Wrong. A body would not be defined as healthy if it did not have T
cells. They usually call that "AIDS."

HIV readily infects people of quite robust health.

When someone is infected with HIV, the virus replicates quite readily
in a number of sites, mostly the gut.

t4 is a shorthand for CD4 which is a co-receptor on a subset of immune
system cells known as lymphocytes. Here, you need to read a bit of
basic immunology.

Wrong. After initial infection, virus spikes up quite dramatically,
for example. So this statement is meaningless.

Absolutely wrong. The body's response to HIV is sometimes excessive;
part of the reason lymph nodes deteriorate and gut function is
compromised.

The major cell type that is depleted during HIV disease is the CD4+ T
lymphocyte or T cell. "T4" is a rather arcane term at this point.

What the hell is auto response? Do you mean autoimmune?

Simple answer: no. HIV is an external agent.

Nuanced answer: some people with HIV may also have some autoimmune
reactions develop as a result of HIV infection.

An excellent question--a number of mechanisms. See below.

        George M. Carter
At 06:43 PM 8/19/2006, you wrote:

What mitochondrial damage do you know of which is caused by HIV?

To the best of my knowledge, all mitochonrial damage in people with
HIV is caused by nucleosides and NNRTIs.

An excellent question!

There are myriad ways HIV can cause mitochondrial damage. Broadly
speaking, one could say through direct and indirect mechanims.

For example, involvement of HIV in the peripheral nervous system
manifests as neuropathy while in the central nervous system as minor
cognitive motor disorder and dementia. Here, as with many of the CD4+
T lymphocytes that die, the neurons are NOT infected by HIV, but
rather by expression of inflammatory cytokines and/or by various HIV
proteins like gp120 (e.g., second abstract below). How does this
happen?

Indeed--why is that the majority of CD4 cells lost in the progression
of HIV disease are not infected?

Within infected cells, there are a variety of ways that HIV proteins
can affect mitochondria. One candidate mechanism to explain induction
of apoptosis (cell suicide) for example is the vpr protein (see first
abstract below). Others have noted that vpr may induce apoptosis by
directly depolarizing the mitochondria membrane potential (see Biochem
Biophys Res Commun. 2003 May 9;304(3):583-92).

The apoptosis of UNinfected cells may be brought about by expression
of fas or TNF, which are part of the aberrant and overactive immune
response to HIV infection that are part of the underlying CAUSE of the
clinical development of AIDS. (By contrast, sooty mangabeys, for
example, have an infection that has actively replicating virus but
their lymph nodes remain intact, gut function normal and CD4 counts
generally don't decline too much--they don't develop AIDS).

This is a critical point: HIV disease leads to hyperactivation of
immune functions which result in the eventual deterioration of lymph
node architecture, damage to the CNS, depleted gut function and so
forth that are the ultimate cause of AIDS. Indeed, as the forth
abstract below notes, "Finally, HIV-infected cells from naive patients
behaved identically to activated T cells, displaying hyperpolarized
mitochondria, while lymphocytes from patients under highly active
antiretroviral therapy (which included HIV protease inhibitors) seemed
to react as resting cells."

The third abstract below gives a nice little precis of these
"intrinsic" and "extrinsic" pathways to cell death. The mitochondria
play a key role in sending a cell into that abject state of cell
suicide. Part of that acitvity may be regulated by the intracellular
redox status, as underscored in the 5th abstract below.  The
therapeutic implications are delineated in the last
abstract--underscoring the need for further clinical evaluation of
these types of approaches, both in people with higher CD4 counts not
on ARV and those on ARV.

Of course, the last one was written 12 years ago. Have we had the
studies? Will we get them? Probably not. NIH is in the pocket of
pharma which can't patent these so they can't rob every dime from
every pocket so they can maintain the high lifestyle and power
politics to which they have become accustomed and, apparently,
entitled.
George M. Carter

**
Zhao LJ, Zhu H.  Structure and function of HIV-1 auxiliary regulatory
protein Vpr: novel clues to drug design. Curr Drug Targets Immune
Endocr Metabol Disord. 2004 Dec;4(4):265-75.

Institute for Molecular Virology, St. Louis University School of
Medicine, 3681 Park Avenue, St. Louis, MO 63110, USA. zhaol@slu.edu

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.

**
Ahr B, Robert-Hebmann V, Devaux C, Biard-Piechaczyk M.  Apoptosis of
uninfected cells induced by HIV envelope glycoproteins. Retrovirology.
2004 Jun 23;1(1):12.

