.M. Jones and Francis A. Plummer
[Abstract]
Fetal-Maternal HLA-A and –B Discordance is Associated
with Placental RNase Expression and Anti-HIV-1 Activity
Pp. 380-387
Victoria I. Bedoya, Fabian A. Jaimes, Julio
C. Delgado, Claudia Rugeles, Xiomara Usuga, Wildeman Zapata,
María E. Castaño, Adriano B.G. Shearer
and María T. Rugeles
[Abstract]
Abstracts
[Back to top]
Proven Intra and Interobserver Reliability in the Echographic
Assessments of Body Fat Changes Related to HIV Associated
Adipose Redistribution Syndrome (HARS)
Rosario Gulizia, Alessia Uglietti, Antonella
Grisolia, Cristina Gervasoni, Massimo Galli and
Carlo Filice
Objective: To prove intra- and inter-observer’s
reliability of ultrasound (US) in the assessment of lipoatrophic
findings related to the HIV associated Adipose Redistribution
Syndrome (HARS).
Patients and Methods: In two separated sessions,
2 consecutive measurements of subcutaneous fat thickness (SFT)
were performed by each observer at the deepest point of Bichat
pad, the dorsal face of arm and the mid thigh for the assessment
of facial, brachial and crural lipoatrophy, respectively.
We enrolled 20 HIV patients, rotating an experienced and untrained
sonologist. The assessments were performed avoiding any stand
off pads in the skin and excluding artefacts due to the too
abundant quantity of gel to obtaining, with minimal transducer
pressure, the best resolution of the reference points.
Results: Means of facial, brachial and crural SFT
showed no significant differences between the workers. Coefficients
of variability (SD/mean x100) were similar for facial (ranges:
4.7-5.2% vs 4.9-5.6%, respectively), brachial (ranges:
5.8-8.4% vs 9.7-11.2%) and crural SFTs (ranges: 5.9-6%
vs 6.2-8.7%). There was greater consistency in the
measurements performed by the experienced vs the untrained
worker. Inter-observer agreement, assessed through kappa statistic
(k) analysis, confirmed increased measurement’s agreement
in the facial (k ranged from 0.40 to 0.60), brachial (k: 0.23-0.63)
and crural SFT assessments (k: 0.58-0.70) from the 1st
to 2nd session.
Conclusions: US shows low intra observer variability
and good inter observer reliability in the assessment of body
fat changes related to the HARS. The different degree of consistency
by the workers and the improvement of interobserver agreement,
suggest to stating a well defined period of training to obtain
better US reliability.
[Back to top]
A Careful Look at “A Re-Look
at Recent Statistics on Mortality in the Context of HIV/AIDS
with Particular Reference to South Africa”
Rob Dorrington and Tom
A. Moultrie
An article recently published in this journal argues
that the life expectancies (and other mortality statistics)
produced by models of the HIV/AIDS epidemic in Southern Africa
are inconsistent, and questions their reliability. To demonstrate
the argument, the author of that paper derived empirical estimates
of several mortality statistics from three different sources
of data and, on the grounds that the estimates of life expectancy
for 2001 and 2006 are somewhat higher than is typically estimated
by projection models, concludes that the empirical evidence
supports the theoretical view outlined in that paper.
If correct, the reasoning (and its empirical demonstration)
could be construed as a strong challenge to a dominant ortho-doxy
surrounding the estimation of mortality statistics in an era
of HIV/AIDS and offering some comfort to governments with
low Human Development Indices because of the index’s
dependence, inter alia, on estimates of life expectancy
at birth derived from such models.
This paper shows how, on theoretical, methodological and empirical
grounds, the reasoning and estimates in the paper are severely
flawed, and thus that the conclusions drawn in that paper
are unjustified.
