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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 6, Number 5, September 2008
Contents
Review Articles
Cellular Reservoirs of HIV-1 and their
Role in Viral Persistence Pp. 388-400
Aikaterini Alexaki, Yujie Liu and Brian
Wigdahl
[Abstract]
Combining Drug and Immune Therapy: A
Potential Solution to Drug Resistance and Challenges of
HIV Vaccines? Pp. 401-410
Aaron N. Endsley, Noha N. Salama and
Rodney J.Y. Ho
[Abstract]
Platelets and HIV-1 Infection: Old and New Aspects
Pp. 411-418
Donato Torre and Agostino Pugliese
[Abstract]
The Indian Pediatric HIV Epidemic: A Systematic Review Pp.
419-432
Harjot Kaur Singh, Amita Gupta, George Kelly
Siberry, Nikhil Gupte, Jayagowri Sastry, Arti Kinikar, Ira
Shah, Raman Raghunathrao Gangakhedkar, Robert Cyril Bollinger
and Vinay Kulkarni
[Abstract]
NK Cell Function in HIV-1 Infection Pp.
433-440
Andrea De Maria and Lorenzo Moretta
[Abstract]
Original Research Papers
HHV-6 is Frequently Detected in Dried
Cord Blood Spots from Babies Born to HIV-Positive Mothers
Pp. 441-446
Pierlanfranco D’Agaro, Paola Burgnich,
Manola Comar, Gianna Dal Molin, Maria Bernardon, Marina Busetti,
Salvatore Alberico, Albino Poli, Cesare Campello and
the SIGO Italian Group
[Abstract]
Effect of HAART on Salivary Composition
and Oxidative Profile in HIV-Infected Patients Pp.
447-451
Eduardo Shahar, Shimon Pollack, Eynat Kedem,
Gammal Hassoun and Rafael Nagler
[Abstract]
Anti-HIV-1 and Anti-HBV Immune Responses
in Mice After Parenteral and Nasal Co-Administration of a
Multiantigenic Formulation Pp. 452-460
Enrique Iglesias, Daymir García,
Yamilka Carrazana, Julio C. Aguilar, Aniel Sánchez,
Lariza Gorobaya and Aracelys Blanco
[Abstract]
Development and Evaluation of Single
Sperm Washing for Risk Reduction in Artificial Reproductive
Technology (ART) for Extreme Oligospermic HIV Positive Patients
Pp. 461-465
Alionka Bostan, Anne-Sophie Vannin, Serena
Emiliani, Laurent Debaisieux, Corinne Liesnard and
Yvon Englert
[Abstract]
Better CD4+ T Cell Recovery in Brazilian
HIV-Infected Individuals Under HAART Due to Cumulative Carriage
of SDF-1-3’A, CCR2-V64I, CCR5-D32 and CCR5-Promoter
59029A/G Polymorphisms Pp. 466-473
Paula O. Rigato, Marisa A. Hong, Jorge Casseb,
Mirthes Ueda, Isac de Castro, Gil Benard and Alberto
J.S. Duarte
[Abstract]
Evaluating the Role of Etravirine in
the Second-Line Antiretroviral Therapy After Failing an Initial
Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimen
in a Resource-Limited Setting Pp. 474-476
Somnuek Sungkanuparph, Weerawat Manosuthi,
Sasisopin Kiertiburanakul, Bucha Piyavong and Wasun
Chantratita
[Abstract]
Correlation Between HIV-1 RNA Load in
Blood and Seminal Plasma Depending on Antiretroviral Treatment
Status, Regimen and Penetration of Semen by Antiretroviral
Drugs Pp. 477-484
Derek J. Chan, John E. Ray, Leon McNally,
Marijka Batterham and Don E. Smith
[Abstract]
Abstracts
[Back to top]
Cellular Reservoirs of HIV-1 and their Role
in Viral Persistence
Aikaterini Alexaki, Yujie Liu and Brian
Wigdahl
A major obstacle in human immunodeficiency virus type
1 (HIV-1) eradication is the ability of the virus to remain
latent in a subpopulation of the cells it infects. Latently
infected cells can escape the viral immune response and persist
for long periods of time, despite the presence of successful
highly active antiretroviral therapy (HAART). Given the appropriate
stimulus, latently infected cells can reactivate and start
producing infectious virions. The susceptibility of these
cell populations to HIV-1, their life span, their proliferative
capacity, and their ability to periodically produce infectious
virus subsequent to alterations in cellular physiology and/or
immunologic controls are critical issues which determine the
contribution of these cells to viral persistence.
