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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 4, Number 4, October 2006
Contents
Review Articles
HIV-1 Entry Inhibitors: Classes, Applications and
Factors Affecting Potency Pp. 387-400
Jasminka Sterjovski, Melissa J. Churchill, Steve L. Wesselingh
and Paul R. Gorry
[Abstract]
Interaction Between HIV-1 and APOBEC3 Sub-Family
of Proteins Pp. 401-409
Maria E. Arriaga, Jillian Carr, Peng Li, Bin Wang and
Nitin K. Saksena
[Abstract]
DNA Repair in HIV-1 Infection: A Case for Inhibitors
of Cellular Co-Factors? Pp. 411-421
René Daniel
[Abstract]
Interleukin-18: A Proinflammatory Cytokine in
HIV-1 Infection Pp. 423-430
Donato Torre and Agostino Pugliese
[Abstract]
Animal Models Used for the Evaluation of Antiretroviral
Therapies Pp. 431-446
Andreia S.P. Dias, Megan J. Bester, Rozane F. Britz and
Zeno Apostolides
[Abstract]
Original Research Papers
High Frequency of Grossly Deleted nef Genes in HIV-1
Infected Long-Term Slow Progressors Treated with Korean Red
Ginseng Pp. 447-457
Young K. Cho, Ji Y. Lim, You S. Jung, Sun K. Oh, Hee J.
Lee and Heungsup Sung
[Abstract]
A Clinical Scoring System as Useful as FNAC in
the Diagnosis of Tuberculous Lymphadenitis in HIV Positive
Patients Pp. 459-462
Satya D. Purohit, Vimlesh Purohit and Murli L. Mathur
[Abstract]
Prevalence of Thyroid Dysfunction in Thai HIV-Infected
Patients Pp. 463-467
Channarong Ketsamathi, Wallaya Jongjaroenprasert, La-or
Chailurkit, Umaporn Udomsubpayakul and Sasisopin Kiertiburanakul
[Abstract]
Estimation of Mortality from Vital Registrations
in South Africa Pp. 469-474
Eric O. Udjo
[Abstract]
Lentivirus-Like Particles Without Reverse Transcriptase
Elicit Efficient Immune Responses Pp. 475-484
Sean P. McBurney, Kelly R. Young, Casmiar I. Nwaigwe,
Adam C. Soloff, Kelly Stefano Cole and Ted M. Ross
[Abstract]
Abstracts
[Back to top]
HIV-1 Entry Inhibitors: Classes, Applications and
Factors Affecting Potency
Jasminka Sterjovski, Melissa J. Churchill, Steve L. Wesselingh
and Paul R. Gorry
Antiviral agents targeting human immunodeficiency virus
type-1 (HIV-1) attachment, co-receptor engagement and fusion,
collectively referred to as entry inhibitors, are emerging
as promising therapeutic agents in the treatment of HIV-1
infection. Viral evolution and concomitant emergence of resistant
strains will continue to be an important consideration in
the development of any new therapeutic against HIV-1. However,
unique challenges facing the development of entry inhibitors
center around the highly variable and flexible nature of the
HIV-1 envelope protein (Env). For example, the evolution of
Env during the course of HIV-1 infection increases the efficiency
of Env-CCR5 interactions, which consequently increases Env-mediated
fusogenicity and decreases sensitivity to entry inhibitors.
This points to a relationship between co-receptor interactions
and fusogenicity that merits further consideration in the
design of HIV-1 entry inhibitors. It also underscores the
importance of considering the biological properties of late-emerging
HIV-1 variants in the design of new therapeutics. This review
examines the various entry inhibitors that are undergoing
preclinical or clinical testing or which are in the early
stages of clinical use, their applications in a clinical setting
and possible factors that may affect potency against HIV-1.
