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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 7, Number 1, January 2009
Contents
Simian Immunodeficiency Virus Pathogenesis
Guest Editor: Donald Sodora
Editorial
Pp. 1
[Full
Text Article]
The Rhesus Macaque Pediatric SIV Infection Model -
A Valuable Tool in Understanding Infant HIV-1 Pathogenesis
and for Designing Pediatric HIV-1 Prevention Strategies
Pp. 2-11
Kristina Abel
[Abstract] [Full
Text Article] [PMID:
19149549 PubMed - indexed for MEDLINE]
A Case for Innate Immune Effector Mechanisms
as Contributors to Disease Resistance in SIV Infected Sooty
Mangabeys Pp. 12-22
Lara E. Pereira and Aftab A. Ansari
[Abstract] [Full
Text Article] [PMID:
19149550 PubMed - indexed for MEDLINE]
Studies of Plasmacytoid Dendritic Cell Dynamics
in Simian Immunodeficiency Virus Infection of Nonhuman Primates
Provide Insights into HIV Pathogenesis Pp. 23-29
Viskam Wijewardana, Kevin N. Brown and Simon
M. Barratt-Boyes
[Abstract] [Full
Text Article] [PMID:
19149551 PubMed - indexed for MEDLINE]
Coreceptor Switch in Infection of Nonhuman Primates
Pp. 30-38
Cecilia Cheng-Mayer, Silvana Tasca and Siu-hong
Ho
[Abstract] [Full
Text Article] [PMID:
19149552 PubMed - indexed for MEDLINE]
African Non Human Primates Infected by SIV -
Why Don't they Get Sick? Lessons from Studies on the Early
Phase of Non-Pathogenic SIV Infection Pp. 39-50
Anne-Sophie Liovat, Béatrice Jacquelin, Mickaël
J. Ploquin, Françoise Barré-Sinoussi and
Michaela C. Müller-Trutwin
[Abstract] [Full
Text Article] [PMID:
19149553 PubMed - indexed for MEDLINE]
Pirate Primates in Uncharted Waters: Lymphocyte Transfers
in Unrelated, MHC-Matched Macaques Pp. 51-56
Benjamin J. Burwitz, Justin M. Greene and David
H. O’Connor
[Abstract] [Full
Text Article] [PMID:
19149554 PubMed - indexed for MEDLINE]
AIDS in African Nonhuman Primate Hosts of SIVs:
A New Paradigm of SIV Infection Pp. 57-72
Ivona Pandrea, Guido Silvestri and Cristian Apetrei
[Abstract] [Full
Text Article] [PMID:
19149555 PubMed - indexed for MEDLINE]
Multiple Roles for Chemokines in the Pathogenesis
of SIV Infection Pp. 73-82
Todd A. Reinhart, Shulin Qin and Yongjun Sui
[Abstract] [Full
Text Article] [PMID:
19149556 PubMed - indexed for MEDLINE]
IL-2,IL-7 and IL-15 as Immuno-Modulators During
SIV/HIV Vaccination and Treatment Pp. 83-90
Amanda Leone, Louis J. Picker and Donald L. Sodora
[Abstract] [Full
Text Article] [PMID:
19149557 PubMed - indexed for MEDLINE]
Review Articles
Cellular Proteins and HIV-1 Rev Function Pp. 91-100
Modem Suhasini and Thipparthi R. Reddy
[Abstract] [Full
Text Article] [PMID:
19149558 PubMed - indexed for MEDLINE]
Cessation of HIV-1 Transcription by Inhibiting
Regulatory Protein Rev-Mediated RNA Transport Pp.