Memory CD4+ T cells due to the long life span, which may be
several years, and their ability to reactivate upon encounter
with their cognate antigen or other stimulation, are considered
a critical reservoir for maintenance of latent HIV-1 proviral
DNA. Cells of the monocyte-macrophage lineage, which originate
in the bone marrow (BM), are of particular importance in HIV-1
persistence due to their ability to cross the blood-brain
barrier (BBB) and spread HIV-1 infection in the immunoprivileged
central nervous system (CNS). Hematopoietic progenitor cells
(HPCs) are also a potential HIV-1 reservoir, as several studies
have shown that CD34+ HPCs carrying proviral DNA can be found
in vivo in a subpopulation of HIV-1-infected patients.
The ability of HPCs to proliferate and potentially generate
clonal populations of infected cells of the monocyte-macrophage
lineage may be crucial in HIV-1 dissemination. The contribution
of these and other cell populations in HIV-1 persistence,
as well as the possible strategies to eliminate latently infected
cells are critically examined in this review.
[Back to top]
Combining Drug and Immune Therapy: A Potential Solution to
Drug Resistance and Challenges of HIV Vaccines?
Aaron N. Endsley, Noha N. Salama and
Rodney J.Y. Ho
According to the World Health Organization’s 2007
estimates, close to 33 million people worldwide are living
with HIV/AIDS. Over the past two decades, significant progress
has been made in understanding HIV pathogenesis and disease
progression, which has allowed the identification of a multitude
of drug and vaccine targets. Although currently available
drug therapies have greatly increased the time from HIV infection
to development of AIDS, drug resistance is an inevitable consequence
that limits the duration of successful treatment. Consequently,
a preventative vaccine remains the top priority; however,
no vaccine trial performed to date has shown efficacy in human
trials. Therefore, we must use all of our current resources
in new creative therapies and strive to develop new methods
to reduce persistent viral levels until an effective preventative
vaccine is developed. One possible strategy is to use therapeutic
vaccination or immune modulators to augment the immune response
while antiretroviral chemotherapy limits viral replication.
This combination approach is being utilized with success in
the treatment of Hepatitis B infections and several trials
have been completed and others are ongoing to determine the
potential of combination immunological and chemical therapies
for HIV infection. We will review the progress to date of
anti-HIV drugs, preventative vaccines, and therapeutic vaccines
and discuss the future strategies of combination drug and
vaccine therapeutic strategies in the fight against HIV.
[Back to top]
Platelets and HIV-1 Infection: Old and New Aspects
Donato Torre and Agostino Pugliese
In this review we summarize the data on interaction of
platelets with HIV-1 infection. Thrombocytopenia is a common
finding among HIV-1 infected patients; several combined factors
contribute to low peripheral platelet counts, which are present
during all the stages of the disease. In addition, a relationship
between platelet count, plasma viral load and disease progression
has been reported, and this shows the potential influence
platelets may have on the natural history of HIV-1 disease.
Several lines of evidence have shown that platelets are an
integral part of inflammation, and can be also potent effector
cells of innate immune response as well as of adaptive immunity.
Thus, we rewieved the role of inflammatory cytokines, and
chemokines as activators of platelets during HIV-1 infection.
Moreover, platelets show a direct interaction with HIV-1 itself,
through different pathogenic mechanisms as binding, engulfment,
internalisation of HIV-1, playing a role in host defence during
HIV-1 infection, by limiting viral spread and probably by
inactivating viral particles.