[Back to top]
Factors Controlling Chromatin Organization
and Nucleosome Positioning for Establishment and Maintenance
of HIV Latency
Ivan Sadowski, Pedro Lourenco and
Tom Malcolm
Transcription of the integrated HIV provirus is
subject to regulation by chromatin organization and must employ
host cell transcription factors and chromatin modifying complexes
to promote the formation of latency, and then reverse this
process to replicate in response to T cell activation. The
repressed latent HIV-1 proviral 5' LTR is organized into a
defined structure where two de-acetylated and positioned nucleosomes
flank the enhancer region, presumably imposing a block to
transcriptional initiation and elongation. LTR-associated
nucleosomes undergo further histone H3 K9 trimethylation,
to cause silencing by recruitment of HP1. In this article,
we review current understanding of how the transcriptionally
silenced provirus might be established through the function
of transcription factors that bind conserved cis-elements,
including SP1, YY1, NF-κB,
CBF-1 and RBF-2 (USF/TFII-I), and propose mechanisms by which
factors bound to the repressed LTR can enable reactivation
in response to cell signaling.
[Back to top]
Levels of N-linked Glycosylation
on the V1 Loop of HIV-1 Env Proteins and their Relationship
to the Antigenicity of Env from Primary Viral Isolates
Zuhu Huang, Arthur Chou, Jonathan Tanguay,
Siyuan Shen, Innocent Mboudjeka, Te-Hui Chou, Shan Lu and
Shixia Wang
A good understanding about the structure and function
of the envelope glycoprotein (Env) from primary human immunodeficiency
virus-1 (HIV-1) isolates is important in facilitating the
development of effective neutralizing antibody responses as
a component of an effective HIV-1 vaccine. In the current
study, the antigenicity of a panel of diverse HIV-1 primary
Env from different clades of HIV-1 Group M was analyzed using
rabbit sera produced by either 3- or 9-valent gp120 DNA vaccine
formulations. Both the 3- and 9-valent gp120 DNA vaccine formulations
elicited HIV-1 gp120-specific antibodies in immunized rabbits.
However, we observed two levels of primary envelope antigenicity
to the same set of rabbit immune sera and that the level of
glycosylation, particularly in the V1 loop, may contribute
to such diversity. Bioinformatics analysis on the distribution
and average number of the N-linked glycosylation sites in
all variable regions (V1–V5) was conducted. A linear
plot demonstrated that the average number of potential N-glycosylation
sites in the V1 and V4 loops correlates to the size of the
loop. These data provide further evidence on the complexity
of primary HIV-1 Env antigens and offers new insight into
the mechanisms that HIV-1 uses to escape protective immune
responses.
[Back to top]
Response of Feline Immunodeficiency Virus (FIV)
to Tipranavir may Provide New Clues for Development of Broad-Based
Inhibitors of Retroviral Proteases Acting on Drug-Resistant
HIV-1
Sandro Norelli, Sary El Daker, Daniela D’Ostilio,
Federico Mele, Fabiola Mancini, Fabiana Taglia, Anna Ruggieri,
Massimo Ciccozzi, Roberto Cauda, Alessandra Ciervo, Maria
Letizia Barreca, Mauro Pistello, Mauro Bendinelli and
Andrea Savarino
The feline AIDS model for HIV-1 treatment failed
in the 1990s, due to structural features resembling protease
inhibitor (PI) resistant HIV-1 variants. Widespread drug-resistance
to PIs now invokes the possibility of rescuing feline immunodeficiency
virus (FIV) as a model for PI treatment. We here analyzed
susceptibility of FIV to second generation PIs, lopinavir,
atazanavir, and the structurally unrelated non-peptidic PI
tipranavir. We found that FIV protease resembles HIV-1 protease
drug resistance mutations limiting binding of lopinavir and
atazanavir but not tipranavir. All three PIs were found to
inhibit FIV replication in a concentration-dependent manner,
but only tipranavir inhibited FIV similarly to HIV-1. This
drug inhibited FIV synergistically with ritonavir. Inhibition
of protease activity was confirmed by Western blot analysis.
In molecular docking simulations, tipranavir displayed energetically
favorable interactions with the catalytic cavity of the mature
dimeric FIV protease. The calculated hydrogen bond network
was similar to that found in HIV-1 pro-tease/tipranavir complexes
and involved atoms in the protein backbone. We also modeled
the interaction of tipranavir with an immature protease monomer,
suggesting that inhibition of protease dimerization may be
a secondary modality for FIV inhibition by tipranavir. In
conclusion, tipranavir is the first FDA-approved non-reverse
transcriptase inhibitor of HIV-1 to show anti-FIV properties.
