Bud’s Therapeutic Guidelines
1. Introduction
2. “Boosting” the Immune System
3. “Killing ” Virus
4. “Boosting” Immunity Vs “Killing” Virus"
5. What’s Missing
1. Introduction
What follows is an attempt to lay out basic guidelines of FIV therapy based on what has been
learned by researchers and practitioners of HIV therapy. The interpretation of that research and
practice is my own and represents my own sense of how they might be applied to FIV therapy.
Possible therapeutic responses follow descriptions of problems posed by the virus.
There are, I believe, a number of questionable assumptions, both theoretical and practical, to be
found among practicing veterinarians and pet owners following the advice of other pet owners.
My primary purpose is not to rigorously evaluate specific agents used to treat FIV–although a
liberal number of examples have been offered-- but rather to look at the assumptions that
underlie their use, and to suggest what it is generally that one ought to be trying to do in FIV
therapy–and why. Also what one ought not to be trying to do because a wise therapeutic program
is defined as much by the latter as by the former. The attribution of a certain activity to a given agent should not be seen as an endorsement of its use, but as a jumping off point for
inquiry.
Wise choices, unfortunately, are not always easy to make. The Feline Immunodeficiency Virus,
like its human counterpart, is seemingly designed by nature to frustrate the most dedicated efforts
to gain control over it. Its wide reach in the body and its many fail-safe devices for survival
account for much of its success as an infective agent. So do its very “imperfections.” FIV and
HIV are so genetically unstable that, it is estimated, millions of genetic errors occur every day in
the body of an infected individual. The same process of Natural Selection that drives entire
species in their adaptation to their environment is telescoped into one infected body, for
somewhere in those millions of random errors are “accidental” adaptations that alter minutely the
viruses operations and make it a constantly shifting target for the would-be therapist. The virus
one is fighting today is never quite the same virus that one was fighting yesterday.
2. “Boosting” the Immune System
The most potentially problematical concept applied by most well-meaning owners of FIV+ cats
and by some of their veterinarians, as well–at least by that minority of vets inclined to do
anything whatever about the cats’ primary disease–is to “boost” the immune system of an
immune-suppressed cat. On the face of it, this seems a perfectly reasonable approach. But the
more deeply it is looked into, the more complex the matter becomes. The reasons have to do
with the nature of the virus, the workings of the immune system, and how they interact. If the
thing is to be done, it should be done in the right way. But it is not always easy to judge what the
right way is.
Specific and Non-Specific Immune response. The initial response to pathogens is from cells of
the non-specific (or natural) immune response, that is, cells which are ready to defend as they are
and require no special tailoring to destroy invading bacteria or virus. The specific (or adaptive)
immune response requires time to configure weapons attuned to the particular invader.
Specific Immune Response. The specific immune system consists of two types of lymphocytes,
B cell and T cell, the first created in the bone marrow (B), the second also created there, but sent
to the thymus (T) for further processing to perform specific functions. Cells of the specific
immune response have the ability to recognize specific alien antigens and configure themselves
to destroy them.
B Lymphocytes. It is generally underappreciated that B cells are infected by FIV in surprising numbers. Moreover, infected B cells can
infect T cells in the course of interfacing with them for purposes of antigen presentation
(See Dendritic Cells). B cells evolve through several stages to become plasma cells,
which create a number of immunoglobulins (a.k.a. “antibodies”) for use against invading
pathogens. This is called the “humoral response” because B cells act in body fluids.
● Problem.
HIV and FIV cause gammaglobulinemia, a chronic stimulation of antibody
production. The cause is not fully understood, but the most persuasive explanation is that
particles of the abundant viral envelope protein detach from the viruses and become
attached to uninfected immune cells. This in turn activates antibody production from B cell-derived plasma
cells, which mistakenly regard the uninfected cells as infected. Since there are so many
uninfected cells bearing particles of envelope protein, stimulation of B cells is ongoing.