Platelets may also play an intriguing role on endothelial
dysfunction present in HIV-1 infection, and this topic begins
to receive systematic study, inasmuch as interaction between
platelets and endothelial cells is important in the pathogenesis
of atherosclerosis in HIV-1 infected patients, especially
in those patients treated with antiretroviral drugs.
Finally, this review attempts to better define the state of
this emerging issue, to focus areas of potential clinical
relevance, and to suggest several directions for future research.
[Back to top]
The Indian Pediatric HIV Epidemic: A Systematic Review
Harjot Kaur Singh, Amita Gupta, George Kelly
Siberry, Nikhil Gupte, Jayagowri Sastry, Arti Kinikar, Ira
Shah, Raman Raghunathrao Gangakhedkar, Robert Cyril Bollinger
and Vinay Kulkarni
Despite an estimated 70,000 Indian children living with
HIV infection, little is known about India’s pediatric
HIV epidemic. Generalizations about epidemiology, natural
history, and treatment outcomes from other resource-limited
settings (RLS) may be inaccurate for several biologic and
social reasons. A review of the Indian literature is needed
to optimize country-specific HIV management and examine these
generalizations. MEDLINE and EMBASE were searched for articles
published in English by November 2007 on HIV-infected, Indian
children (0-18 years) that detailed epidemiology, natural
history, or treatment. Articles with original, extractable
data were selected and summarized using descriptive statistics.
Of 370 citations, 58 studies were included in this review
(median study size 24 children). Significant heterogeneity
was noted among the studies. HIV infection was reported nearly
twice as often in males (male/female ratio 1.9) and diagnosed
earlier (4.7 years) than in other RLS. Over 2% of hospitalized
children were reported to be HIV-infected. The reported mortality
among HIV-infected newborns of 22% at 18 months was lower
than other RLS. Improved anthropometrics were the only consistently
reported and comparable benefit of shortterm HAART to other
RLS. Review of the Indian literature yielded potentially unique
epidemiology and natural history compared to other RLS. However,
important questions about the accuracy and representativeness
of the Indian data limit its generalizability and comparability.
Targeted interventions to curb India’s pediatric HIV
epidemic require urgent clarification of these findings. If
such differences truly exist, management guidelines should
be tailored accordingly.
[Back to top]
NK Cell Function in HIV-1 Infection
Andrea De Maria and Lorenzo Moretta
The parallel development of precise knowledge on NK cell
receptors and on their function has considerably supported
our understanding of the extension of their involvement during
HIV-1 infection. The relevant reduction of NK cell function
is dependent on well-described perturbations of their expression
of specific receptors, leading not only to inhibition of their
patrolling activity against invading pathogens, but also to
alterations of their crosstalk with other cells of the immune
system. With NK cell failure, boosted viral replication reduces
immune surveillance towards opportunistic neoplasm and impaired
control of adaptive responses prevails. NK cell function in
human and animal models showing efficient control of disease
progression may offer new insights in mechanisms underlying
the protection from infectious disease.
[Back to top]
HHV-6 is Frequently Detected in Dried Cord Blood Spots
from Babies Born to HIV-Positive Mothers
Pierlanfranco D’Agaro, Paola Burgnich,
Manola Comar, Gianna Dal Molin, Maria Bernardon, Marina Busetti,
Salvatore Alberico, Albino Poli, Cesare Campello and
the SIGO Italian Group
Intrauterine transmission of HHV-6 is well established in
immunocompetent women while few data are available on infections
in babies born to HIV-positive mothers. To assess the rate
of HHV-6 vertical transmission in comparison to CMV, we analyzed
cord blood spots dried on cards (Dried Blood Spots, DBS) collected
during a multi-center study on HIV congenital infections in
Italy.
DBS were tested by PCR for HHV-6 and CMV footprints. HHV-6
amplimers were sequenced and characterized. As control group,
cards taken from babies born to HIV-negative mothers were
analyzed.
