Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 4, No. 4, 2004
Contents
Regulatory/Accessory HIV-1 Proteins
Guest
Editor: Maurizio Federico
Blocking HIV-1 Vif Restores a Natural
Mechanism of Intracellular Antiviral Defense Pp.257-263
Structure and Function of HIV-1 Auxiliary
Regulatory Protein Vpr: Novel Clues to Drug Design Pp.265-275
L.J. Zhao and H. Zhu
The HIV-1 Tat Protein: A Multifaceted Target
for Novel Therapeutic Opportunities Pp.277-285
Mauro Giacca
Controlling HIV-1 Rev Function Pp.287-295
Alan Cochrane
Recent Advances in the Understanding of HIV-1
Vpu Accessory Protein Functions Pp.297-307
Julie Binette and Eric
A. Cohen
Functions of the HIV-1 Nef Protein Pp.309-313
Andreas Baur
Therapeutic Targeting of Interactions Between
Nef and Host Cell Proteins Pp.315-319
Kalle Saksela
Targeting the Nef Induced Increase of HIV
Infectivity Pp.321-326
Maurizio Federico
General Articles
The Impact of Body Mass Index and Type 2
Diabetes on Breast Cancer: Current Therapeutic Measures of Prevention Pp.327-333
F. Resta, V.
Triggiani, C. Sabba, B. Licchelli, S. Ghiyasaldin, A. Liso, F. Schittulli, M.
Quaranta, A. Paradiso E. Tafaro and E. Guastamacchia
New Perspectives in the Treatment of
Cushing´s Syndrome Pp.335-342
M. Labeur, E. Arzt,
G.K. Stalla and M. Paez-Pereda
Chemokine-Chemokine Receptor Network in
Immune Cell Trafficking Pp.343-361
Chang H. Kim
Abstracts
[Back to top] Blocking
HIV-1 Vif Restores a Natural Mechanism of Intracellular Antiviral Defense
Chiara Bovolenta
AIDS has become the greatest pandemic in the
human history counting approximately 40 millions people worldwide. To purge
HIV-1 infection, new therapeutic approaches need to be searched in alternative
and/or in addition to the current pharmacological ones. Recently, several
independent laboratories have unveiled a nonimmune intracellular anti-HIV-1
defense strategy based on the cytidine deaminase APOBEC3G, which restricts HIV-
1 production by directly mutating the proviral DNA in infected cells. To
counteract this defense pathway, HIV-1 has developed an evasion strategy by
acquiring the accessory protein Vif, which blocks the action of APOBEC3G by
inducing its proteasome-mediated degradation.
[Back to top] Structure and
Function of HIV-1 Auxiliary Regulatory Protein Vpr: Novel Clues to Drug Design
L.J. Zhao and H. Zhu
Vpr is a 96-amino acid auxiliary regulatory
protein that is packaged in the HIV-1 virion. It enhances the nuclear transport
of the pre-integration complex, and regulates cell cycle, transcription and
apoptosis. These biological activities suggest strongly that Vpr interacts with
cellular biochemical pathways to regulate HIV-1 replication and pathogenesis.
The karyophilic property of Vpr appears to be due to direct interaction of Vpr
with nuclear transport factors and residents of the nuclear pore complex,
whereas transcriptional effects of Vpr may be exerted through direct and
indirect mechanisms. Cell cycle arrest at the G2/M checkpoint by Vpr is
correlated with the hyperphosphorylation of Cdc2. The pro-apoptotic activity of
Vpr is dependent on the subtype of the HIV-1 isolate, and may be dramatically
enhanced by a single L64P mutation. Mitochondria- and caspase-dependent
mechanisms appear to mediate Vpr-induced apoptosis. Recent evidence suggests
that Vpr interacts with a cellular ubiquitination machinery and promotes
degradation of Vpr mutants carrying the L64P mutation. Vpr interaction with the
ubiquitination machinery may contribute to the regulation of the HIV-1 life
cycle at various stages. NMR studies of Vpr have shown a Vpr monomer with three
helical domains arranged in a twisted-U shape. However, Vpr most likely exists
as a trimer in vivo. Structural/functional domains have been tentatively mapped
for Vpr induction of apoptosis and for Vpr interaction with the ubiquitination
machinery. Structural refinement of Vpr, specially by crystallography of the
potential Vpr trimer, should help design therapeutic approaches to specifically
target Vpr.
