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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 6, Number 2, March 2008
Contents
Advances in the Structural Understanding of Vif Proteins
Pp. 91-99
Pierre Barraud, Jean-Christophe Paillart, Roland
Marquet and Carine Tisné
[Abstract]
Patients’ Characteristics and Clinical Implications
of Suboptimal CD4 T-Cell Gains After 1 Year of Successful
Antiretroviral Therapy Pp. 100-107
Félix Gutiérrez, Sergio Padilla,
Mar Masiá, José A. Iribarren,Santiago Moreno,
Pompeyo Viciana, José Hernández-Quero,Remedios
Alemán, Francesc Vidal, Miguel Salavert, José
R.Blanco, Manuel Leal, Fernando Dronda, Santiago Perez Hoyos,Julia
del Amo and CoRIS-MD
[Abstract]
Continuous Crossover(s) Events of HIV-1 CRF01_AE
and B Subtype Strains in Malaysia:Evidence of Rapid and Extensive
HIV-1 Evolution in the Region Pp. 108-116
Katherine A. Lau, Bin Wang, Adeeba Kamarulzaman,
Kee-Peng Ng and Nitin K. Saksena
[Abstract]
Nef and TNFα
are Coplayers that Favor HIV-1 Replication in Monocytic
Cells and Primary Macrophages Pp. 117-129
Georges Herbein, Audrey Varin, Anis Larbi,
Carl Fortin, Ulrich Mahlknecht, Tamas Fulop and Bharat B.
Aggarwal
[Abstract]
Impact of Residues in the Nonnucleoside Reverse
Transcriptase Inhibitor Binding Pocket on HIV-1 Reverse Transcriptase
Heterodimer Stability Pp. 130-137
Anna Figueiredo, Shannon Zelina, Nicolas
Sluis-Cremer and Gilda Tachedjian
[Abstract]
Relationship Between HIV-RNA Load in Blood and
Semen in Antiretroviral-Naïve and Experienced Men and
Effect of Asymptomatic Sexually Transmissible Infections
Pp. 138-142
Derek J. Chan, Leon McNally, Marjika Batterham
and Don E.Smith
[Abstract]
A Re-Look at Recent Statistics on Mortality in
the Context of HIV/AIDS with Particular Reference to South
Africa Pp.143-151
Eric O. Udjo
[Abstract]
Photopheresis in HIV-1 Infected Patients Utilizing
Benzoporphyrin Derivative (BPD)Verteporfin and Light Pp.
152-163
Zale P. Bernstein, Thomas Dougherty, Sandra
Gollnick, Stanley A. Schwartz, Supriya D. Mahajan, James.
Kepner, Adam Sumlin,Carleton Stewart, Paul Wallace, Adaffaras
Adal, Harold Walder and Bernard Poiesz
[Abstract]
Adherence to Highly Active Antiretroviral
Therapy in HIV Infected Inmates Pp. 164-170
Sandra M. Inés, Leticia Moralejo,
Miguel Marcos, Aurelio Fuertes and Guillermo Luna
[Abstract]
Antiretroviral Therapy Voluntarily Taken
at Half-Dosage, but Fully Effective After 6-10 Years:A Provocative
Issue for Adherence Requirements: Case Report Pp.
171-172
Roberto Manfredi, Sergio Sabbatani and Leonardo Calza
[Abstract]
Impact of Occult HBV Infection in HIV/HCV
Co-Infected Patients: HBV-DNA Detection in Liver Specimens
and in Serum Samples Pp. 173-179
Paolo Fabris, Maria R. Biasin, Maria T. Giordani, L. Berardo,Vania
Menini, Antonio Carlotto, Maria G. Miotti, Vinicio Manfrin,
Vincenzo Baldo, Gaia Nebbia and Domenico Infantolino
[Abstract]
Abstracts
[Back to top]
Advances in the Structural Understanding of Vif Proteins
Pierre Barraud, Jean-Christophe Paillart, Roland Marquet and
Carine Tisné
The multidomain HIV-1 Vif protein recruits several cellular
partners to achieve neutralization of the antiviral activity
of APOBEC3 proteins. Vif neutralizes APOBEC3G and APOBEC3F
predominantly by forming an E3 ubiquitin ligase with Cullin5,ElonginB
and ElonginC that targets these proteins for degradation by
the ubiquitin-proteasome pathway. Vif associates with the
Cullin5-ElonginB-ElonginC complex by binding directly to ElonginC
via its SOCS-box motif and to Cullin5 via hydrophobic
residues within a zinc-binding region formed by a conserved
HCCH motif. The HIV-1 Vif-Cullin5-ElonginBC complex is then
able to ubiquitinate the APOBEC3G factor bound to Vif by its
Nterminal domain. In this review, we summarize the current
knowledge about the structural determinants of Vif that allow
it to interact with cellular and viral partners.