Because HIV and FIV preferentially infect the subset of T-Helper cells (TH2) that codes
for antibody response and because infected cells no longer express the molecule that
attracts envelope protein, the subset of T-Helper cells (TH1) that upregulates the
“cell-mediated immunity” provided by CD8+ T cells (see below) disproportionately
attracts both envelope protein and antibodies against envelope protein. The coating of
antibody marks them for destruction by other immune cells. The infected cells,
ironically, outlive the uninfected antibody-coated cells and, by a classic feedback loop,
continue the upregulation of antibody response from B cells. The result is an unbalanced
and misdirected immune response that promotes inflammatory antibody-mediated
autoimmune disorders and that probably plays a role in the development of B-Cell
cancers to which FIV+ cats are liable.
T Lymphocytes. The main T lymphocytes are CD4+ lymphocytes, called “helper” T
cells, and CD8+ lymphocytes, called a “cytotoxic,” or “Killer,” T cell ( CTL). Together
they constitute what is called the “cell-mediated” immune response. The function of the
second is to destroy infected host cells in order to prevent the spread of disease and to produce soluble factors that interfere with the RNA products of viral transcription. A strong
CD8+ response early in and throughout the disease process is a crucial predictor of
prognosis, and the loss of an effective CD8+ response is a central event in the progression
to AIDS. The function of the CD4+ lymphocytes is to choreograph the activity of CD8+
cells and other arms of the immune response (including the humoral and non-specific)
through interface with APCs (see Dendritic Cells) and the secreting of regulatory
cytokines (signaling proteins) based on the information they receive. The progressive
loss of CD4+ lymphocytes to HIV and FIV is the primary cause of deteriorating immune
function.
● Problem. HIV and FIV preferentially attack CD4+ lymphocytes, although they
can also infect and affect CD8+ lymphocytes. The progressive inversion of the
CD4:CD8 ratio occurs until the final stage of infection, when CD8+ numbers
collapse, as well. Advance of infection initiates a cycle that increases viral
replication in T cells. Cytokines upregulated by HIV and FIV, such as
TNF-alpha* and IL-6, promote the production of free oxygen radicals, which
activate the pathway of a host gene transcriptional-regulating factor called
NF-κB** (nuclear factor-kappa B) by dissociating it from its natural inhibitor; the
factor binds to the LTR (long terminal repeat) region of the “provirus” integrated
in the host DNA and throws the “on switch” for replication.
*Tumor Necrosis Factor-alpha (TNF-α) is a crucial substance in HIV infection. It can have either
proliferative or inhibitory effects depending on the receptors and co-acting
cellular agents involved, and can be equally destructive in both regards. In other
disease contexts it is a very important and necessary component of the immune
system. One FIV study has suggested that the pro-viral effect of TNF-α on FIV
may be strain specific and that TNF-α may upregulate viral production only in
strains with NF-kB binding sites. This view is unsupported by other testimony,
but even if true, the harmful role of TNF-α in other regards is well supported.
**NF-κB is one of several host- produced transcriptional factors which can
activate viral replication independently of virally-produced transactivators. (A
transactivator is a protein that facilitates the production of new viral messenger
RNA (mRNA) from integrated proviral DNA.) And viral transactivators can
activate proviral replication independently of NF-κB. But NF-κB in the presence
of viral transactivators is a far more potent replication stimulator than either
acting independently. Since some strains of FIV lack a binding site for NF-κB, it
is assumed that it is a less important transcriptional factor for FIV than for HIV.
Research to date suggests that ATF and AP-1 are active binding sites for
transactivation of all FIV strains. AP-1 has been shown to respond to some
agents that also inhibit NF-κB, providing some basis for believing that other
transcriptional factors act and are potentially controllable in the same way as
NF-κB.
