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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 4, Number 2, April 2006
Contents
Dynamics of Virus-Host Interplay in HIV-1 Replication
Pp. 117-130
Masha Sorin and Ganjam V. Kalpana
[Abstract]
Retrovirus Translation Initiation: Issues and Hypotheses
Derived from Study of HIV-1 Pp. 131-139
Alper Yilmaz, Cheryl Bolinger and Kathleen Boris-Lawrie
[Abstract]
Intracellular Restriction Factors In Mammalian Cells
- An Ancient Defense System Finds A Modern Foe Pp.
141-168
Jörg G. Baumann
[Abstract]
Viral Piracy: HIV-1 Targets Dendritic Cells for Transmission
Pp. 169-176
Annemarie N. Lekkerkerker, Yvette van Kooyk and
Teunis B.H. Geijtenbeek
[Abstract]
Is Autoimmunity a Component of Natural Immunity to
HIV?
Pp. 177-190
Silvia Russo and Lucia Lopalco
[Abstract]
Fitness Constraints on Immune Escape from HIV: Implications
of Envelope as a Target for Both HIV-Specific T Cells and
Antibody Pp. 191-97
Viv Peut and Stephen J. Kent
[Abstract]
HAART-Persistent HIV-1 Latent Reservoirs: Their
Origin, Mechan-isms of Stability and Potential Strategies
for Eradication Pp. 199-208
Kulkosky and Stacie Bray
[Abstract]
Prevention of Sexually Transmitted Human Immunodeficiency
Virus (HIV) Infection in Adolescents Pp. 209-219
Athena P. Kourtis, Joan Marie Kraft, Lorrie Gavin,
Dmitry Kissin,Pamela McMichen-Wright and Denise J. Jamieson
[Abstract]
Factors Influencing Adherence to Highly Active Antiretroviral
Therapy in Spain Pp. 221-227
Leticia Moralejo, Sandra Inés, Miguel Marcos, Aurelio
Fuertes and Guillermo Luna
[Abstract]
Deletion of the V1/V2 Region Does Not Increase the
Accessibility of the V3 Region of Recombinant gp125 Pp.
229-237
Samer Sourial, Charlotta Nilsson, Anette Wärnmark,
Adnane Achour and Robert A. Harris
[Abstract]
Takotsubo-Like Left Ventricular Dys-function in an
HIV-Infected Patient Pp. 239-241
Giuseppe Barbaro, Adriano Pellicelli, Giorgio
Barbarini and
Yoshihiro J. Akashi
[Abstract]
Abstracts
[Back to top]
Dynamics of Virus-Host Interplay in HIV-1 Replication
Masha Sorin and Ganjam V. Kalpana
HIV-1, the causative agent of AIDS, is an obligate intracellular
parasite that has both evolved to invade the complex human
system and adapted to utilize the host machinery for its own
propagation. A dynamic interaction between the virus and the
host systems can be observed at every step of HIV-1 life cycle.
Host factors are involved not only for mounting antiviral
responses but are also hijacked by the virus to assist in
its replication. The host factors are necessary for viral
replication during entry, reverse transcription, nuclear import,
integration, transcription, nuclear export, translation, assembly
and budding. All retroviruses including HIV-1, are species-specific
and the replication of the retroviruses is blocked in the
restrictive host by the action of “host restriction
factors”. These restriction factors act as barriers
to retroviral replication at various stages within the infected
cell of a restrictive host. Nevertheless, HIV-1 virus has
learned to subvert these antiviral responses and successfully
propagate within the permissive host environment. This review
article describes identification and mechanism of action of
several pro- and anti-HIV-1 host factors. It is likely that
we are just beginning to get a glimpse of an ongoing complex
battle between the HIV-1 and the host, understanding of which
should provide valuable information for the development of
novel therapeutic strategies against HIV-1.