The tipranavir response by FIV may 1) support the idea of
using FIV as a small animal model for PIresistant HIV-1, thus
expanding access to animal AIDS models; and 2) pave the way
for development of novel broad-based inhibitors for treatment
of drug resistant HIV-1.
[Back to top]
Detection of the Active Components of Calf Thymus
Nuclear Proteins (TNP), Histones that are Binding with High
Affinity to HIV-1 Envelope Proteins and CD4 Molecules
Grigor Mamikonyan, Anatoly Kiyatkin, Nina
Movsesyan, Mikayel Mkrtichyan, Anahit Ghochikyan, Irina Petrushina,
Jimmy Hwang, Thomas E. Ichim, Haig Keledjian and
Michael G. Agadjanyan
VGV-1™, a clinical-grade formulation of bovine
thymus nuclear protein (TNP) has been demonstrated to possess
anti-viral activity in HIV-1 patients in five clinical trials,
one of which was placebo controlled double-blinded. However,
to date molecular mechanisms remain to be identified. Using
surface plasmon resonance we observed TNP components bind
with high affinity to HIV-1 proteins involved in viral entry,
gp41 and pg120, as well as the T cell HIV-1 receptor CD4.
To identify protein components of TNP, gel electrophoresis
was performed followed by tandem mass spectrometry (MS/MS).
Searching of bovine protein databases revealed the presence
of numerous histones. Further analysis of TNP by immunoaffinity
chromatography using gp120 and CD4 molecules as targets followed
by gel electrophoresis and MS/MS analysis confirmed these
data, demonstrating that H1.1, H2B, H4, and H2A histones are
the active component of TNP that bind to HIV envelop glycoprotein
and its receptor. To conclusively demonstrate binding of histones
to target proteins, we repeated the surface plasmon resonance
experiments using commercially available bovine histones and
demonstrated high-affinity interaction of histones with gp120,
and CD4. The binding of histone proteins to CD4, as well as
viral molecules has profound implications for basic understanding
of immune functions as well as a possible mechanism of VGV-1
activity in AIDS patients.
[Back to top]
Increase of Non-B Subtypes and Recombinants Among
Newly Diagnosed HIV-1 Native Spaniards and Immigrants in Spain
Africa Holguín, Miguel de Mulder,
Gonzalo Yebra, Marisa López and Vincent
Soriano
Although HIV-1 clade B variants are predominant in Western
Europe, non-B subtypes are rapidly spreading, mainly due to
immigration from endemic regions. All newly diagnosed HIV-1-infected
individuals at a HIV/AIDS clinic in Madrid from 2000 to 2007
were identified. Subtype assignment was based on phylogenetic
analysis of pol sequences from plasma specimens collected
at first visit. A total of 1,430 newly diagnosed HIV-1 individuals
were identified: 902 Spaniards, 232 South Americans, and 162
Africans, among others. The proportion of South-Americans
and Africans among diagnosed HIV-1 patients increased from
2000 to 2007 (from 17% to 22% and from 4% to 21%, respectively).
Half of diagnosis of HIV-1 in 2007 was in foreigners whereas
in previous years Spaniards were predominant. Non-B variants
were found in 157 (24%) of the 649 subjects who could be subtyped:
11A, 6C, 2D, 1F2, 13G, 4H, 1J, 3CRF01_AE, 64CRF02_AG, 2CRF03_AB,
3CRF06_cpx, 3CRF10_CD, 7CRF11_cpx, 9CRF12_BF, 9CRF14_BG, 1CRF18_cpx,
1CRF19_cpx, 2CRF31_BC, 10 URF and 5 outgroups. They represented
93%, 14% and 4% of newly-diagnosed HIV-1 Africans, South-Americans
and native Spaniards, respectively. Non-B subtypes increased
from 9% in 2000 to 32% in 2007, specially among South-Americans
(from 11% to 20%) and native Spaniards (from 4% to 10%). Most
(75%) were recombinant viruses. The highest number and diversity
of HIV-1 variants among natives was observed in 2007. HIV-1
non-B subtypes are increasingly present among newly diagnosed
HIV-1 individuals in Madrid, representing a third of cases
in 2007, whereas 10% of newly diagnosed HIV-1 native Spaniards
had non-B viruses.