● Problem. In HIV and FIV, disease progression is marked by increasing
“apoptosis” in uninfected CD4+ and CD8+ lymphocytes. Apoptosis, the
programmed self-destruction of a cell by shriveling rather than bursting, is an
action central to an understanding of HIV and FIV. Induction of apoptosis is a
normal immune-system activity, a way of eliminating damaged or infected cells
and also “autoreactive” healthy cells (i.e., cells that would attack bodily tissue in
an autoimmune response) without releasing the cell contents into the lymphatic or
peripheral blood circulation. FIV accelerates this process by a number of
pathways. Antibody coating by B cells (previously discussed) can induce apoptosis by a process called “cross-linking” (i.e, forming a bridge between cell-surface receptors, a sort of “"short circuit”). Also, exposure to viral envelope protein can induce T cells to express molecules on their surface that invite apoptotic signals. A unique feature of FIV infection is that apoptosis occurs in
uninfected bystander cells that are in an inactivated state (rather than an activated
state, as with HIV and SIV), suggesting that feline lymphocytes are programmed
to upregulate molecules favoring apoptosis when a growth factor (Interleuken-2)
present in normal T cell proliferative response is missing. The suppression of
IL-2 growth factor is a hallmark of immunodeficiency virus infection. In some
cases, an alternative state of “anergy”* is induced: cells do not self-destruct, but
exist in a “zombie-“like state of partial activation, unable to proliferate or perform
normal immune function.
*Anergy is an important concept to grasp in understanding the effects of FIV
infection because it explains why immune deficiency is not solely a matter of cell
counts. FIV+ cats have an excess of lymphocytes, both CD4+ and CD8+,
expressing molecules on their surface normally characteristic of
“antigen-presenting” cells (see Dendritic Cells). These cells adopt a suppressor
instead of an effector function and induce anergy ( or apoptosis, depending on
certain variables) in other T cells with which they interact in their pseudo-antigen
presenting modes and which bear a suppressor-receptive complementary
molecule.
Possible Therapeutic Response.
1. Supplement with antioxidants to prevent activation of NF-κB transcriptional factors. Among
frequently recommended antioxidants: Alpha Lipoic Acid (ALA), N-Acetyl-Cysteine (NAC)
read more, Dimethylglycine (DMG), CoQ 10, S-Adenosylmethionine (SamE), L-Glutathione, Superoxide Dismutase (SOD),
L-Carnitine or Acetyl-L-Carnitine read more, Green Tea., Milk Thistle, Licorice. Omega-3s, St.
Johnswort, Gingko, DHEA, Quercetin, Cat’s Claw, Curcumin, Grape Seed, Melatonin, Selenium
read more, Resveratrol, Niacinamide read more, Vitamin A, C & E read more. Pentoxifylline, a
blood thinner, inhibits interaction of NF-κB and LTR. Olive, Curcumin, Green Tea, Cat's Claw, Resveratrol,
and Alpha Lipoic Acid are known inhibitors of AP-1.
2. Supplement with agents that inhibit expression of TNF-α: Thalidomide, Pentoxifylline,
Curcumin, Olive Leaf, Green Tea, Cat’s Claw, SPV-30/boxwood, Quercetin, Resveratrol, Lactoferrin,
Siberian Ginseng, Milk Thistle, Niacinamide, L-Carnitine/Acetyl-L-Carnitine, Fish Oil,
Ketotifen, Glucocorticoids
Note: Though a proinflammatory cytokine, TNF-α is upregulated by a number of
anti-inflammatory agents, such as aloe derivatives like acemannan. Curcumin, on the other
hand, downregulates TNF-α and has known anti-inflammatory properties but favors a TH2
response profile. Such trade-offs pose difficult questions about the long-term consequences of
agents that appear to have undeniable short-term benefits.
3. Supplement with agents known to inhibit FIV- and/or HIV- induced apoptosis and preserve T
cells. NAC and L-Carnitine or Acetyl-L-Carnitine are particularly useful in increasing resistance
to apoptosis. Vitamins C & E and Niacinamide have also shown positive results in that regard,
as have the botanicals Curcumin, Olive leaf. Resveratrol downregulates bcl-2, a gene upregulated by FIV and implicated in FIV-induced apoptosis.