101-108
Yuan Cao, Xinyong Liu and Erik De Clercq
[Abstract] [Full
Text Article] [PMID:
19149559 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[Full
Text Article]
Editorial
The etiologic agent that causes human AIDS was identified
in 1981. Only a few years later Rhesus macaques at the New
England Primate Center were observed exhibiting clinical signs
representative of AIDS, leading to the isolation and identification
of the simian immunodeficiency virus (SIV). Since that time,
numerous studies have been undertaken utilizing the SIV/monkey
model and a range of pathogenic outcomes identified due to
genetic, virologic and immunologic differences. The distinct
disease outcomes are quite evident when assessing the SIV
infection in different monkey species. The majority of monkey
species in Africa harbor SIV infections in the wild, and have
been termed SIV natural host species. Sooty mangabeys (West
Africa) and African green monkeys (found throughout Africa)
are two of the more commonly studied SIV natural hosts. SIV
is able to replicate to high levels in the natural host species
yet the virus and host generally coexist, without exhibiting
any clinical signs of simian AIDS. In contrast, macaques are
from Asia and are not naturally infected with SIV in the wild.
Therefore, SIV infection of macaques represent a cross-species
transmission of the virus and in this regard is similar to
HIV in humans. The SIV infection of macaques is similar to
infectio of natural hosts as it also results in high levels
of viral replication, however there are also clear indications
of immune dysfunction commonly seen in AIDS patients (CD4
T cell decline, wasting, opportunistic infections). Although
a small number of macaques are able to resist progression
to AIDS, the vast majority of SIV infected macaques develop
AIDS clinical signs and die by 6 months to 2 years post-infection.
In this issue of Current HIV Research, three reviews
assess various aspects of the infection of natural host species.
Liovat et al. provide a clear assessment of the similarities
and differences between the SIV infection in pathogenic and
nonpathogenic primate hosts. One of the key findings is that
during the earliest times post-infection SIV infections are
similar in all species, however nonpathogenic infections distinguish
themselves during the chronic phase of the infection when
elements of immune activation and subsequent immune dysfunction
are suppressed. Pereira and Ansari expanded upon the natural
host analysis by assessing the role of innate cell subsets,
NK cells and DCs, in keeping natural host species from progressing
to AIDS. Pandrea et al. provide a more complete understanding
of the nonpathogenic infection models by providing evidence
that these host species can, under some circumstances develop
clinical signs of simian AIDS. Based on these rare cases in
more aged nonpathogenic species the authors of this review
suggest that we should more accurately refer to natural hosts
of SIV as being ‘persistently nonprogressive’.
Six of the reviews assess and provide key insights into the
pathogenic SIV infection of macaques. While the reviews have
an overall focus that is immunologic in nature, they also
provide information with regard to how the SIV infection itself
is the trigger and underlying force that propels SIV-positive
macaques toward simian AIDS. Cheng-Mayer et al. describe
how coreceptor utilization impacts disease progression in
the SIV/SHIV model, with a focus on the impact of coreceptor
switching. Abel assesses the SIV macaque model for its use
for studying pediatric SIV infections addressing aspects of
transmission and immunologic implications of SIV/HIV infection
of newborns. The ability of SIV/HIV infections to impact the
functionality of plasmacytoid DCs is investigated by Wijewardana
et al. Whereas Reinhart et al. focus on
how dysregulation of chemokines impacts disease progression
in SIV infected macaques. Burwitz et al. describe
how studying Mauritian Cynomolgus macques, which have simple
MHC genetics, might provide a model for utilizing lymphocyte
adoptive transfer studies to better understand how to improve
vaccine design. And finally, Leone et al. describes
how cytokines that can impact T cell homeostasis are being
utilized as both immune therapeutics and vaccine immune modulators
in the SIV macaque model.
These reviews provide a broad overview of the ways that SIV-monkey
models are able to provide insights into pathogenesis of primate
lentiviral infections. Many of the studies described herein
could not be undertaken in HIV-positive patients nor through
in vitro tissue-culture based assessment of patient
cells. Therefore, the AIDS community has benefited greatly
from having the SIV-monkey models, and these model systems
are likely to continue to provide key insights into SIV/HIV
disease progression, therapy and vaccine design into the future.