[Back to top]
Interaction Between HIV-1 and APOBEC3 Sub-Family of
Proteins
Maria E. Arriaga, Jillian Carr, Peng Li, Bin Wang and
Nitin K. Saksena
A variety of mechanisms of innate immunity that protect organisms
from retroviral infections, including HIV, are known. Lentiviruses
express viral infectivity factor (Vif) protein that has the
ability to counter antiviral activity exhibited by the recently
discovered host cytidine deaminases APOBEC3G and 3F. Although
these host factors are present in diverse mammalian species
and have been shown to act against various organisms, their
importance in HIV infection has been highlighted because of
their suggested activities against HIV in vivo and
the strong conservation of the HIV vif gene encoding the Vif
protein capable of countering this innate activity. The main
purpose of this review is to provide a detailed overview on
HIV-specific interaction of APOBEC3 subfamily of proteins
and discuss its potential role in HIV pathogenesis.
[Back to top]
DNA Repair in HIV-1 Infection: A Case for Inhibitors
of Cellular Co-Factors?
René Daniel
At each step of its life-cycle, human immunodeficiency virus
type 1 (HIV-1) interacts with cellular proteins. In some cases,
such as the cellular cytidine deaminase APOBEC3G, cellular
proteins repress HIV-1 replication. In other cases, cellular
proteins serve as essential co-factors, and inhibition of
their function blocks HIV-1 replication. This review explores
the opportunities for anti-HIV-1 therapy that stem from the
recent discoveries that cellular proteins, which are involved
in double-strand break DNA repair, are also required for completion
of integration of HIV-1 DNA into host cell DNA.
[Back to top]
Interleukin-18: A Proinflammatory Cytokine in HIV-1
Infection
Donato Torre and Agostino Pugliese
Interleukin (IL)-18 is a proinflammatory cytokine that plays
an important role in both innate and adaptive immune responses
against viruses and intracellular pathogens. Increased levels
of circulating IL-18 from HIV-1 infected patients have been
reported especially in the advanced and late stages of the
disease, whereas in the initial stage serum levels of IL-18
were not increased. In contrast, low production of Il-18 was
observed in vitro from peripheral blood mononuclear
cells (PBMC) of HIV-1 infected patients, and these results
were also observed in macaques infected with simian immuno-deficiency
virus (SIV). In addition, decreased IL-18 production from
PBMC was significantly correlated with low production of IL-2.
Furthermore, serum levels of IL-18 significantly decreased
after highly active antiretroviral therapy. During the early
stage of HIV-1 infection there is a decreased production of
gamma interferon (IFN), IL-12 and IL-2 as well as not activation
of IL-18 production and this leads to inhibition of Th1 immune
response, whereas in the advanced stage of the disease, strong
activation of IL-18 production along with persistent decreased
production of gamma IFN, IL-12 and IL-2 may promote a Th2
immune response, which leads to persistent viral replication.
Several studies have shown increased levels of IL-18 in HIV-seronegative
subjects with obesity, insulin resistance and type II diabetes.
Metabolic disorders, fat redistribution and cardiovascular
manifestations are becoming more frequent in HIV-1 infected
patients treated with antiretroviral drugs. Consequently,
involvement of IL-18 in these disorders has been postulated
and demonstrated in patients with lipodistrophy, or with hypertriglyceridemia.
Finally, higher serum levels of IL-18 may represent an useful
marker in HIV-1 infected patients with metabolic disorders
and fat redistribution, as well as a sensitive predictor of
cardiovascular complications in treated patients.
[Back to top]
Animal Models Used for the Evaluation of Antiretroviral
Therapies
Andreia S.P. Dias, Megan J. Bester, Rozane F. Britz and
Zeno Apostolides
Several animal models for the study of HIV/AIDS have
been established and characterized and have been widely used
to study the pathogenesis of HIV/AIDS as well as vaccine development.
The purpose of this study was to review the literature and
identify the animal models most frequently used for the evaluation
of drugs, drug combinations, plant extracts and drug-plant
combinations. Four of these animal models were evaluated namely
the SIV model due to its similarities in pathogenesis of disease
to humans, the FIV and the LP-BM5 model due to wide availability
and the SCID murine model that combines components of both
systems. The pathogenesis of disease in each model, application
in the evaluation of drugs, drug combinations and plant extracts
as well as the inherent advantages and disadvantages of each
model are discussed. The LP-BM5 murine AIDS (MAIDS) model
with its in vitro equivalent was identified as the
animal model, although not identical to HIV/AIDS, most suitable
for the rapid and cost effective initial screening of drugs,
drug combinations, plant extracts and drug-plant combinations.