[Back to top]
Retrovirus Translation Initiation: Issues and Hypotheses
Derived from Study of HIV-1
Alper Yilmaz, Cheryl Bolinger and Kathleen Boris-Lawrie
Human immunodeficiency virus type 1 (HIV-1) has a small,
multifunctional genome that encodes a relatively large and
complex proteome. The virus has adopted specialized post-transcriptional
control mechanisms to maximize its coding capacity while economically
maintaining the information stored in cis-acting replication
sequences. The conserved features of the 5’ untranslated
region of all viral transcripts suggest they are poor substrates
for cap-dependent ribosome scanning and provide a compelling
rationale for internal initiation of translation. This article
summarizes key experimental results of studies that have evaluated
HIV-1 translation initiation. A model is discussed in which
cap-dependent and cap-independent initiation mechanisms of
HIV-1 co-exist to ensure viral protein production in the context
of 1) structured replication motifs that inhibit ribosome
scanning, and 2) alterations in host translation machinery
in response to HIV-1 infection or other cellular stresses.
We discuss key issues that remain to be understood and suggest
parameters to validate internal initiation activity in HIV-1
and other retroviruses.
[Back to top]
Intracellular Restriction Factors In Mammalian Cells
- An Ancient Defense System Finds A Modern Foe
Jörg G. Baumann
Cross-species transmission of retroviruses poses a threat
to mammalian species. Zoonoses have given rise to devastating
diseases because the host organism is not prepared to resist
a new pathogen. Mammals have developed several layers of defense
against viruses, including an intracellular antiretroviral
defense, a part of innate immunity. Retroviral restrictions
had been studied for decades using murine leukemia virus in
mice, however it has become clear that primates too have intrinsic
mechanisms to ward off infections by retroviruses. Several
of these antiretroviral restriction mechanisms have recently
been identified, with two particularly well described factors
being members of the tripartite motif (Trim) and APOBEC families.
Both systems provide a strong barrier against lentiviral infections.
The viruses have developed countermeasures that allow them
to replicate despite the host factors. This review discusses
our current knowledge of this ancient battle between mammalian
hosts and their retroviral opponents.
[Back to top]
Viral Piracy: HIV-1 Targets Dendritic Cells for Transmission
Annemarie N. Lekkerkerker, Yvette van Kooyk and
Teunis B.H. Geijtenbeek
Dendritic cells (DCs), the professional antigen presenting
cells, are critical for host immunity by inducing specific
immune responses against a broad variety of pathogens. Remarkably
the human immunodeficiency virus-1 (HIV-1) subverts DC function
leading to spread of the virus. At an early phase of HIV-1
transmission, DCs capture HIV-1 at mucosal surfaces and transmit
the virus to T cells in secondary lymphoid tissues. Capture
of the virus on DCs takes place via C-type lectins
of which the dendritic cell-specific intercellular adhesion
molecule-3 (ICAM-3) grabbing nonintegrin (DC-SIGN) is the
best studied. DC-SIGN-captured HIV-1 particles accumulate
in CD81+ multivesicular bodies (MVBs) in DCs and
are subsequently transmitted to CD4+ T cells resulting
in infection of T cells. The viral cell-to-cell transmission
takes place at the DC-T cell interface termed the infectious
synapse. Recent studies demonstrate that direct infection
of DCs contributes to the transmission to T cells at a later
phase. Moreover, the infected DCs may function as cellular
reservoirs for HIV-1. This review discusses the different
processes that govern viral piracy of DCs by HIV-1, emphasizing
the intracellular routing of the virus from capture on the
cell surface to egress in the infectious synapse.
[Back to top]
Is Autoimmunity a Component of Natural Immunity to
HIV?
Silvia Russo and Lucia Lopalco
Antibody neutralization would be a major way to prevent
HIV infection and disease progression, but the complex relationship
between host and pathogen makes tough to achieve this target
through immunogens based on viral envelope proteins. Autoimmunity
has been associated to bacterial and viral diseases, as a
consequence of inflammatory response to pathogens; it may
eventually lead to harm host cells and organs. However, autoimmune-like
responses have also been observed in HIV-infected patients,
raising many questions about their clinical significance.