Donald L. Sodora
(Guest Editor)
Seattle Biomedical Research Institute
Seattle, WA
USA
E-mail:don.sodora@sbri.org
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:tmr15@pitt.edu
[Back to top]
[PMID:
19149549 PubMed - indexed for MEDLINE]
The Rhesus Macaque Pediatric SIV Infection Model - A Valuable
Tool in Understanding Infant HIV-1 Pathogenesis and for Designing
Pediatric HIV-1 Prevention Strategies
Kristina Abel
[Full
Text Article]
Worldwide, the AIDS pandemic continues almost relentlessly.
Women are now representing the fastest growing group of newly
infected HIV-1 infected patients. The risk of mother-to-child-transmission
(MTCT) of HIV-1 increases proportionally as many of these
women are of childbearing age. The screening of pregnant women,
the early diagnosis of HIV-1 infection, and the administration
of antiretroviral therapy (ART) have helped to reduce MTCT
significantly. However, this holds true only for developed
countries. In many resource-poor countries, access to ART
is limited, and breastfeeding, a major route of HIV-1 transmission,
is essential to protect the infant from other infectious diseases
preponderant in those geographic regions. HIV-1 infected children,
in contrast to adult patients, have higher levels of vi-rus
replication that decline only slowly, and a subset progresses
to AIDS within the first two years. Thus, it is imperative
to understand pediatric HIV-1 pathogenesis to design effective
prevention strategies and/or a successful pediatric HIV-1
vaccine. The review summarizes how MTCT of HIV-1 in humans
can be modeled in the infant macaque model of SIV infection.
Importantly, the infant macaque model of SIV infection provides
the opportunity to study early virus-host interac-tions in
multiple anatomic compartments. Furthermore, the review underlines
the importance of evaluating SIV/HIV immune responses in the
context of the normal developmental changes the immune system
undergoes in the newborn. Thus, the pediatric SIV infection
model provides a unique resource for preclinical studies of
novel intervention therapies and vaccine strategies to stop
MTCT of HIV-1.
[Back to top]
[PMID:
19149550 PubMed - indexed for MEDLINE]
A Case for Innate Immune Effector Mechanisms as Contributors
to Disease Resistance in SIV Infected Sooty Mangabeys
Lara E. Pereira and Aftab A. Ansari
[Full
Text Article]
Natural or experimental infection of the African sooty
mangabey (SM) with the simian immunodeficiency virus (SIV)
results in chronic high levels of virus replication but is
associated with none of the debilitating immunopathology,
including the marked CD4 T-cell depletion, persistent cell
activation and acquired immunodeficiency, that afflicts non-natural
hosts such as SIV-infected Asian rhesus macaques (RM) and
HIV-infected humans. Although SIV-infected RM have served
as important models of AIDS given their remarkably similar
course of disease to HIV-infected humans, deci-phering the
immune mechanisms that enable SIV-infected SM to resist disease
development despite high viremia has yet to be defined. Intense
studies for the past two decades using these nonhuman primate
models have been conducted with the hope that this will yield
better insight into the pathogenesis of AIDS, translating
into the development of therapeutic strategies for HIV-infected
individuals such as but not limited to identifying correlates
of protective immunity that can be harnessed for the preparation
of effective vaccines. Although much has been reported about
SIV-specific adaptive immune responses in both the natural
and unnatural hosts of SIV, we submit that innate immunity
may play a larger than previously appreciated role in SIV
pathogenesis, in particular during the period of acute infection.
The purpose of this review is to therefore highlight the recent
advances that have been made in understanding innate immune
responses in SIV-infected SM and to discuss the role(s) of
the major innate immune cell lineages that potentially contribute
to disease resistance in this non-human primate species.