[Back to top]
HIV-1-Specific Cytotoxic T Lymphocyte (CTL) Responses
Against Immunodominant Optimal Epitopes Slow the Progression
of AIDS in China
Song Zhai, Yan Zhuang, Yang Song, Shu Li,
Dedong Huang, Wenzhen Kang, Xinhong Li, Qi Liao, Yanhou Liu,
Zhongfang Zhao, Yichen Lu and Yongtao Sun
To assess the immunodominance patterns of HIV-1-specific
cytotoxic T lymphocyte (CTL) responses and the contribution
of these responses against the peptides scanning optimal epitopes
in chronic infection, we test the HIV-1-specific CTL responses
against a panel of 413 overlapping peptides spanning HIV-1
Asian B sequence, including 147 peptides corresponding to
optimal clade B epitopes in 49 chronically HIV-1 infected
individuals by interferon-γ
Elispot assay. A large variation in the recognition of peptides
restricted by the same HLA class I allele is presented. Some
epitopes are targeted frequently by individuals while other
epitopes restricted by the same allele are rarely recognized
in our research. HLA-B35 and HLA-A03 rather than other HLA
alleles contribute greatly to total virus-specific CTL responses.
Furthermore, there is a significant inverse correlation between
the total contribution of HIV-1-specific CTL responses restricted
by different HLA alleles to virus-specific immune responses
and viral load in the individuals during advanced infection
(P=0.002, r=-0.549). The peptidesrget taed by individuals
have significantly lower entropy compared with those not targeted
but restricted by the same HLA class I alleles (P<0.05)
in 49 individuals infected by HIV-1, especially the advanced
infection subgroup (P=0.044). These data demonstrate
that the consistent immunodominance patterns of HIV-1-specific
CTL responses of Chinese HIV-1 infected individuals and an
inverse correlation between the relative contribution of responses
restricted by HLA alleles and viral load, which indicates
the important protective effect of optimal epitopes against
slow disease progression even in advanced infection.
[Back to top]
The Unique Features of Pediatric
HIV-1 in Sub-Saharan Africa
Anniek J. De Baets, Jose Ramet, Philippe
Msellati and Philippe Lepage
In order to adapt African programs for antiretroviral
treatment (ART) to children’s needs, a good understanding
of the unique features of pediatric HIV in Africa and realistic
expectations of the results of such programs are crucial.
We compared pediatric HIV in African settings to pediatric
HIV in Western settings and to adult HIV in African settings.
As an illustration, we also compared baseline characteristics
and ART-outcomes from 15 African pediatric studies, 11 Western
pediatric studies and 15 studies of African adults. Several
differences in diagnostic, clinical, immunological and virological
characteristics were identified, as well as variations in
the most influential factors for disease progression and response
to ART. Environmental factors may influence disease progression,
mortality, loss to follow-up, adherence and the need to adapt
the regimen. Many of the responses to ART are two-phased,
the first phase taking longer in children than in adults.
The selected African pediatric programs recorded a higher
increase in median CD4-percent than the selected Western pediatric
programs and a higher increase in CD4-count than the selected
African adult programs. Compared to the adult programs, the
African pediatric programs had lower drop-out rates, higher
reported adherence levels and comparable mortality rates.
The Western pediatric programs, however, had the lowest mortality
rates. While several challenges complicate comparisons between
ART-programs, increased knowledge of the unique features of
pediatric HIV in Africa may greatly assist in improving pediatric
HIV care on a global level.
[Back to top]
Evaluation of HIV-1 and CD4+
T Cell Dynamic Parameters in Patients Treated with Genotypic
Resistance Testing-Guided HAART
Antonio Cappuccio, Filippo Castiglione,
Benedetto Piccoli and Valerio Tozzi
The extent of immune restoration in HIV-1 patients on
antiretroviral therapy is an important marker of disease progression.