DBS of 187 babies born to HIV-positive and 372 to HIV-negative
mothers were analyzed. The prevalence of HHV-6 was 3.2% in
babies born to HIV-positive mothers. CMV was found in the
HIV-positive group with a prevalence rate of 1.6%. In newborns
of control pregnant women, HHV-6 prevalence rate was 1.1%
(p=0.09), while CMV was not detected (p=0.04). Sequence analysis
could distinguish between HHV-6 A and B variant in both groups
and one A/B coinfection was found in a baby born to a HIV-positive
mother.
HIV-infected mothers transmit HHV-6 and CMV viruses to their
babies more frequently than uninfected women.
[Back to top]
Effect of HAART on Salivary Composition and Oxidative Profile
in HIV-Infected Patients
Eduardo Shahar, Shimon Pollack, Eynat Kedem,
Gammal Hassoun and Rafael Nagler
Although it has been widely suggested that oxidative
stress contributes to the pathogenesis of HIV infection, salivary
composition and its oxidative related aspects have never been
studied in HIV patients, both HAART-treated and untreated.
Human saliva and serum were collected and analyzed for various
biochemical, redox related and immunological parameters from
43 consenting HIV-infected patients (20 untreated and 23 treated
with HAART) and 20 healthy controls, age and gender matched.
Saliva composition of HIV infected patients was completely
altered but returned to normal following HAART. HIV patients
had significantly-increased levels of oxidative stress damaging
markers, compared to healthy controls. Carbonyl levels increased
by 110% (p=0.005), and superoxide dismutase enzyme (SOD) and
antioxidant capacity (ImAnOx) levels by 45% and 16% (0.035)
respectively, but returned to normal levels in treated patients
(p=0.005, p=0.03 and 0.02 respectively). Also, the significantly-altered
salivary composition (pH and lactate dehydrogenase (LDH) enzyme)
and concentration (calcium (Ca), magnesium (Mg), albumin,
salivary total protein, secretory IgA) of HIV-infected patients
reverted to normal following HAART treatment. Salivary analysis
may be used for assessing patient status: treated vs untreated,
based on the increase or decrease in the concentration of
a given salivary parameter in the HIV-untreated group vs controls,
and a return to normal following the HAART treatment. Salivary
collection is simple, non-invasive and not associated with
risk of infection spread. Antioxidants in HIV patients may
be recommended, as well as local oral means aimed at resuming
salivary functions compromised in HIV patients.
[Back to top]
Anti-HIV-1 and Anti-HBV Immune Responses in Mice After Parenteral
and Nasal Co-Administration of a Multiantigenic Formulation
Enrique Iglesias, Daymir García,
Yamilka Carrazana, Julio C. Aguilar, Aniel Sánchez,
Lariza Gorobaya and Aracelys Blanco
The cell-mediated immune response to HIV-1 is an essential
element of the mechanisms for viral replication control. Currently,
most of the vaccine candidates in clinical trials were developed
to stimulate HIV-1-specific CD8+ cytotoxic (CTL) and CD4+
T helper (Th) lymphocytes. We have been working on a novel
approach to develop a vaccine formulation for HIV-1 using
a recombinant multiepitopic protein (named CR3), which comprises
CTL and Th epitoperich regions of HIV-1 from several subtype
B isolates, co-inoculated with the hepatitis B virus surface
(HBsAg) and core (HBcAg) antigens of the hepatitis B virus
(HBV) as adjuvant. According to our studies in mice, the nasal-subcutaneous
co-administration of this multiantigenic formulation induces
a strong Th1-biased specific response against CR3, CD8+ T
cells in mice spleen and IFN-γ-secreting
cells in mesenteric lymph nodes. Cross-reactive p24-specific
IFN-γ-secreting
cells in spleen were also detected. Moreover, Nef-specific
antibodies were elicited in mice sera which might avoid the
toxic effects of this antigen. However, a marginal anti-CR3
antibody response was elicited in vaginal mucosa. Additionally,
we observed anti-HBsAg and anti-HBcAg cellular and humoral
responses. In this regard, our multiantigenic formulation
might provide immunity against HBV as an additional benefic
considering the high HIV-1-HBV co-infection rate reported
worldwide.