[Back to top] The HIV-1 Tat Protein:
A Multifaceted Target for Novel Therapeutic Opportunities
Mauro Giacca
Transcription of the integrated HIV-1 proviral
genome is an essential step in the retrovirus life cycle and thus an appealing
target for chemotherapeutic intervention to restrict retroviral replication. A
fundamental role in this process is exerted by the viral protein Tat, a
powerful transactivator of viral gene expression. This protein binds a
structured RNA sequence at the 5’-ends of all nascent viral mRNAs and promotes
transcription by mediating the recruitment to the viral promoter of cellular
factors required for chromatin remodelling and transcriptional processivity. In
addition to these transcriptional activities, Tat is released from the cells
and enters neighbouring cells when present in the extracellular environment, a
process that is possibly involved in HIV disease pathogenesis. Given its
pleiotropic functions, the protein represents a highly appealing target for
drug development. Here I will summarise the known molecular mechanisms by which
Tat exerts its activities and review the currently available compounds that
interfere with the process of transcriptional activation of the HIV-1 provirus.
[Back to top] Controlling HIV-1
Rev Function
Alan Cochrane
Although current therapies used in the treatment
of HIV-1 infection have proven effective in reducing mortality due to the
infection, the increase in drug resistant strains of the virus call for
increased effort to explore and develop alternative treatment modalities. In
this review, the various strategies to control HIV-1 replication through the
disruption of Rev function are outlined. A wide range of methods have been
developed including antisense DNA, ribozymes, decoy RNAs, transdominant
proteins and suicide vectors targeted at disrupting Rev function. Although many
of these methods have proven effective alone, it is hoped that a more robust
antiviral response can be attained through combination of these strategies. As
the methods of delivering these therapeutic agents matures through the
development of lentiviral-based vectors, it is hoped that they will eventually
reach the clinic where they may not only supplement the current treatment strategies
but also provide resistance to those at high risk of infection or failing
therapy.
[Back to top] Recent Advances in
the Understanding of HIV-1 Vpu Accessory Protein Functions
Julie Binette and Eric
A. Cohen
HIV-1 encodes a number of accessory proteins,
which are not commonly found in other retroviruses. These proteins, which
include Vif, Vpr, Vpu and Nef, act as multifunctional adapters capable of
recruiting and modulating basic host cell processes to optimize wide-ranging
aspects of viral replication. This review describes our current understanding
of how the Vpu accessory protein functions to modulate HIV-1 particle release
and CD4 receptor expression during HIV-1 infection and underlines the potential
opportunities afforded by this viral protein for therapeutic intervention.
[Back to top] Functions of the
HIV-1 Nef Protein
Andreas Baur
The Nef protein of the human immunodeficiency
virus is as important for disease progression as it is perplexing in its number
of target molecules and functions. In this chapter I will try to give an
overview on the numerous functions of HIV from a molecular as well as
functional point of view. Due to space restriction and for the sake of clarity
I will not describe or list all the effects reported in the literature but
rather concentrate on the most important aspects of Nef function.
[Back to top] Therapeutic
Targeting of Interactions Between Nef and Host Cell Proteins
Kalle Saksela
Nef is a viral pathogenicity factor that has an
important role in disease progression associated with HIV infection. Yet, no
antiviral drugs capable of inhibiting of Nef are available or in clinical
trials today. In this review the challenges and potential involved in
pharmaceutical targeting of Nef are discussed in light of current understanding
of the molecular mechanisms of Nef action, with a special emphasis on effector
functions of Nef that are mediated via SH3 domain-directed interactions with
host cell proteins.
[Back to top] Targeting the Nef
Induced Increase of HIV Infectivity
Maurizio Federico
Nef is a regulatory protein expressed exclusively
by HIV-1/2 and SIV. It is critical for the optimal viral infectivity and for the
destruction of the host immune system. This renders Nef a rather attractive
therapeutic target. The most affordable point(s) of attack for effective
anti-Nef therapeutic strategies can be individuated on the basis of a detailed
knowledge of the mechanisms underlying the Nef induced enhancement of
infectivity. However, the emerging picture still appears rather complex and not
always coherent, so that additional, intensive endeavours in basic research are
required for an effective exploitation of the Nef induced increase of
infectivity as a therapeutic target.
