Bavituximab concern

[Guest guest]

Bavituximab is a drug being investigated for hep C. It's based on the

notion that infected cells undergo preliminary steps toward cell

suicide (apoptosis). Cells in this state express phosphatidylserine

(PS) and the Bavi drug binds to them, ostensibly killing infected cells.

The problem in HIV disease (Hep C too?) is that a significant number

(most?) of the T cells (CD4+ T lymphocytes) that are dying are not

infected. They die even though there is no HIV inside them.

They undergo apoptosis/cell suicide. This can arise from many HIV

proteins (like env, tat) interacting with uninfected cells. It arises

in part due to the expression of inflammatory cytokines, like the TNF

family. Apoptosis includes the expression of PS as part of the

process. They also undergo autophagy (the cell " eats itself " from the

inside).

So I think the preliminary concern in HIV disease is that this drug

might cause many uninfected cells to die. I think this issue needs to

be explored first, carefully before even Phase I testing. One can

hope the drug will preferentially target only HIV-infected cells.

Some abstract below to consider. Any thoughts?

M.

***

Trends Immunol. 2008 Feb;29(2):61-7.

Is HIV infection a TNF receptor signalling-driven disease?

Herbein G, Khan KA.

Department of Virology, EA3186, IFR133, Franche-Comté

University, Hôpital Saint-Jacques, Besançon Cedex, France.

gherbein@...

Recent studies indicate that TNF (tumor necrosis factor)

receptor signalling is a key player in HIV infection. HIV proteins

have been shown to target TNF receptor signalling, leading both to

apoptosis of uninfected bystander T cells and to sustained viral

replication in infected T cells and macrophages. This article

proposes a model that highlights the role of HIV proteins in the

modulation of TNF receptor signalling and could explain both immune

suppression and the formation of viral reservoirs during HIV infection.

***

AIDS Rev. 2006 Oct-Dec;8(4):221-36.Links

Mechanisms of CD4 T-cell depletion triggered by HIV-1 viral

proteins.

Varbanov M, Espert L, Biard-Piechaczyk M.

Laboratoire Infections Rétrovirales et Signalisation Cellulaire,

UM1, CNRS, Institut de Biologie, Montpellier, France.

Infection with HIV-1 leads to progressive CD4 T-cell death,

resulting in AIDS development. The mechanisms that trigger this CD4 T-

cell death are still not fully understood, but a lot of data

indicates that apoptosis plays a major role in this cell demise. Both

infected and uninfected CD4 T-cells can die during HIV-1 infection by

different cell-death pathways, but HIV-1-induced, bystander, CD4 T-

cell killing is now recognized as central to immunodeficiency. The

HIV-1 directly modulates CD4 T-cell death using multiple different

strategies in which several viral proteins have an essential role.

Recent data demonstrate that relationships can exist between the

three main types of programmed cell death, i.e. apoptosis, autophagic

programmed cell death, and necrosis-like programmed cell death.

Almost nothing is currently known about the role of necrosis-like

programmed cell death in CD4 T-cell death induced by the viral

proteins, but a very recent study demonstrates that autophagy is

needed to trigger apoptosis of bystander CD4 T-cells, further

increasing the level of complexity of this pathology. This review

presents an overview of the major types of programmed cell death and

details the mechanisms by which the HIV-1 viral proteins control both

infected and uninfected CD4 T-cell death.

***

Shearer is one smart cookie...this study underscores the role of even

" non-infectious " HIV to cause CD4 cells to undergo apoptosis.

AIDS Rev. 2006 Jan-Mar;8(1):3-8.Links

Are blockers of gp120/CD4 interaction effective inhibitors of

HIV-1 immunopathogenesis?

Herbeuval JP, Shearer GM.

Experimental Immunology Branch, Centers for Cancer Research,

National Cancer Institute, National Institutes of Health, Bethesda,

MD, USA.

OBJECTIVE: The immunopathogenic mechanisms that result in the

depletion of CD4+ T-cells after HIV-1 infection remain controversial.

We consider here mechanisms that have been suggested, and propose a

data-supported model in which CD4+ T-cells undergo apoptosis that is

signaled by the binding of viral gp120 to cellular CD4. PROCEDURES:

Blood leucocytes from HIV-1-uninfected donors, including CD4+ and CD8

+ T-cells, monocytes, myeloid and plasmacytoid dendritic cells (pDC)

were cultured with either infectious or noninfectious HIV-1. The

cultures were tested for expression of interferon-alpha, TRAIL, DR5

and apoptosis. Inhibitors of IFNalpha, TRAIL, DR5 and gp120/CD4

binding were added to the cultures. Ex vivo studies were performed

using peripheral blood mononuclear cells (PBMC) from HIV-1-infected

patients to test the validity of our in vitro findings. FINDINGS:

Both infectious and noninfectious HIV-1 induced pDC to produce

IFNalpha, which induced expression of TRAIL by CD4+ but not CD8+ T-

cells. CD4+ T-cells expressed the TRAIL death receptor 5 (DR5), upon

HIV-1 binding to CD4. Antibodies against TRAIL and DR5 partly

inhibited apoptosis. However, soluble CD4 (sCD4-IgG) efficiently

blocked IFNalpha production, TRAIL and DR5 expression and apoptosis

of T helper cells. Studies of HIV-1-infected patients' PBMC indicated

increased plasma TRAIL production and CD4+ T-cell DR5 expression,

which correlated directly with viral load and inversely with CD4

count. CONCLUSION: Noninfectious interactions between HIV-1 and CD4

are major contributors to CD4+ T-cell death via IFNalpha-induced

TRAIL expression and HIV-1-induced DR5 expression on CD4+ T-cells.

Since noninfectious as well as infectious HIV-1 induces the death

cascade resulting in selective apoptosis of CD4+ T-cells, these HIV-1/

CD4-dependent binding events would not necessarily be reflected in

HIV-1 RNA and DNA expression by the CD4+ target T-cells. Because each

step of this model leading to apoptosis requires the binding of gp120

to CD4, we suggest that molecules which block this very early event

in virus/target cell interaction will be effective in preventing or

reducing the depletion of CD4+ T-cells during progression to AIDS.

The above mechanisms and the effect of sCD4-lgG are summarized in our

proposed model.

***

Curr Pharm Des. 2008;14(3):237-44.

Apoptosis and HIV infection: about molecules and genes.

Cossarizza A.

Chair of Immunology, University of Modena and Reggio Emilia

School of Medicine, Italy. cossarizza.andrea@...

During the evolution, the immune system has developed several

strategies to fight viral infections. Apoptosis, autophagy and

necrosis are different types of cell death that play a main role in

the interactions between infective agents and the host, since they

are often important defence mechanisms that have to avoid the

spreading of the infection. In turn, viruses have evolved numerous

ways to evade the host immune system by influencing the behaviour and

functionality of several components. HIV infects and kills CD4+ T

helper lymphocytes, preferentially those that are antigen-specific,

but also encodes proteins with apoptotic capacities, including gp120,

gp160, Tat, Nef, Vpr, Vpu, Vif and, last but not least, the viral

protease. This latter protein can kill infected and uninfected

lymphocytes through the action of several host molecules, mainly

members of the tumor necrosis factor family, or via the mitochondrial

apoptotic pathway. The proinflammatory state that is characteristic

of both the acute and chronic phase of HIV infection facilitates cell

death, and is an additional cause of immune damage. Potent

antiretroviral drugs that are largely use in therapy can reduce

apoptosis by different mechanisms, that not only include the

diminished production of the virus by infected cells and the

subsequent reduction of inflammation, but also a direct action on the

viral protease. The role of the host genetic background is finally

crucial in understanding the process of cell death in HIV infection.

***

J Leukoc Biol. 2006 Oct;80(4):953-60. Epub 2006 Aug 2.

Signal transduction induced by apoptotic cells inhibits HIV

transcription in monocytes/macrophages.

Gekonge BN, Schiralli G, Schlegel RA, AJ.

Department of Biochemistry and Molecular Biology, Pennsylvania

State University, University Park, PA 16802, USA.

The primary targets of HIV are CD4(+) T cells and macrophages.

HIV infection is associated with an increase in apoptosis of infected

and uninfected CD4(+) T cells, and these infected cells undergo

apoptosis and produce HIV virions with phosphatidylserine (PS) on

their surface. During phagocytosis of apoptotic cells, macrophages,

using an array of receptors, are able to perceive various surface

changes on apoptotic cells. The engagement of phagocytic receptors by

ligands on the apoptotic cell surface results in the activation of

signaling cascades, which facilitate engulfment. In this study, we

examined how PS associated with virions and apoptotic cells

influences HIV replication. We demonstrate that virus-associated PS

is required for HIV infection of macrophages at a step prior to

integration but following strong-stop, indicating that PS-initiated

signals alter the establishment of HIV provirus. Conversely,

apoptotic cells inhibited HIV transcription in infected macrophages,

although this ability to suppress transcription was independent of

PS. Furthermore, we show that ELMO, a key signaling molecule that

participates in the phagocytosis of apoptotic cells, inhibited HIV

transcription; however, knocking down endogenous ELMO expression in

infected U937 cells rescued HIV transcription when these cells were

coincubated with apoptotic targets. Taken together, these data show

that apoptotic cells and the signals, which they initiate upon

recognition by macrophages, influence the successful establishment of

HIV infection and provirus transcription.