Laboratoire Infections Retrovirales et Signalisation Cellulaire, CNRS
UMR 5121-UM1, Institut de Biologie, 4, Bd Henri IV, CS 89508, 34960
Montpellier Cedex 2, France. barbara.ahr@univ-montp1.fr

Apoptosis, or programmed cell death, is a key event in biologic
homeostasis but is also involved in the pathogenesis of many human
diseases including human immunodeficiency virus (HIV) infection.
Although multiple mechanisms contribute to the gradual T cell decline
that occurs in HIV-infected patients, programmed cell death of
uninfected bystander T lymphocytes, including CD4+ and CD8+ T cells,
is an important event leading to immunodeficiency. The HIV envelope
glycoproteins (Env) play a crucial role in transducing this apoptotic
signal after binding to its receptors, the CD4 molecule and a
coreceptor, essentially CCR5 and CXCR4. Depending on Env presentation,
the receptor involved and the complexity of target cell contact,
apoptosis induction is related to death receptor and/or
mitochondria-dependent pathways. This review summarizes current
knowledge of Env-mediated cell death leading to T cell depletion and
clinical complications and covers the sometimes conflicting studies
that address the possible mechanisms of T cell death.

**
Lum JJ, Badley AD.  Resistance to apoptosis: mechanism for the
development of HIV reservoirs. Curr HIV Res. 2003 Jul;1(3):261-74.

Ottawa Health Research Institute, University of Ottawa, Ottawa,
Ontario, Canada.

New insights into the physiological cell death program in mammalian
cells have further confounded the central issue of T lymphocyte
destruction during HIV infection. Although infected and uninfected
cells die following infection, recent evidence indicates that infected
and uninfected cells may have unique pathways controlling death. Two
widely accepted models for apoptosis have been described, namely the
intrinsic and extrinsic apoptotic pathway. In the extrinsic pathway,
ligation of TNF death ligands to their receptors causes
oligomerization of the death receptors and recruitment of adaptor
proteins typically involving caspase 8 activation. In the intrinsic
pathway, apoptotic signals converge on mitochondria to cause
activation and subsequent release of cytochrome c, which leads to
formation of a multiprotein complex containing Apaf-1, cytochrome c,
dATP and procaspase 9. Expression of HIV proteins alters these
pathways resulting in enhanced levels of apoptosis. Although HIV
infection results in T cell apoptosis, under some circumstances a
small fraction of CD4+ T cells and macrophages do not die following
infection, indicating that this may be a critical step in the
development of viral reservoirs. In addition, monocyte differentiation
into macrophages leads to an apoptosis resistant phenotype
characterized by upregulation of antiapoptotic molecules and lower
levels of proapoptotic molecules. The development of these stable
antiretroviral resistant cells represents the major obstacle in
achieving a complete sterile cure. However, this provides a unique
opportunity to further understand the regulation of apoptosis and may
facilitate novel immune based therapies aimed at modifying apoptosis
in HIV disease.

**
Matarrese P, Gambardella L, Cassone A, et al. Mitochondrial membrane
hyperpolarization hijacks activated T lymphocytes toward the
apoptotic-prone phenotype: homeostatic mechanisms of HIV protease
inhibitors. J Immunol. 2003 Jun 15;170(12):6006-15.

Department of Ultrastructures, Istituto Superiore di Sanita, Rome,
Italy.

A decrease of mitochondrial membrane potential has been hypothesized
to be a marker of apoptotic cells, including activated T lymphocytes.
It was recently demonstrated that HIV protease inhibitors,
independently from any viral infection, can hinder lymphocyte
apoptosis by influencing mitochondrial homeostasis. To analyze the
mechanisms underlying these effects, a specific study was undertaken
in both resting and activated human PBL exposed to either receptor
(e.g., anti-Fas)- or nonreceptor (e.g., radiation)-mediated apoptotic
stimuli. T cell activation was found to be accompanied by a
significant increase in mitochondrial membrane potential, or
hyperpolarization, which was undetectable in resting cells. We also
detected apoptotic hindering by HIV protease inhibitors only in
activated T lymphocytes. This was apparently due to the ability of
these drugs to block activation-associated mitochondria
hyperpolarization, which, in turn, was paralleled by an impairment of
cell cycle progression. Remarkably, protease inhibitors also prevented
zidovudine-mediated mitochondrial toxicity. Finally, HIV-infected
cells from naive patients behaved identically to activated T cells,
displaying hyperpolarized mitochondria, while lymphocytes from
patients under highly active antiretroviral therapy (which included
HIV protease inhibitors) seemed to react as resting cells. Altogether
these results clearly indicate that the hyperpolarization state of
mitochondria may represent a prerequisite for the sensitization of
lymphocytes to the so-called activation-induced cell death. They also
suggest that HIV protease inhibitors, by interfering with induction of
the mitochondrial hyperpolarization state, can result in cell survival
even independent of any viral infection.