[Back to top]
Development and Evaluation of Single Sperm Washing for Risk
Reduction in Artificial Reproductive Technology (ART) for
Extreme Oligospermic HIV Positive Patients
Alionka Bostan, Anne-Sophie Vannin, Serena
Emiliani, Laurent Debaisieux, Corinne Liesnard and
Yvon Englert
The serodiscordant couples, where the male is HIV-positive,
are treated in fertility clinics, using the sperm washing
technique by gradient centrifugation. This protocol cannot
be carried out in oligo-azoospermic patients, where spermatozoa
retrieval from the epididymis and testis must be performed.
We developed a single sperm washing technique, where the spermatozoa,
after the retrieval, are washed with the aid of a micromanipulator,
to obtain virus decontamination and then used for the intracytoplasmic
sperm injection (ICSI). The experiment was performed by using
sperm samples containing three different viral loads. After
one hour of incubation, spermatozoa were taken one by one
from the HIV loaded drop and washed in four different microdrops.
Before each passage into the next washing drop, the pipette
was emptied in a first waste drop and then loaded with new
washing medium from a second separate loading drop. After
transferring of 10 spermatozoa in these four successive drops,
the washing medium and the virus-loaded drops were tested
for the HIV RNA presence by the nested RT-PCR technique. The
presence of the virus was detected in the waste drop of all
three viral loads. The four washing microdrops were each time
negative for the presence of HIV-1 RNA, tested by the nested
RT-PCR technique. The results show that by rinsing the spermatozoa
four times, we are able to diminish the viral load to an undetectable
level. Our data demonstrate that single sperm washing can
be performed in the cases of extreme male sterility in HIV-positive
men. From now on the couples, where the male is oligoazoospermic
and HIV positive, could be included in our ICSI program, respecting
the usual viral safety level of the ART techniques for the
embryo.
[Back to top]
Better CD4+ T Cell Recovery in Brazilian HIV-Infected Individuals
Under HAART Due to Cumulative Carriage of SDF-1-3’A,
CCR2-V64I, CCR5-D32 and CCR5-Promoter 59029A/G Polymorphisms
Paula O. Rigato, Marisa A. Hong, Jorge Casseb,
Mirthes Ueda, Isac de Castro, Gil Benard and Alberto
J.S. Duarte
Polymorphisms of chemokines and chemokine-receptors genes
have been shown to influence the rate of progression to AIDS;
however, their influence on response to HAART remains unclear.
We investigated the frequency of the SDF-1-3’A, CCR2-64I,
CCR5-D32 and CCR5-Promoter-59029-A/G polymorphisms in Brazilian
HIV-1-infected and uninfected individuals and their influence
on CD4+ T-cell evolution HIV-1 infected individuals before
and during HAART. Polymorphism detection was done in a transversal
study of 200 HIV-1-infected and 82 uninfected individuals.
The rate of CD4+ T cell increase or decrease was studied in
a cohort of 155 HIV-1 infected individuals on pre and post-HAART.
Polymorphisms were determined by PCR associated with RFLP.
The rate of CD4+ T-cell decline or increase was also de-termined.
HIV-1 infected and uninfected subjects showed, respectively,
frequencies of 0.193 and 0.220 for SDF-1-3’A, of 0.140
and 0.110 for CCR2-V64I, of 0.038 and 0.055 for CCR5-D32,
and of 0.442 and 0.390 for CCR5-P-59029-A/G. HIV-1-infected
subjects carrying one, two or three of these four polymorphisms
showed better CD4+ T-cell recovery than HIV-1-infected subjects
carrying the four wildtype alleles (+2.7, +1.6, +3.5, and
-0.9 lymphocytes/μl/month,
respectively). Regression logistic analysis showed that the
CCR5-D32/CCR2-V64I association was predictor of positive CD4+
T cell slope after HAART. The distribution of polymorphisms
did not differ between HIV-1-infected and uninfected individuals,
but differed from more homogenous ethnic groups probably reflecting
the miscegenation of the Brazilian population. We add further
evidence of the role of these polymorphisms by showing that
the CD4 gain was influenced by carriage of one or more of
the polymorphisms studied here. These results highlight the
possibility that these genetic traits can be useful to identify
patients at risk for faster progression to AIDS or therapeutic
failure.