[Back to top] [PMID:
19149551 PubMed - indexed for MEDLINE]
Studies of Plasmacytoid Dendritic Cell Dynamics in Simian
Immunodeficiency Virus Infection of Nonhuman Primates Provide
Insights into HIV Pathogenesis
Viskam Wijewardana, Kevin N. Brown and Simon
M. Barratt-Boyes
[Full
Text Article]
Plasmacytoid dendritic cells (pDC) play a key role in
antiviral immunity through their immense capacity to produce
type I interferons (IFN) and other cytokines and through induction
of antigen-specific T cell responses. Several reports have
documented decreased numbers and reduced function of pDC in
the circulation of HIV patients associated with progression
to disease, indicating that pDC are likely to be important
in control of HIV infection. The mechanism of pDC loss has
not been determined and is difficult to address in natural
infection of humans. As highlighted in this brief review,
the study of pDC dynamics in simian immunodeficiency virus
(SIV) infection of nonhuman primates paves the way to understanding
the complex biology of this important innate system cell in
HIV and other viral infections.
[Back to top]
[PMID:
19149552 PubMed - indexed for MEDLINE]
Coreceptor Switch in Infection of Nonhuman Primates
Cecilia Cheng-Mayer, Silvana Tasca and Siu-hong
Ho
[Full
Text Article]
The human immunodeficiency virus (HIV) enters target
cells via interaction of the viral glycoprotein with
the cellular receptor CD4 and two principal coreceptors, CCR5
(R5 viruses) and CXCR4 (X4 viruses). Most HIV-1 transmissions
result in a predominantly R5 virus infection. With time, X4
variants arise and coexist with R5 virus variants in ~50%
of subtype B infected individuals. The underlying basis for
virus coreceptor switch late in infection remains an enigma,
but will be important to understand given that the appearance
of X4 virus in HIV-1 infected patients inevitably heralds
an unfavorable clinical outcome. Recently, emergence of X4
viruses was observed in rhesus macaques experimentally infected
with a CCR5-tropic simian-human immunodeficiency virus (SHIV)
with progression to disease, providing some insights into
the process of coreceptor switching in vivo. Further
studies in this animal model should enhance our understanding
of the mechanistic basis for, and obstacles to, coreceptor
switch.
[Back to top]
[PMID:
19149553 PubMed - indexed for MEDLINE]
African Non Human Primates Infected by SIV - Why Don't they
Get Sick? Lessons from Studies on the Early Phase of Non-Pathogenic
SIV Infection
Anne-Sophie Liovat, Béatrice Jacquelin, Mickaël
J. Ploquin, Françoise Barré-Sinoussi and
Michaela C. Müller-Trutwin
[Full
Text Article]
African non human primates are natural hosts of SIV. The infection
is generally non-pathogenic despite high steady-state levels
of plasma viral RNA that in HIV-1 and SIVmac infections are
associated with progression towards AIDS. The viral loads
in the gut also are as high as in pathogenic HIV-1/SIVmac
infections; but replication levels are lower in peripheral
lymph nodes of chronically infected African green monkeys.
There is a transient loss of CD4+
T cells in the blood in SIVagm and SIVsm infections and an
early dramatic and more persistent decrease in the gut. Although
SIV in natural hosts is thus cytopathic, the continuous viral
replication is not associated with immunopathology. T CD4+
cells in blood, lymph nodes and gut manifest
no or little increase of cell-death by apoptosis. The lymph
node and gut architecture is not disrupted. The most striking
difference between non-pathogenic SIV and pathogenic HIV-1/SIVmac
infections is the lack of chronic T cell activation. Several
studies are currently in progress to determine which factors
are involved in the maintenance of the low activation level
in the non-pathogenic SIV infections. There are two ways in
which this could be achieved: (i) a lack of immune activation
induction or (ii) an active downregulation of the immune activation.
The arguments in favor of each of these two possible ways
of immune activation control will be discussed in view of
the most recent data in the literature. A particular focus
is put on data on the innate immune system and the timing
of induction of immunosuppressive mediators during the early
phase of SIV infection.