**
Perl A, Gergely P Jr, Puskas F, Banki K.  Metabolic switches of T-cell
activation and apoptosis. Antioxid Redox Signal. 2002 Jun;4(3):427-43.

Departments of Medicine, Microbiology and Immunology, and Pathology,
State University of New York Upstate Medical University, College of
Medicine, 750 East Adams Street, Syracuse, NY 13210, USA.
perla@upstate.edu

The signaling networks that mediate activation, proliferation, or
programmed cell death of T lymphocytes are dependent on complex redox
and metabolic pathways. T lymphocytes are primarily activated through
the T-cell receptor and co-stimulatory molecules. Although activation
results in lymphokine production, proliferation, and clonal expansion,
it also increases susceptibility to apoptosis upon crosslinking of
cell-surface death receptors or exposure to toxic metabolites.
Activation signals are transmitted by receptor-associated protein
tyrosine kinases and phosphatases through calcium mobilization to a
secondary cascade of kinases, which in turn activate transcription
factors initiating cell proliferation and cytokine production.
Initiation and activity of cell death-mediating proteases are
redox-sensitive and dependent on energy provided by ATP. Mitochondria
play crucial roles in providing ATP for T-cell activation through the
electron transport chain and oxidative phosphorylation. The
mitochondrial transmembrane potential (DeltaPsi(m)) plays a decisive
role not only by driving ATP synthesis, but also by controlling
reactive oxygen species production and release of cell death-inducing
factors. DeltaPsi(m) and reactive oxygen species levels are regulated
by the supply of reducing equivalents, glutathione and thioredoxin, as
well as NADPH generated in the pentose phosphate pathway. This article
identifies redox and metabolic checkpoints controlling activation and
survival of T lymphocytes.

**
Favier A, Sappey C, Leclerc P, Faure P, Micoud M.  Antioxidant status
and lipid peroxidation in patients infected with HIV. Chem Biol
Interact. 1994 Jun;91(2-3):165-80.

GREPO: Groupe de Recherches sur les Pathologies Oxydatives, Faculte de
Pharmacie, Universite de Grenoble, La Tronche, France.

Deficiency in antioxidant micronutrients have been observed in
patients with AIDS. These observations concerning only some isolated
nutrients demonstrate a defect in zinc, selenium, and glutathione. An
increase in free radical production and lipid peroxidation has been
also found in these patients, and takes a great importance with recent
papers presenting an immunodeficiency and more important an increase
in HIV-1 replication secondary to free radicals overproduction. We
have assessed different studies, trying to obtain a global view of the
antioxidant status of these patients. In adults we observe a
progressive decrease for zinc, selenium, and vitamin E with the
severity of disease, except that selenium remains normal at stage II.
However, the main dramatic decrease concerns carotenoids whose level
at stage II is only half the normal value. To understand if these
decreases in antioxidant and increases in oxidative stress occur
secondary to the aggravation of the disease or, conversely, are
responsible for it, we undertook a longitudinal survey of asymptotic
patients. The preliminary results of this evaluation are presented.
Paradoxically, lipid peroxidation is higher at stage II than at stage
IV. This may be consecutive to a more intense overproduction of oxygen
free radicals by more viable polymorphonuclear (PMN) at the
asymptomatic stage. The free radicals production and lipid
peroxidation seem secondary to a direct induction by the virus of PMN
stimulation and cytokines secretion. N-Acetyl cysteine or ascorbate
have been demonstrated in cell culture to be capable of blocking the
expression of HIV-1 after oxidative stress and N-acetyl cysteine
inhibits in vitro TNF-induced apoptosis of infected cells. In regard
to all these experimental data, few serious and large trials of
antioxidants have been conducted in HIV-infected patients, although
some preliminary studies using zinc or selenium have been performed.
In our opinion it is now time to evaluate in humans the beneficial
effect of antioxidants. The more promising candidates for presenting
synergistic effects when associated with N-acetyl cysteine seem to be
beta-carotene, selenium and zinc.