Contents
HIV
Capsid Assembly Pp. 1-14
Yuko Morikawa
[Abstract]
Transmission
and Immunopathogenesis of FIV in Cats as a Model for HIV Pp. 15-29
Mary Jo Burkhard and Gregg A. Dean
[Abstract] [Full
text article]
How
HIV Evades CTL Recognition Pp. 31-40
Kathleen L. Collins
[Abstract]
[Full text article]
In
Vivo Analysis of Nef Function Pp. 41-50
Bangdong L. Wei, Vivek K. Arora, John L. Foster, Donald
Sodora and J. Victor Garcia
[Abstract]
[Full text article]
Update
on D-Ala-Peptide T-Amide (DAPTA): A Viral Entry Inhibitor that Blocks CCR5
Chemokine Receptors Pp. 51-67
Michael R. Ruff, Maria Polianova, Quan-en Yang, Gifford
S. Leoung, Francis W. Ruscetti and Candace B. Pert
[Abstract] [Full text article]
Measuring
the Infectiousness of Persons with HIV-1: Opportunities for Preventing Sexual
HIV-1 Transmission Pp. 69-86
Jared M. Baeten and Julie Overbaugh
[Abstract] [Full text article]
Sugar
and Spice: Viral Envelope-DC-SIGN Interactions in HIV Pathogenesis Pp.
87-99
Stephen V. Su, Kevin B. Gurney and Benhur Lee
[Abstract] [Full text article]
HIV
Vaccine Development: Lessons from the Past and Promise for the Future Pp.
101-120
Paul Spearman
[Abstract] [Full text article]
Rodent
Models for HIV-1 Infection and Disease Pp. 121-130
[Back to top] HIV Capsid
Assembly
Yuko Morikawa
[Full text article]
HIV Gag assembly is the first and most essential step in
the formation of virus particles. Following protein synthesis, Gag relocates
from ribosomes and forms a virus particle at the plasma membrane, using host
factors and machinery. Early studies focused on mapping the regions within Gag
required for assembly and identified three distinct domains (M, I, and L),
although their precise locations within the three-dimensional structure of Gag
awaited later study. In this review, I summarize the mapping results in the
light of recent progress on Gag structures made by nuclear magnetic resonance
and X-ray crystallography as well as further functional analysis. These data
are largely consistent and provide sufficient information for an understanding
of the interactions and functions of the assembly domains at a macromolecular
level. Current studies have moved on to the identification of the host factors
and machinery used in the process of Gag assembly. Cumulative data suggest that
the dynamics of Gag assembly and transport are achieved not by simply using,
but rather by taking control of, cellular machinery. Key area in the process
include interactions with TSG101, L domain receptor which normally functions in
the endosomal sorting pathway and with lipid rafts, a type of M domain
receptor, which has been suggested to be the sites for effective concentration
of Gag. The review provides a summary of these data and discusses the likely
direction of future studies.
[Back to top] Transmission
and Immunopathogenesis of FIV in Cats as a Model for HIV
Mary Jo Burkhard and Gregg A. Dean
[Full text article]
The feline immunodeficiency virus (FIV) model provides a
system to study lentivirus transmission, virus kinetics, pathogenesis, host
responses, and immune dysfunction in a natural, out-bred host, under controlled
conditions with specific-pathogen-free animals. The diversity of primary FIV
strains can be exploited to mirror the range of disease manifestations
associated with HIV infection. FIV is infectious via intravenous,
intraperitoneal, intradermal, or subcutaneous injection as well as by
atraumatic instillation onto the oral, vaginal, or rectal mucosa. Together,
these features allow investigators to model specific aspects of HIV infection
in a highly relevant and relatively inexpensive animal model. Well-developed
areas of the FIV model include: (1) transmission of cell-associated as well as
cell-free virus; (2) mucosal infectivity and immunopathogenesis; (3) vertical
transmission; (4) acquired immunodeficiency including defects of the innate
immune system; (5) thymic dysfunction; (6) neurotropism and neuropathogenesis;
(7) host-virus interactions and the role of specific gene products; (8)
efficacy of antiviral therapy; and (9) efficacy and immune correlates of
experimental vaccines. This review will encompass areas specific to
transmission and immunopathogenesis.