[Back to top] [PMID:
19149554 PubMed - indexed for MEDLINE]
Pirate Primates in Uncharted Waters: Lymphocyte Transfers
in Unrelated, MHC-Matched Macaques
Benjamin J. Burwitz, Justin M. Greene and David
H. O’Connor
[Full
Text Article]
An HIV vaccine remains elusive despite the concerted
efforts of investigators and clinicians over the past two
decades. Animal models are regularly used to obtain new insights
on disease pathogenesis and have become invaluable tools in
the translation of treatments from basic research laboratories
to the clinic. Vaccination of macaques with live, attenuated
simian immunodeficiency virus is currently the most effective
method of garnering protection against subsequent pathogenic
SIV challenge. However, immunization of humans with live,
attenuated HIV is not feasible due to safety concerns. Therefore,
clues to an effective and safe vaccine against HIV may be
found by studying immune correlates of protection in the live,
attenuated, vaccinated macaque model. Previous studies have
identified the immune correlates of protection against Friend
retrovirus in live, attenuated vaccinated mice using allogeneic
adoptive transfers. Similar experiments in macaques have thus
far been hindered due to the vast genetic diversity found
within outbred populations. Here we review the current state
of SIV adoptive transfer research and present a novel macaque
model that allows for allogeneic adoptive transfers.
[Back to top] [PMID:
19149555 PubMed - indexed for MEDLINE]
AIDS in African Nonhuman Primate Hosts of SIVs: A New Paradigm
of SIV Infection
Ivona Pandrea, Guido Silvestri and Cristian Apetrei
[Full
Text Article]
It is generally considered that African nonhuman primates
(NHPs) do not progress to AIDS. In the wild, due to either
a shorter life span or an insufficient follow-up of the animals,
no AIDS cases were described to date. However, in captivity,
at least one case of immunodeficiency was reported for each
of the currently available models of natural infection (African
green monkey, sooty mangabey and mandrill). Furthermore, experimental
infection of three other African NHP species, the black mangabey
(BkM), the chimpanzee and the baboon with heterologous viruses,
such as SIVsmm, HIV-1 and HIV-2, respectively also resulted
in progression to AIDS. Here, we present the clinical, pathologic
and virologic findings of these cases of progressive disease
in African NHP hosts. Similar to pathogenic infections of
humans and rhesus macaques, progression to AIDS in natural
hosts is characterized by: CD4+
T cell depletion in peripheral blood and intestine, opportunistic
infections and neoplasia, severe weight loss, lymphocytic
interstitial pneumonia, lymphoid tissue hypoplasia, and giant
cell disease. Importantly, in these animals the set point
levels of viral loads (VLs) were higher than in the majority
of naturally-infected African NHPs, with significant increases
of VLs occurring in association with disease progression.
Finally, African NHP progressors showed increased levels of
immune activation and cell proliferation, which differentiate
them from the vast majority of African NHPs in which immune
activation is not significantly increased during the chronic
SIV infection compared to their SIV uninfected counterparts.
Despite the rarity of AIDS cases in African NHPs, the spectrum
and morphology of the observed lesions are very similar to
those encountered in humans or macaques with AIDS. Therefore,
we suggest that the “nonpathogenic” models of
SIV infection should be reconsidered as “persistently
nonprogressive” SIV infections. The fact that SIV-infected
African NHPs may, in fact, occasionally progress to AIDS emphasizes
the importance of studying these models to better understand
AIDS pathogenesis and design new therapeutic and preventative
interventions for HIV infection.