[Back to top]
Patients’ Characteristics and Clinical Implications
of Suboptimal CD4 T-Cell Gains After 1 Year of Successful
Antiretroviral Therapy
Félix Gutiérrez, Sergio Padilla, Mar Masiá,
José A. Iribarren, Santiago Moreno, Pompeyo Viciana,
José Hernández-Quero, Remedios Alemán,
Francesc Vidal, Miguel Salavert, José R. Blanco, Manuel
Leal, Fernando Dronda, Santiago Perez Hoyos, Julia del Amo
and CoRIS-MD
To describe characteristics and prognosis of patients
with suboptimal immunological response to combined antiretroviral
therapy (CART). Using data from a multicenter cohort study,
we selected patients who initiated CART and showed suboptimal
CD4-T cell response (defined as <50 cells/L increase) after
1 year of therapy, despite sustained virological suppression.
Characteristics of those patients were compared with subjects
who showed optimal immunological response. Of 650 patients
with virological suppression, 108 (16.6%) showed suboptimal
CD4-T cell response. Independent predictors of suboptimal
response were previous injection drug use (OR, 1.85; 95% CI,1.12-2.98)
and age at CART initiation (OR, 1.04 per year increase; 95%CI,
1.01-1.06). Hepatitis C virus coinfection was not associated
with impaired inmunological response. As compared with patients
with optimal immunological response, those with suboptimal
response had a higher mortality rate(3.22 versus 0.71 per
100 person-years; p=.001), but a similar rate of new AIDS-defining
events. In patients with sustained virological suppression
with CART, previous injection drug use,but not hepatitis C
virus coinfection, and older age at initiation of therapy
were associated with suboptimal CD4 T-cell responses. Patients
with suboptimal response had a higher mortality over time,
mainly due to diseases other than AIDS defining events.
[Back to top]
Continuous Crossover(s) Events of HIV-1 CRF01_AE and
B Subtype Strains in Malaysia:Evidence of Rapid and Extensive
HIV-1 Evolution in the Region
Katherine A. Lau, Bin Wang, Adeeba Kamarulzaman, Kee-Peng
Ng and Nitin K. Saksena
The Asian HIV epidemic appears to be complex, characterized
by the prevalence of multiple subtypes and circulating recombinant
forms with gradual replacement of pure HIV-1 subtypes in several
geographical regions. The main objectives of the present study
are to identify and analyse the full-length viral genomes
of three unique recombinant forms (URFs); the HIV-1 isolates
07MYKLD47, 07MYKLD48 and 07MYKLD49 from Malaysia. Long-range
polymerase chain reaction (PCR) amplification of seven overlapping
reading frames was used to derive near full-length HIV-1 genomes.
Detailed phylogenetic and bootscanning analyses were performed
to determine phylogenetic associations and subtypic assignments.
We further confirmed the mosaic composition of these CRF01_AE/B
inter-subtype recombinant forms, which are composed of B-subtype
fragment(s) in the backbone of CRF01_AE. Both 07MYKLD47 and
07MYKLD48 have an insertion of B subtype (880 bp and 532 bp)
in the gag-pol and gp41-env gene regions,
respectively. Whereas the isolate 07MYKLD49 has three B-subtype
fragments inserted in different gene region along the genome;
one each in the gag-pol(1862 bp) and pol-vif
(1935 bp) regions, and a short B-subtype insertion (541 bp)
in the 5’ LTR-gag region. This highlights the
public health relevance of newly emerging second generation
HIV-1 recombinant forms and their dispersal, along with their
rapid and continuous evolution in the region.