[Back to top] How HIV
Evades CTL Recognition
Kathleen L. Collins
[Full text article]
The human immunodeficiency virus (HIV) is unique in its
capacity to produce chronic disease in almost all infected hosts. To accomplish
this, it has evolved multiple mechanisms to effectively evade the immune
response. HIV encodes at least one protein that makes infected cells resistant
to CTL killing by downmodulating epitope (peptide plus MHC-I protein) density
on the infected cell surface. In addition, HIV encodes several mechanisms to
promote apoptosis of HIV-specific CTLs. The end result is that infected cells
have a reduced susceptibility to CTLs, survive longer and produce more viral
antigenic variants that can further evade the immune response.
[Back
to top] In Vivo Analysis of Nef Function
Bangdong L. Wei, Vivek K. Arora, John L. Foster, Donald
Sodora and J. Victor Garcia
The nef gene is present in all primate lentiviruses
(HIV-1, HIV-2, and SIVs). In vivo, Nef has been shown to be a major determinant
of virus pathogenicity. In vitro, many different Nef activities have been
reported, including CD4 and MHC I downregulation, enhanced virion infectivity,
and T-cell activation. These four different activities have been extensively
investigated and appear to increase the pathogenicity of the virus. However,
the contribution that these activities (individually or together) make to the
in vivo phenotype has not been elucidated. The mechanism(s) by which Nef
modulates distinct host cell properties has provided great insights into the
intricate interaction between virus and host. In this manuscript, we review the
different model systems that have been used to study Nef function in vivo and
the information that they have provided regarding the best characterized in
vitro Nef activities. The knowledge that has been accumulated has provided
clues to our understanding of Nef function but they have also left us with many
unanswered questions that should be the focus of future in vivo analysis of Nef
function.
[Back to top] Update on D-Ala-Peptide T-Amide (DAPTA): A Viral Entry
Inhibitor that Blocks CCR5 Chemokine Receptors
Michael R. Ruff, Maria Polianova, Quan-en Yang, Gifford
S. Leoung, Francis W. Ruscetti and Candace B. Pert
Peptide T, named for its high threonine content
(ASTTTNYT), was derived by a database search which assumed that a relevant
receptor binding epitope within env (gp120) would have sequence homology to a
known signaling peptide. Binding of radiolabeled gp120 to brain membranes was
displaced by peptide T and three octapeptide analogs (including “DAPTA”,
Dala1-peptide T-amide, the protease- resistant analog now in Phase II clinical
trials) with the same potency that these four octapeptides blocked infectivity
of an early passage patient isolate. This 1986 report was controversial due to
a number of laboratories’ failure to find peptide T antiviral effects; we now
know that peptide T is a potent HIV entry inhibitor selectively targeting CCR5
receptors with minimal effects on the X4 tropic lab adapted virus exclusively
in use at that time. Early clinical trials, which demonstrated lack of toxicity
and focused on neurological and neurocognitive benefits, are reviewed and data
from a small ongoing Phase II trial---the first to assess peptide T’s antiviral
effects---are presented. Studies using infectivity, receptor binding,
chemotaxis, and blockade of gp120-induced neurotoxicity in vitro and in vivo
are reviewed, discussed and presented here. Peptide T and analogs of its core
pentapeptide, present near the V2 stem of numerous gp120 isolates, are potent
ligands for CCR5. Clinical data showing peptide T’s immunomodulation of plasma
cytokine levels and increases in the percentage of IFNg secreting
CD8+ T cells
in patients with HIV disease are presented and suggests additional therapeutic
mechanisms via regulation of specific immunity.