[Back to top]
Evaluating the Role of Etravirine in the Second-Line Antiretroviral
Therapy After Failing an Initial Non-Nucleoside Reverse Transcriptase
Inhibitor-Based Regimen in a Resource-Limited Setting
Somnuek Sungkanuparph, Weerawat Manosuthi,
Sasisopin Kiertiburanakul, Bucha Piyavong and Wasun
Chantratita
Etravirine demonstrates activity against NNRTI-resistant
HIV-1 but its efficacy depends on the number of etravirine
resistance-associated mutations (RAMs). This study aimed to
evaluate the role of etravirine in the second regimen in a
resource-limited setting. Genotype resistance assay was conducted
in a cohort of HIV-infected patients who experienced virological
failure from an initial NNRTI-based regimen. We focused on
etravirine-RAMs previously described: V90I, A98G, L100I, K101E/P,
V106I, V179D/F, Y181C/I/V, and G190A/S. Frequency and predicting
factors for ≤2 etravirine-RAMs were evaluated. There
were 158 patients with a median duration of ART prior to failure
of 22 months. The median CD4 cell count and HIV-1 RNA at the
time of virological failure were 173 cells/mm3
and 4.1 log copies/mL, respectively. Of all, 75.3% of patients
were predicted to have ≤2 etravirine-RAMs. From logistic
regression, there was no clinical factor to predict etravirine
susceptibility. Patients with ≤2 etravirine-RAMs had
lower rates of K65R (3.4% vs 17.9%, p=0.005),
Q151M (5.9% vs 20.5%, p=0.012), and multi-NRTI
resistance mutations (16.8% vs 48.7%, p<0.001)
when compared to patients with >2 etravirine-RAMs. Etravirine
may have activity for using in the second regimen in most
patients in resource-limited setting who fail an initial NNRTI-based
regimen. Genotype testing is needed to identify this group.
Some of these patients, indicated by genotype results, may
be able to use etravirine plus 2 active NRTIs for second ART
regimen. This strategy may be an option for patients who cannot
afford or tolerate protease inhibitor. Prospective study to
evaluate this strategy should be conducted in resource-limited
setting.
[Back to top]
Correlation Between HIV-1 RNA Load in
Blood and Seminal Plasma Depending on Antiretroviral Treatment
Status, Regimen and Penetration of Semen by Antiretroviral
Drugs
Derek J. Chan, John E. Ray, Leon McNally,
Marijka Batterham and Don E. Smith
To assess the correlation between HIV-1 RNA load in blood
and semen by antiretroviral therapy status and the relative
penetration of antiretroviral drugs in seminal plasma. We
performed a cross-sectional cohort study of 119 HIV-1 subjects
divided into three groups according to treatment status. Blood
and semen were collected concurrently. Seminal viral load
determined by NucliSens® HIV-1 QT PCR (BioMerieux).
Viral suppression over time was assessed in a second semen
sample collected from 10 treated subjects. Antietroviral plasma
concentrations were measured by high performance liquid chromatography
and recovery experiments were performed on semen samples to
validate quantitation in this matrix. All subjects taking
non nucleoside reverse transcriptase inhibitors (n = 36, mean
treatment 33 months ± 14) or protease inhibitors (n
= 45, mean treatment 31 months ± 25) had blood viral
load < 50 copies/mL and seminal viral load < 250 copies/mL.
In untreated subjects (n = 38), blood and semen viral loads
were positively correlated (Spearman´s ρ = 0.489,
p = 0.002). Blood and semen nevirapine concentrations were
positively correlated (r2
= 0.795, p = 0.005) and therapeutic concentrations
achieved in both compartments. Lopinavir and atazanavir also
penetrated semen but efavirenz did not. We find that there
is compartmentalisation of HIV-1 within the male genital tract
and propose that new infections may originate from untreated
men and that suppressive antiretroviral regimens may reduce
the risk of sexual transmission.
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