Recent studies have elucidated both similarities and differences
between anti-self responses in HIV infection and autoimmune
diseases, identifying new molecular players that might enhance
immune protection to HIV and/or modulate the clinical progression
of the established infection. This paper will present the
current knowledge on auto-antibodies observed in HIV infection,
their putative mechanisms of generation and their possible
implications for immune therapy.
[Back to top]
Fitness Constraints on Immune Escape from HIV: Implications
of Envelope as a Target for Both HIV-Specific T Cells and
Antibody
Viv Peut and Stephen J. Kent
Sterilising immunity against HIV-1 infection, whilst ideal,
appears an unrealistic vaccination goal in the short term.
More achievable is slowing the progression to disease and
decreasing transmission by mounting strong T cell and neutralising
antibody responses to maintain low viral loads. However, in
both acute and chronic infection, mutant virus is selected
to escape both arms of the adaptive immune system. Each mutation
away from wildtype virus likely incurs at least some reduction
in replicative capacity (“fitness”) of the virus.
Rapid reversion to wildtype of some immune escape mutations
upon transmission, suggests fitness costs may be significant.
HIV-1 Envelope is unique in that it is subject to both neutralising
antibody and cell-mediated immune responses. Although Envelope
is variable between strains, considerable serial pressure
and mutational escape from both neutralising antibody and
cytotoxic T lymphocyte attack may result in impaired structure
and function. This could ultimately be exploited in HIV vaccine
design.
[Back to top]
HAART-Persistent HIV-1 Latent Reservoirs: Their Origin,
Mechan-isms of Stability and Potential Strategies for Eradication
Kulkosky and Stacie Bray
HIV-1 infection persists despite long-term administration
of highly active antiretroviral therapy (HAART). The mechanism
of this persistence appears to result primarily from viral
infection of CD4+ T-lymphocytes that have the ability to duplicate
and revert into a quiescent state. These infected resting
cells are long-lived and evade immune surveillance or clearance.
The inability to eradicate this class of cells, bearing the
viral DNA, suggests life-long persistence of virus in HIV-1-infected
individuals, even if HAART were administered for decades.
This review discusses the origins and mechanisms accounting
for stability of these latent HIV-1 cellular reservoirs. It
further provides an overview of recent clinical trials aimed
at their eradication. There have been a limited number of
immune activation (IAT) trials directed at HAART-persistent,
viral reservoir eradication. These trials have not resulted
in purging of these highly stable viral reservoirs though
results from such efforts suggest partial effects. The properties
of novel compounds that might be included into IAT eradication
protocols are continuing to be evaluated and their potential
for inclusion into future IAT trials will be discussed.
[Back to top]
Prevention of Sexually Transmitted Human Immunodeficiency
Virus (HIV) Infection in Adolescents
Athena P. Kourtis, Joan Marie Kraft, Lorrie Gavin,
Dmitry Kissin,Pamela McMichen-Wright and Denise J. Jamieson
Sexual behavior can threaten the physical and social well-being
of young people in the United States in a variety of ways,
as it can put them at risk for infection with the human immunodeficiency
virus (HIV), other sexually-transmitted diseases (STDs) and
unintended pregnancy. This review describes the current extent
of HIV infection in American adolescents, identifies and characterizes
particular high-risk groups and risk-bearing and protective
behaviors, and identifies barriers to adopting preventive
behaviors and using health care services. Our main focus is
to present findings from intervention research; we summarize
the effects of strategies that operate at the individual level
(i.e. biomedical or behavioral, in and outside of the clinic)
and environmental level (i.e. family, school and community
behavioral) to influence behavioral change and the prevention
of HIV infection. Overall, even though abstinence eliminates
the risk altogether and the use of condoms can effectively
reduce the risk of sexual transmission of HIV, adolescents
do not optimally employ these practices. Various approaches
to counseling by providers and other behavioral interventions
aimed at reducing high-risk sexual behavior have been effective,
but have met with limited and short-lived success. Among the
areas receiving inadequate attention to date have been the
link between biomedical and community-based behavior change
interventions and the correspondence of biologic and behavioral
outcomes. These areas are explored and directions for future
research are suggested.