[Back to top] Measuring the Infectiousness of Persons with HIV-1:
Opportunities for Preventing Sexual HIV-1 Transmission
Jared M. Baeten and Julie Overbaugh
Methods to reduce sexual transmission of HIV-1 are
urgently needed to slow the global HIV-1 epidemic. These methods should include
interventions that minimize susceptibility in uninfected populations at risk,
as well as interventions that decrease the infectiousness of HIV-1 infected
individuals. Surprisingly few interventions to prevent HIV-1 transmission have
been targeted at persons who are already infected, although such interventions
could have a significant impact on population-wide HIV-1 spread. This review
summarizes current knowledge of factors that influence HIV-1 infectiousness,
with special attention on the role of genital tract HIV-1 as a surrogate marker
of infectiousness. Epidemiologic studies have demonstrated good agreement
between factors associated with increased HIV-1 transmission and increased
HIV-1 genital tract shedding. Treatment of sexually transmitted diseases and
initiation of antiretroviral therapy have been shown to reduce HIV-1 shedding
and thus are promising interventions that may reduce HIV-1 transmission.
Unresolved issues related to optimal measurement techniques for genital HIV-1,
promises and limitations of antiretroviral therapy and vaccines to reduce
infectiousness, and other intervention strategies still in development are
reviewed.
[Back to top] Sugar and Spice: Viral
Envelope-DC-SIGN Interactions in HIV Pathogenesis
Stephen V. Su, Kevin B. Gurney and Benhur Lee
[Full text article]
DC-SIGN is a calcium dependent lectin that binds to HIV
envelope, gp120, with high affinity. Its expression on dendritic cells, coupled
with its ability to facilitate the binding and subsequent transfer of virions
to permissive T-cells, has led to the hypothesis that DC-SIGN may serve as a
conduit the transfer of HIV from the peripheral mucosa to secondary lymphoid
organs. Studies have shown that DC-SIGN bound virions can maintain their
infectivity for prolonged periods of time despite evidence that DC-SIGN itself
may serve as an antigen receptor. How HIV subverts the normal function of
DC-SIGN to establish a primary infection in the host is unclear. Therefore,
understanding the structural and immunological basis for DCSIGN’s function will
help us realize the role that DC-SIGN may play in viral transmission and
pathogenesis. Importantly, DC-SIGN/envelope interactions may represent a new
target for microbicide and vaccine development efforts. Here, we review recent
studies on DC-SIGN’s structure and function in an effort to present testable
models of DC-SIGN’s role in HIV pathogenesis.
[Back to top] HIV Vaccine Development: Lessons from the
Past and Promise for the Future
Paul Spearman
[Full text article]
The global HIV epidemic continues to expand, exceeding
previous predictions and causing tremendous suffering. An effective vaccine
represents the best hope to curtail the HIV epidemic. The past fifteen years of
HIV vaccine clinical trials have not identified an ideal HIV vaccine, but have
provided many valuable lessons that contribute to the current generation of
promising HIV vaccine regimens. An enhanced understanding of HIV and SIV
immunopathogenesis has facilitated the design of vaccination regimens that
elicit specific immune responses and effector mechanisms. Intensive
investigation of recombinant gp120 subunit vaccines has revealed a previously
unexpected complexity in eliciting neutralizing antibodies that are active
against primary isolate viruses. The importance of CD8+ CTL responses in
controlling HIV and SIV viremia has led to a series of vaccine candidates that
effectively induce these responses. Proof that vaccination can prevent SIV/HIV
disease has now been obtained in simian models of AIDS. A number of promising
HIV vaccine regimens are currently being evaluated in human trials, and the
pipeline of new vaccine vectors and combination regimens appears robust.
Although challenges to the development of a safe and effective global HIV
vaccine remain, the outlook for HIV vaccines in the future is bright.
[Back to top] Rodent Models for HIV-1 Infection and
Disease
Marc van Maanen and Richard E. Sutton
[Full text article]
The development of a predictive, small animal model for
human immunodeficiency virus type 1 (HIV-1) disease would greatly facilitate
the analysis of many aspects of viral infection, pathogenesis and treatment.
While numerous small animal models exist which emulate various aspects of HIV-1
infection and/or disease in humans, none of these models support robust HIV-1
replication within the context of an intact immune system. Despite this major
limitation, these models have helped to elucidate different aspects of HIV-1
pathogenesis in humans. Moreover, recent advances regarding the underlying
nature of the blocks to viral replication in non-human cells have raised the
possibility that rodents may be engineered to support HIV-1 infection. This
review will focus on recent attempts to develop a rodent model for HIV-1
disease, and will also describe currently available systems for studying HIV-1.