[Back to top]
Nef and TNFα
are Coplayers that Favor HIV-1 Replication in Monocytic
Cells and Primary Macrophages
Georges Herbein, Audrey Varin, Anis Larbi, Carl Fortin, Ulrich
Mahlknecht, Tamas Fulop and Bharat B. Aggarwal
The human immunodeficiency virus (HIV) Nef protein is
myristoylated and plays a critical role in AIDS pathogenesis
by enhancing viral replication, survival of the virus within
infected cells and by facilitating its spread in vivo.
We observed that, in the promonocytic cell line U937, myristoylated
exogenous Nef protein activates NF-κB
and AP-1, whereas unmyristoylated exogenous Nef protein does
not. Using methyl-β-cyclodextrin
(MβC)
treatment, we observed that the activation of NF-κB
and AP-1 by exogenous Nef protein is mediated primarily via
lipid rafts both in U937 cells and in primary human macrophages.
In agreement with this observation, exogenous Nef protein
colocalized with GM1 ganglioside, a major component of lipid
rafts, in U937 cells as detected by confocal microscopy. Since
tumor necrosis factor alpha (TNFα
) activates NF-κB
and AP-1,we investigated the role of exogenous Nef protein
in TNFα
stimulated U937 cells and primary macrophages. We observed
that exogenous Nef and TNFα
synergistically activate NF-κB
and AP-1 in U937 cells and primary macrophages resulting in
enhanced stimulation of the HIV-1 long terminal repeat (LTR),and
subsequently in enhanced viral replication in both chronically
infected promonocytic U1 cells and acutely HIV-1-infected
primary macrophages. Both enhanced LTR stimulation and viral
replication following treatment with exogenous Nef and TNFα
were mediated via lipid rafts. Therefore, our results
indicate that exogenous Nef protein and enhanced TNFα
production detected in HIV-infected subjects could synergize
to fuel the progression of the disease via lipid
raft-dependent stimulation of the HIV-1 provirus present in
such cellular reservoirs as mononuclear phagocytes.
[Back to top]
Impact of Residues in the Nonnucleoside Reverse Transcriptase
Inhibitor Binding Pocket on HIV-1 Reverse Transcriptase Heterodimer
Stability
Anna Figueiredo, Shannon Zelina, Nicolas Sluis-Cremer and
Gilda Tachedjian
Previous studies have demonstrated that nonnucleoside
reverse transcriptase (RT) inhibitors (NNRTIs) act as chemical
enhancers of human immunodeficiency virus type 1 (HIV-1) RT
dimerization. In the current study, we sought to define the
role of key residues(101, 103, 108, 181, 188, 190, 225 and
318) in the NNRTI-binding pocket on HIV-1 RT heterodimer stability.
Thirteen mutant RTs were constructed and evaluated for p66/p51
RT heterodimer formation using the well-established yeast
two-hybrid assay. We found that the mutations K101A, P225H,Y318F
and Y318W decreased RT heterodimer stability whereas K103N,
V108I, V108W, Y181C, Y188L, G190A, G190E, G190W and P225W
increased RT heterodimer stability. While these results demonstrate
that residues that comprise the NNRTI-binding pocket contribute
to the stability of p66/p51 HIV-1 RT,they did not suggest
any obvious correlation between RT dimer stability and the
extent of NNRTI resistance. Remarkably,mutations at residue
G190 (A, E, W) in the p66 RT subunit were found to dramatically
increase heterodimer stability. Notably, the G190W mutation
increased RT dimer stability almost to the same extent as
did 5 µM efavirenz. In light of these findings, we characterized
the in vitro activity of recombinant RT ex-pressing
mutations at G190 in the p66 subunit only and compared them
with a wild-type enzyme complexed with efavirenz. We found
that while mutations at G190 had a significant effect on both
the DNA polymerase and ribonuclease H activity of the enzyme,
their phenotypic effects did not mirror those induced by efavirenz
binding to RT
[Back to top]
Relationship Between HIV-RNA Load in Blood and Semen
in Antiretroviral-Naïve and Experienced Men and Effect
of Asymptomatic Sexually Transmissible Infections
Derek J. Chan, Leon McNally, Marjika Batterham and Don E.