[Back to top]
High Frequency of Grossly Deleted nef Genes in HIV-1
Infected Long-Term Slow Progressors Treated with Korean Red
Ginseng
Young K. Cho, Ji Y. Lim, You S. Jung, Sun K. Oh, Hee J.
Lee and Heungsup Sung
To investigate the association between Korean red ginseng
(KRG) intake in HIV-1 infected patients and the occurrence
of grossly deleted nef genes (gΔnef), we characterized
nef genes in 10 long-term slow progressors (LTSP)
infected with HIV-1 subtype B and 34 control patients. LTSP
was defined by the annual decrease in CD4 T cells being less
than 20/μl
over 10 years in the absence of antiretroviral therapy. They
were treated with KRG for a prolonged period. Nef
genes were amplified from peripheral blood mononuclear cells
(PBMC) using nested PCR and the products were sequenced directly.
It was observed that the patients CD4 T cell counts decreased
from 444 ± 207/μl
to 294 ± 177/μl
over 136 ± 23 months of KRG intake. This corresponds
to an annual decrease in the level of CD4 T cells of 13.3/μl.
A total of 479 nef genes were amplified from 137
PBMC samples. Nine out of the 10 patients, 47 (34.3%) out
of the 137 samples, and 90 out of the 479 genes revealed gΔnef.
The deletion extended outside the nef gene in 25 gΔnef
obtained from 6 patients. The proportion of samples with gΔnef
(34.3%) was significantly higher than 4.8% in control patients
(P < 0.001). In addition, it significantly increased as
the duration of KRG intake prolongs (P < 0.01). These data
suggest that the occurrence of gΔnef might be
associated with long-term intake of KRG.
[Back to top]
A Clinical Scoring System as Useful as FNAC in the
Diagnosis of Tuberculous Lymphadenitis in HIV Positive Patients
Satya D. Purohit, Vimlesh Purohit and Murli L. Mathur
Among HIV positive patients, Fine needle aspiration cytology
(FNAC) or biopsy for diagnosis of tuberculous lymphadenopathy
is often avoided due to an unspoken stigma. Earlier, we had
developed a clinical scoring scale for the diagnosis of tuberculous
lymphadenitis (TBLN), which had 88% sensitivity and detected
no false positives. In the present study, we attempted to
develop similar scale that could assist in diagnosing TBLN
in AIDS. All 42 HIV positive patients of adenitis attending
Ramdeo Hospital and Research Centre, Jodhpur between August
2001 and December 2004 were studied. History of past tuberculosis,
age, history of rapid weight loss, site, size, consistency,
and the presence of matting and sinus formation of enlarged
lymph nodes, result of tuberculin test, sputum smear and findings
in chest radiograph were compared between patients diagnosed
as TBLN and those showing non-tuberculous lymphadenitis (Non-TBLN)
on cytopathological examination of material obtained by fine
needle aspiration. Based on the results, clinical scores from
zero to two were assigned to different clinical features.
The total clinical score was then calculated for each patient.
A total clinical score of five or more included all TBLN cases
and only 10.5% false positives. This scoring system can be
used in remote peripheral areas, which do not have the facility
for biopsy or FNAC.
[Back to top]
Prevalence of Thyroid Dysfunction in Thai HIV-Infected
Patients
Channarong Ketsamathi, Wallaya Jongjaroenprasert, La-or
Chailurkit, Umaporn Udomsubpayakul and Sasisopin Kiertiburanakul
Increasing prevalence of thyroid function abnormality has
been reported in HIV-infected patients. We aim to evaluate
the prevalence and assess risk factors of thyroid dysfunction
in Thai HIV-infected patients. A cross-sectional study was
conducted. Serum thyroid hormone concentrations (FT4, FT3,
and TSH) and thyroid autoantibodies (TgAb and TPOAb) were
measured by electrochemiluminescence immunoassay. A total
of 200 HIV infected outpatients were included. Ninety-seven
patients (48.5%) were men (mean age of 36.3 ± 8.3 years).