[Back to top]
The Impact of Body Mass Index and
Type 2 Diabetes on Breast Cancer: Current Therapeutic Measures of Prevention
F.
Resta, V. Triggiani, C. Sabba, B. Licchelli, S. Ghiyasaldin, A. Liso, F.
Schittulli, M. Quaranta, A. Paradiso, E. Tafaro and E. Guastamacchia
Epidemiological data have suggested a possible
relationship between obesity, diabetes mellitus and cancer risk, particularly
breast cancer. We set out to investigate the effect of body mass index and
diabetes mellitus on the presence of breast cancer in the Apulian population.
We selected 1,663 women affected with primary breast cancer and 4,702 control
patients. All patients with breast cancer underwent surgical excision of the
tumor and their tumors were histologically confirmed. The prevalence of type 2
diabetes (8%) in the women affected by breast cancer was significantly higher
than in the control group (5%) (p<0.05). The majority of the diabetic women
affected by breast cancer had a BMI value >25, both in premenopause and in
postmenopause. With respect to BMI, the non-diabetic patients with breast
cancer in postmenopause showed the same pattern as the diabetic ones. Instead,
among the women in premenopause a higher percentage (55%) of patients with a
BMI <24.9 was found (p<0.01). In the Apulian population, the presence of
both type 2 diabetes and elevated values of BMI (that is in a condition of hyperinsulinemia)
were found to enhance the frequency of breast cancer.
[Back to top]
New Perspectives in the Treatment of
Cushing´s Syndrome
M.
Labeur, E. Arzt, G.K. Stalla and M. Paez-Pereda
Regardless of etiology, all cases of endogenous
Cushing's syndrome are due to increased production of cortisol by the adrenal
gland. Most are caused by adrenocorticotrophic hormone (ACTH)-secreting
pituitary adenomas. Alternatively, the glucocorticoid excess may be due to
adrenal neoplasia or to ectopic ACTHsecreting tumors. Cushing's syndrome is
characterized by endocrine and metabolic alterations such as truncal obesity,
hypertension, weakness, amenorrhea, hyperglycemia, osteoporosis and depression.
Unless treated, the disease is associated with high morbidity, and ultimately,
mortality. Depending on the etiology of Cushing's syndrome two different
treatment modalities are possible: reduction of pituitary ACTH production or
reduction of adrenocortical cortisol secretion. In the absence of efficient
drug therapy, transsphenoidal resection of the pituitary adenoma is the primary
treatment of choice for the reduction of ACTH secretion. In the last years
there was much progress in understanding the molecular mechanisms that control
the function of the hypothalamic-pituitary-adrenal axis. Thus, new insights
made it possible to identify potential drug targets for the treatment of
Cushing's syndrome. The present article reviews different drug targets and
therapeutic options including drugs that control the central ACTH regulation,
e.g. by modulating signaling pathways and transcriptional regulation of ACTH
biosynthesis, corticotrophin releasing hormone (CRH) or glucocorticoid receptor
antagonists, inhibitors of glucocorticoid synthesis, ketoconazole, somatostatin
and dopamine analogs. Some of these substances might be useful for the
treatment of Cushing's syndrome.
[Back to top]
Chemokine-Chemokine Receptor Network
in Immune Cell Trafficking
Chang
H. Kim
Chemokines play critical roles in leukocyte
trafficking in normal and inflammatory conditions. The primary roles of
chemokines are to activate integrins for leukocyte adherence on endothelial
cells and to induce chemotaxis of leukocytes in tissue microenvironments.
Specificity in leukocyte migration is regulated at multiple levels. First, it
is achieved through differential tissue expression of chemokines and adhesion
molecules. Second, it is achieved by limited and differential expression of
chemokine receptors by leukocyte subsets. Third, combinatorial expression of
multiple chemokine receptors and adhesion molecules makes leukocyte migration
more specific. Homing of leukocytes into various tissue sites (e.g. inflamed
skin, small intestine, mucosal tissues,
T cell areas vs. B cell follicles) requires different chemokines and chemokine
receptors. Furthermore, distinct immune responses and diseases (e.g. Th1 vs.
Th2 responses) involve different sets of chemokines and leukocyte subsets. This
review examines the recent advances in research on chemokines and chemokine
receptors in tissue-specific migration of immune cells, and discusses potential
targets of intervention in chemokine-mediated leukocyte migration in normal and
diseased conditions.