Smith
We assessed the correlation between HIV-RNA viral load
in blood (BPVL) and seminal plasma (SPVL) in a cross-sectional
cohort of 119 asymptomatic, antiretroviral-naive and experienced
HIV-1 subjects (BPVL < 50 copies/mL for minimum 12 months
and stable on one drug regimen). The cohort was divided into
3 groups: 2 according to the non nucleoside reverse transcriptase
inhibitor (NNRTI) and protease inhibitor (PI) used, and 1
untreated group. At the initial visit, subjects were screened
for gonorrhoea, chlamydia and syphilis. Blood was collected
for CD4 count, BPVL, and general biochemistry and haematology.
Semen was collected concurrently and SPVL determined by the
NucliSens®
HIV-1 QT PCR (BioMerieux, Boxtel, The Netherlands). At a subsequent
visit, a second semen sample was obtained and SPVL was repeated
for 10 subjects on ART. All NNRTI subjects (n = 36, mean treatment
33 months ± 14) and PI subjects (n = 45, mean treatment
31 months ± 25) had BPVL <50 copies/mL and SPVL
<250 copies/mL at baseline and with repeat sampling. 9/119
subjects (8%) had an asymptomatic STI; 4 cases in the treated
groups and 5 in the untreated group. Treated subjects were
less likely to have an STI than untreated subjects. In conclusion,
asymptomatic STIs had no effect on BPVL or SPVL in either
treated group and SPVL remains undetectable over time. STIs
minimally increase, or do not increase, SPVL in untreated
patients. Our data supports the role of ART in lowering the
risk of sexual transmission of HIV-1.
[Back to top]
A Re-Look at Recent Statistics on Mortality in the
Context of HIV/AIDS with Particular Reference to South Africa
Eric O. Udjo
Since the outbreak of the HIV epidemic in the 1980s,
various organisations and researchers have produced statistics
on HIV/AIDS including HIV prevalence, incidence, number of
AIDS cases, AIDS-related mortality as well as life expectancy
at birth in the context of HIV/AIDS. Until recently HIV-prevalence
statistics as well as models projecting the impact of HIV/AIDS
utilised HIV-prevalence statistics based on women attending
antenatal clinics as population-based prevalence statistics
were non-existent.Among others, the extrapolation of HIV-prevalence
statistics from surveillance sites to the general population
has been questioned. Recent statistics on HIV-prevalence from
population-based surveys strongly suggest that HIV-prevalence
in many countries may not be as high as earlier estimated
and projected.In addition, model estimates of HIV/AIDS-prevalence
and impact on mortality often use conventional model life
tables such as the Coale-Demeny Regional, UN, and Brass standard
life tables,which in the case of South Africa give female
life expectancy at birth plummeting from about 65 years in
the mid-1990s to around 49-50 years in 2005. The standard
life tables often employed in these estimates do not take
account of the ‘hump’ in the mortality curve due
to AIDS-related deaths as these standard mortality schedules
were developed prior to the HIV/AIDS epidemic. Given this
background, this paper provides a critical look at recent
statistics on infant mortality rates and life expectancies
at birth in the context of HIV/AIDS in parts of Southern and
Eastern Africa with particular reference to South Africa.
[Back to top]
Photopheresis in HIV-1 Infected Patients Utilizing
Benzoporphyrin Derivative (BPD)Verteporfin and Light
Zale P. Bernstein, Thomas Dougherty, Sandra Gollnick, Stanley
A. Schwartz, Supriya D. Mahajan, James. Kepner, Adam Sumlin,
Carleton Stewart, Paul Wallace, Adaffaras Adal, Harold Walder
and Bernard Poiesz
An ex vivo trial utilizing photopheresis with
Benzoporphyrin Derivative as the photoactive compound, identified
the minimum energy levels of light and concentrations of BPD
that eradicated both cell-free and cell-associated HIV-1 infectivity
without destroying the virus particles or infected leukocytes.
Leukocytes remained viable with altered chemokine/cytokine
expression.Apoptosis was induced in a minority of CD4 but
not CD8 positive cells with a statistically significant increase
in cytolytic T-cell activity. In the 24 week clinical trial
in 7 HIV-1 infected patients,three who had rapidly rising
viral loads prior to initiating therapy stabilized. Two had
a sustained greater than 0.5 log decrement and 5 had stable
plasma viral loads (less than a 0.5 log increment or decrement)
with varied effects on absolute CD4 and CD8 positive lymphocytes
counts. One achieved a greater than 1 log decrement in HIV-1
plasma viral load and undetectable in vivo cell-free
and cell-associated HIV-1 infectivity with an increased in
vitro lymphocyte mitogen stimulation index. Under amended
protocol, 5 additional 12 month courses were administered
to three additional patients and two of the previous enrollees.