[Back to top]
Factors Influencing Adherence to Highly Active Antiretroviral
Therapy in Spain
Leticia Moralejo, Sandra Inés, Miguel Marcos, Aurelio
Fuertes and Guillermo Luna
Background. Multiple factors have been previously
described which could influence adherence to HAART. Our objective
is to determine the fundamental factors which influence adherence
to highly active antiretroviral therapy in our population.
Methods. A cross-sectional study was made selecting
143 outpatients attending our hospital HIV unit. 22 factors
were recorded which could influence adherence to treatment
(covering individual factors, the illness itself, the therapeutic
regimen and the medical team). Adherence was estimated by
the combination of two methods (self-report and pharmacy data);
statistical analysis was performed using univariate and multivariate
methods.
Results. 96 patients (67.13%) had good adherence
and 47 (32.87%) did not. Only 3 of the 22 factors studied
were significant and independent factors related with adherence:
employment, housing situation and degree of treatment acceptance.
Conclusions. we have found some differences regarding
HAART adherence in our population compared with previous studies.
Psychosocial and behavioral factors were the principal ones.
We must try to detect patients at high risk of non-adherence
in order to take therapeutic decisions properly, try to reinforce
adherence and modify the factors associated with poor adherence.
[Back to top]
Deletion of the V1/V2 Region Does Not Increase the
Accessibility of the V3 Region of Recombinant gp125
Samer Sourial, Charlotta Nilsson, Anette Wärnmark,
Adnane Achour and Robert A. Harris
Previous analyses of HIV-1 surface glycoprotein indicate
that both the V1/V2 region and the interaction of gp120 with
CD4 influence the accessibility of the V3 region on gp120.
In this study we investigated the accessibility of the V3
region of HIV-2 recombinant gp125 proteins using V3-specific
mAbs (7C8 and 3C4) and analyzed the binding kinetics of soluble
CD4 (sCD4) to recombinant HIV-1 gp120 and HIV-2 gp125 proteins
by surface plasmon resonance (SPR) analysis. Our results indicated
that 7C8 recognized monomers of gp125 and gp125Δv1v2,
(lacking the V1/V2 region) while 3C4 was sensitive to the
conformation of gp125, recognizing only oligomers of gp125Δv1v2.
Furthermore, SPR analysis of 7C8 binding to gp125 demonstrated
that the deletion of the V1/V2 region did not increase the
accessibility of the V3 region in gp125Δv1v2.
Comparative SPR analyses of sCD4 binding HIV recombinant surface
glycoproteins revealed a lower affinity of sCD4 to gp125 as
compared to gp120. Moreover, the analyses suggest that conformational
changes only occur in HIV-1 gp120 upon interaction with CD4.
We hypothesize that the V3 region is accessible in HIV-2 gp125
and thus may not require interaction with CD4 to induce conformational
reorientation of the V1/V2 region.
[Back to top]
Takotsubo-Like Left Ventricular Dysfunction in an
HIV-Infected Patient
Giuseppe Barbaro, Adriano Pellicelli, Giorgio
Barbarini and
Yoshihiro J. Akashi
Takotsubo cardiomyopathy (in Japanese language “takotsubo”
is a fishing pot with a round bottom and a neck that is used
for trapping octopuses) is a new syndrome, which is characterized
by transient left ventricular dysfunction and by a typical
left ventriculogram showing transient extensive akinesis of
the apical and mid portions of the left ventricle with hypercontraction
of the basal segment, from which this disease takes its name.
Since 1990 sporadic cases of takotsubo cardiomyopathy
were reported by Japanese authors, and only a few European
reports are available. We report a case of takotsubo-like
left ventricular dysfunction in an human immunodeficiency
virus (HIV)-infected caucasian patient.
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