In this work, we investigate the dynamics of immune reconstitution
and address the question of whether the early response to
antiretroviral treatments allows to predict the late immune
restoration.
We select a cohort of twelve patients on GRT-HAART who achieve
virological suppression, but show variable recovery of immune
competence. HIV-RNA and CD4+
T cell assessments are used for estimation of the dynamic
parameters of an established mathematical model of the viral-immune
system interactions.
We find that failure in immune reconstitution is associated
with an abnormal increase of the death rate of uninfected
CD4+ T cells. In contrast,
their production rate is up to three times higher than in
healthy seronegative individuals. This finding is in line
with the view of chronic activation as a major cause of immune
depletion. According to non parametric statistics, CD4+
T cell responders and non responders do not show significantly
different dynamic parameters. Such result suggests that the
employed model does not allow to predict the long term immune
reconstitution.
[Back to top]
Systematic Analysis of Host Immunological Pressure
on the Envelope Gene of Human Immunodeficiency Virus Type
1 by an Immunobioinformatics Approach
Binhua Liang, Ma Luo, T. Blake Ball, Xiaojian
Yao, Gary Van Domselaar, Wilfred R. Cuff, Mary Cheang, Steven
J.M. Jones and Francis A. Plummer
As the number of HIV-1 sequences has increased in the
public database and new tools of immunological bioinformatics
have become available, making it possible to better understand
at a population level how host immune response drives the
evolution of HIV-1 envelope (Env). We analyzed 1100 unique
full-length envelope sequences and systematically determined
positive selection (PS) sites by QUASI analysis and found
that PS sites were widely dispersed across Env. The frequency
of Env PS sites appears to be relatively stable over time.
Moreover, between 25% and 61% of PS sites are shared between
subtypes A, B, C, and D, suggesting that host immune responses
target the same regions of Env gene across different clades
at the population level. Significant correlations were observed
between PS sites and Neutralizing antibody (NAb) response,
as well as PS sites and Th epitopes. Furthermore, NAb sites
in combination with cytotoxic-T lymphocyte (CTL) epitopes
and proteasome cleavage sites were also significantly associated
with PS sites, suggesting NAb may be the major force driving
the evolution of HIV-1 Env. We also identified regions that
are free from PS, but heavily targeted by CTL or NAb, implying
that functional constraints may be responsible for the lack
of positive selection in these regions. These findings should
help researchers to identify epitopes or regions of HIV-1
that may aid in designing vaccines.
[Back to top]
Fetal-Maternal HLA-A and –B Discordance
is Associated with Placental RNase Expression and Anti-HIV-1
Activity
Victoria I. Bedoya, Fabian A. Jaimes, Julio
C. Delgado, Claudia Rugeles, Xiomara Usuga, Wildeman Zapata,
María E. Castaño, Adriano B.G. Shearer
and María T. Rugeles
The incidence of maternal-to-fetal human immunodeficiency
virus type 1 (HIV-1) transmission is 25-30% in absence of
antiretroviral therapy, and is inversely associated with Human
leukocyte antigens (HLA) class-I discordance. Based on our
earlier report that mixed lymphocyte reactions (MLR) induce
a ribonuclease (RNase) that inhibits HIV-1 replication, we
proposed that maternal-fetal alloantigen stimulation activates
factors that protect the fetus against vertically-transmitted
infections. We investigate here whether the degree of mother-infant
HLA discordance associates with the ability to produce anti-HIV-1
alloantigen-stimulated factor (ASF), and affects placental
RNases. We also determine whether such HLA association is
influenced by the mother’s HIV-1 status. Paired maternal
and cord blood leukocytes were tested for the induction of
ASF by MLR, and typed for HLA-A and –B. The placentas
were tested for mRNA expression of three RNases. Neonate anti-mother,
but not mother anti-neonate MLR generated supernatants with
anti-HIV-1 activity, that was associated with HLA class I
discordance. This HLA association was not seen in the HIV-infected
cohort. HLA class I discordance was also associated with expression
of placental RNase 1. Our findings are consistent with the
hypothesis that HLA class I discordance induces expression
of RNases in the placenta that contribute to innate host resistance
to HIV-1 and other viral infections.
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