[Back to top]
[PMID:
19149556 PubMed - indexed for MEDLINE]
Multiple Roles for Chemokines in the Pathogenesis
of SIV Infection
Todd A. Reinhart, Shulin Qin and Yongjun Sui
[Full
Text Article]
Chemokines are small chemoattractant cytokines involved
in homeostatic and inflammatory immune cell migration. These
small proteins have multiple functional properties that extend
beyond their most recognized role in controlling cellular
migration. The complex immunobiology of chemokines, coupled
with the use of subsets of chemokine receptors as HIV-1 and
SIV entry co-receptors, suggests that these immunomodulators
could play important roles in the patho-genesis associated
with infection by HIV-1 or SIV. This review provides an overview
of the effects of pathogenic infection on chemokine expression
in the SIV/macaque model system, and outlines potential mechanisms
by which changes in these expression profiles could contribute
to development of disease. Key challenges faced in studying
chemokine function in vivo and new opportunities
for further study and development of therapeutic interventions
are discussed. Continued growth in our understanding of the
effects of pathogenic SIV infection on chemokine expression
and function and the continuing development of chemokine receptor
targeted therapeutics will provide the tools and the systems
necessary for future studies of the roles of chemokines in
HIV-1 pathogenesis.
[Back to top]
[PMID:
19149557 PubMed - indexed for MEDLINE]
IL-2, IL-7 and IL-15 as Immuno-Modulators During SIV/HIV Vaccination
and Treatment
Amanda Leone, Louis J. Picker and Donald L. Sodora
[Full
Text Article]
While highly active antiretroviral therapy (HAART) regimens
have proven to be effective in controlling active HIV replication,
complete recovery of CD4+ T cells does not always occur, even
among patients with high level virologic control. Recent advances
in understanding the biology of T cell production and homeostasis
have created the potential to augment anti-viral therapies
with immunotherapies designed to facilitate recovery of the
HIV-damaged immune system, in particular, the recovery of
CD4+ T cell populations. The common gamma-chain cytokines
IL-2, IL-7 and IL-15 are primary regulators of T cell homeostasis
and thus have been considered prime candidate immunotherapeutics,
both for in-creasing T cell levels/function and for augmenting
vaccine-elicited viral-specific T cell responses. Recent studies
have established that these cytokines have distinct functional
roles in immune homeostasis, which focus on specific T cell
popu-lations. The ability of these cytokines to provide immunotherapeutic
benefit to HIV+ patients will depend on their ability to stably
increase or functionally enhance the desired T cell target
population without adverse virologic or clinical consequences.
[Back to top]
[PMID:
19149558 PubMed - indexed for MEDLINE]
Cellular Proteins and HIV-1 Rev Function
Modem Suhasini and Thipparthi R. Reddy
[Full
Text Article]
The human immunodeficiency virus (HIV-1) differentially
controls viral protein expression at the level of splicing
as well as nuclear export of incompletely spliced viral RNA.
This process, mediated by the Rev protein, interfaces with
cellular components involved in post-transcriptional gene
regulation. While a number of reviews have focused on the
host proteins (i.e., Crm1, importin-β
and nucleoporins) that specifically regulate shuttling of
Rev between the nucleus and cytoplasm, we could find no systematic
review of other cellular proteins implicated in Rev function.
Therefore, we will here focus on other Rev cofactors (eIF5a,
hRIP, Sam68, RNA helicases, etc) and the role they play in
Rev/RRE function and HIV-1 replication.
[Back to top]
[PMID:
19149559 PubMed - indexed for MEDLINE]
Cessation of HIV-1 Transcription by Inhibiting Regulatory
Protein Rev-Mediated RNA Transport
Yuan Cao, Xinyong Liu and Erik De Clercq
[Full
Text Article]
The HIV-1 Rev protein, which traffics through nucleolus
and shuttles between nucleus and cytoplasm, facilitates export
of unspliced and singly spliced viral transcripts containing
RRE RNA by the CRM1 export pathway. Inhibitions of the various
stages of Rev-mediated RNA transport can arrest HIV-1 transcriptional
process. The current understanding to the mechanism of Rev
function, Rev-RRE interaction, as well as inhibitors hereof
is reviewed.
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