Duration of HIV infection was 49.6 ± 35.1 months and
53% had previous opportunistic infections (OI). Mean CD4 cell
count was 340.6 ± 173.1 cells/mm3. Of these, 167 patients
(83.5%) received antiretroviral therapy (ARV). Abnormal thyroid
function test was detected in 32 patients (16%). Twenty-seven
patients (13.5%) had decreased thyroid function (primary hypothyroidism
3, subclinical hypothyroidism 12, and low FT4 with low or
normal TSH 12) whereas 5 patients had increased thyroid function
(overt hyperthyroidism 1, subclinical hyperthyroidism 1, and
isolated high FT3 3). None had clinical features of thyroid
hormone dysfunction. Thirteen patients (6.5%) had thyroid
antibody positive. Patients who received ARV had higher mean
FT3 levels than those who were naïve to ARV (p = 0.017).
History of previous OI was found to be an independently significant
risk factor for decreased thyroid function with the odds ratio
of 3.28 (95% CI =1.183-9.099; p = 0.022). Hypothyroidism was
common among Thai HIV-infected patients, especially in those
who had history of previous OI. It is therefore suggested
that screening and/or monitoring of thyroid hormone in HIV-infected
patients should be considered.
[Back to top]
Estimation of Mortality from Vital Registrations in
South Africa
Eric O. Udjo
Sentinel surveillance surveys combined with epidemiological/demographic
models have been used in monitoring trends in mortality due
to HIV in South Africa as in most other countries. The potential
biases in such surveys have been highlighted in recent studies.
South Africa’s HIV prevalence (29.5% among pregnant
women attending antenatal clinics in 2004) is one of the highest
in the world. National HIV prevalence from population-based
survey has been carried out twice in South Africa, but is
of limited use as a surveillance system independent of antenatal
data.
The use of vital registration in monitoring HIV related mortality
has been largely unexplored. This study utilises data on registered
deaths for the period 1997-2001 to estimate trends in mortality
and TB/HIV related death rates in South Africa.
The analysis utilizes the Growth Balance method to estimate
the completeness of the death records from the registration
system, and hence an adjustment factor for the registered
deaths including TB/HIV related deaths in the period.
The results indicate that coverage of registration of deaths
in South Africa has increased over time but the completeness
of registration of female deaths lags behind completeness
of registration of male deaths. The absolute number of deaths
is estimated to have increased from about 400,000 in 1997
to about 565,000 in 2002. Crude HIV related plus TB-AIDS death
rate is estimated to have increased from about 9.6 per 10,000
in 1997 to about 19.1 per 10,000 in 2002. The increase in
the number of deaths could not be attributed to population
growth.
[Back to top]
Lentivirus-Like Particles Without Reverse Transcriptase
Elicit Efficient Immune Responses
Sean P. McBurney, Kelly R. Young, Casmiar I. Nwaigwe,
Adam C. Soloff, Kelly Stefano Cole and Ted M. Ross
Following infection by HIV or SIV, reverse transcriptase
(RT) directs the conversion of the single-stranded RNA genome
into a double-stranded DNA molecule that integrates into the
host cell genome. RT encodes for several immunogenic epitopes
that are desirable for inclusion in a human vaccine for HIV
infection, however, issues of safety have dampened enthusiasm
for inclusion of an enzymatically-active RT molecule into
an AIDS vaccine. In this study, virally-regulated, replication-incompetent
lentiviral particles were expressed from DNA plasmids. The
sequences for integrase, Vpr, Vif, Nef, and the long terminal
repeats (LTRs) were deleted and mutations were engineered
into capsid to decreases RNA packaging. Virus-like particles
incorporated no RT (HIV-VLP ΔRT or SHIV-VLP ΔRT)
or contained a full-length enzymatically-inactivated RT molecule
(HIV-VLP or SHIV-VLP). Each secreted VLP was enveloped with
a lipid bilayer derived from primate cells with embedded,
native viral envelopes in similar concentrations as infectious
virions. BALB/c mice were vaccinated (weeks 0, 3, and 6) with
purified VLPs via intranasal inoculation in the presence of
cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs).
All VLPs, with or without RT, elicited both robust humoral
and cellular immune responses to Gag, Pol, and Env antigens.
Therefore, the lack of RT enhances the safety of these VLPs
for use in future human clinical trials without a significant
reduction in the overall immunogenicity of these VLP immunogens.
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