Area under the curve for viral load showed a significant decrease
from pre- to post-therapy (p 0.007). No associated toxicities
were observed.
[Back to top]
Adherence to Highly Active Antiretroviral Therapy
in HIV-Infected Inmates
Sandra M. Inés, Leticia Moralejo, Miguel Marcos, Aurelio
Fuertes and Guillermo Luna
Adherence to highly active antiretroviral therapy (HAART)
has been scarcely studied in correctional settings. Our study
aims to evaluate the relationship between adherence and virological
outcome and to determine factors related to adherence in correctional
settings. A cross-sectional retrospective study was performed
in Topas prison (Salamanca, Spain). 50 inmates starting HAART
were studied. Adherence was estimated through a selfreport
questionnaire and variables related to adherence(covering
individual factors, the illness itself and the therapeutic
regimen) were recorded. HIV-RNA levels and CD4 lymphocyte
count were measured before starting therapy and six months
after. Statistical analysis was performed using univariate
and multivariate methods. 21 inmates (42%) were considered
adherent and 29 (58%) were non-adherent.Adherence to treatment,
as measured by our questionnaire, was the only significant
and independent factor associated with an undetectable viral
load at six months of therapy. Five variables were significantly
associated with adherence to treatment, four of them as predictor
factors for good adherence: an active occupation inside prison,
the absence of HIV-related symptoms,a good or average acceptance
of treatment, and a higher academic background; previous injection
drug use as a risk factor for HIV transmission was associated
with nonadherence.A simple self-report questionnaire may be
useful for assessing adherence in prison inmates. Recognizing
variables associated with adherence is essential to identify
prisoners at high risk of being non-adherents in order to
develop strategies for improving compliance.
[Back to top]
Antiretroviral Therapy Voluntarily Taken at Half-Dosage,
but Fully Effective After 6-10 Years:A Provocative Issue for
Adherence Requirements: Case Report
Roberto Manfredi, Sergio Sabbatani and Leonardo Calza
Aim of our report is to discuss some key adherence features
in the real world, by reporting two exceptional patients,
who deliberately took all antiretroviral medications at half-dosage
compared with standard prescriptions, and maintained a fully
stable and sustained virological and immunological response
after 6-10 consecutive years. The potential causes and consequences
of this apparent misconduct of our patients on drug tolerability,
resistance development, compliance monitoring,direct drug
delivery, and health care providers behavior, are discussed.
[Back to top]
Impact of Occult HBV Infection in HIV/HCV Co-Infected
Patients: HBV-DNA Detection in Liver Specimens and in Serum
Samples
Paolo Fabris, Maria R. Biasin, Maria T. Giordani, L. Berardo,
Vania Menini, Antonio Carlotto, Maria G. Miotti, Vinicio Manfrin,
Vincenzo Baldo, Gaia Nebbia and Domenico Infantolino
Prevalence and impact of occult HBV infection in HIV
positiv patients is controversial. The aims of this study
were to determine the prevalence of occult HBV infection and
its impact on histological and virological parameters. 52
HIV/HCV (but HBsAg-negative) co-infected patients, 29 HBsAg
and anti-HCV negative chronic hepatitis, and 20 HBsAg positive
chronic hepatitis controls were studied. DNA was extracted
from frozen biopsies and amplified with primers for S, C and
X regions, and for (ccc) HBV-DNA. Sera were tested for HBV-DNA
with two quantitative assays (Cobas Amplicor HBV Monitor,
and the real time COBAS (r) Taqman HBV Test, Roche Diagnostics,
UK) Occult HBV infection was detected in 7 (13.4%) liver biopsies
o the study group, and in none case of the non viral chroni
hepatitis group (p=0.04). All serum samples were HBV-DNA negative
with Cobas Amplicor HBV monitor assay, while 3 cases were
found positive with real time PCR. Statistical analysis didn’t
show any impact of occult HBV infection on liver histology,
CD4+ cells count, HIV and HCV load, and ALT levels. Occult
B infection is relatively frequent in HIV/HCV co-infected
patients, and is underestimated by common HBV-DNA serological
assays.However, it doesn’t seem to exert a relevant
impact.
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