4. Supplement with immunomodulators that enhance
cell-mediated immunity (T Cells) while controlling runaway humoral response (B cells):
Antihistamines (Thalidomide, Ketotifen), Pentoxifylline, Sterols/Sterolins (Moducare, Sesame
Oil), Transfer Factors, Herbs (Neem Leaf, Astragalus, Licorice, Olive, Grape Seed, Siberian Ginseng), Melatonin, Lactoferrin, DHEA, Thymus,
Fish Oil, Glutathione and Glutathione precursors, Vitamin C, A, & E. Type 1
interferons, though not specifically TH1 cytokines, help to inhibit proliferation of B cells and
excessive antibody synthesis. ( Interferons* also prime other cells for virus suppression and
induce production of chemicals that inactivate the mRNA necessary to viral replication.) Or
supplement with Interferon Inducers (Aloe derivatives, Astragalus, Licorice, Reishi, Korean
Ginseng, DMG, Staphylococcus Protein A, TDF).
*Note: Low-dose orally administered interferon contains too little interferon to act directly. The
precise basis of its therapeutic action is unclear.
5. Supplement with agents known to enhance T cell function and support proliferative response.
Among frequently recommended agents: DMG, Thymus Peptides (Thym-Uvocal,
Thymomodulin, Thymus Protein A), Herbs (Astragalus, Lutein, Echinacea*, Cat’s Claw**),
Mushrooms (Shiitake, Reishi, Agaricus, Maitake), B Vitamins (including Niacinamide). Probiotic bacterium enterococcus faecium raises Helper-T percentage in kittens. Milk
Thistle and Korean Ginseng support lymphocyte proliferation, upregulating IL-2 while
downregulating TNF-α. Astragalus potentiates IL-2 and is said to be synergistic with IL-2, although it upregulates TNF-α. Melatonin complements IL-2 stimulators by independently amplifying
their activity. Vitamin E enhances T cell division capacity and stimulates IL-2 production in
naive nonmemory T cells. Among CD8+ potentiators are IL-12 stimulators cimetidine, grapeseed, melatonin, AHCC (Active Hexose Correlated Compounds) resveratrol, spirulina, and agaricus. Carnitine inhibits IL-12, but has otherwise been associated positively with T cell function.
Note: Diminishing anergy and improving T cell proliferative response involve difficult and
uncertain choices. Agents that support cellular metabolism (e.g., antioxidants) or DNA repair
(e.g., niacinamide) seem safe bets, although some (such as DMG, which facilitates cellular
process through methylation but which also upregulates TNF-α) have potential downsides.
However, studies and clinical experience have produced ambiguous and sometimes
contradictory data regarding the desirability of activating the immune response of FIV+ or
HIV+ individuals. Bystander lymphocytes not themselves infected with HIV and FIV are
nonetheless liable to anergy or apoptosis when adjacent to those that are. Because bystander
cells in FIV+ cats are protected by activation, narrowly targeted therapy which provides a
source of the Interleuken-2 (IL-2, also called T Cell Growth Factor) or IL-12 that these cells
require to maintain an activation profile, may be beneficial, especially in well-advanced
infection. Both CD4+ and CD8+ require IL-2 stimulus to maintain normal proliferative
response, even though the activation state leaves them more liable to actual infection. But
questions linger about many agents which produce possibly undesirable responses along with
the potentially beneficial. Mushroom supplements such as agaricus enhance production of IL-12,
a necessary co-stimulant of CD8+ maturation after activation by IL-2; however,
mushroom-derived 1, 3 beta-glucans are generally found to upregulate TNF-α. (A recent study of Reishi surprisingly found inhibition rather than stimulation, and a recent study of agaricus had strange discrepancies in in vivo and ex vivo results.) Carnitine suppresses TNF-a and helps
prevent T cell apoptosis, but at high dosage suppresses IL-12. A cautionary approach to
immune stimulus*** is provided by the fact that some viruses infect Memory CD4+ lymphocytes
(which store information against later encounter with the same antigen) and go quiet. In this
way they become a latent reservoir of infection and a potential problem if later activated in the
absence of viricidal therapy. Vitamin E has been shown to inhibit activation of latent viruses.
Conversely, resveratrol has been shown to activate “hiding out” virus, a strategy to be
considered in a situation where effective antiviral therapy is already taking place, since the
latent reservoir is thereby reduced. Resveratrol also inhibits dominance of T cell populations by suppressive T-regulatory cells (TREGs). Whether long-term benefit or harm derives from broadly
targeted immune stimulators such as Immunoregulin and Staphylococcus Protein A (SPA) can
only be judged by the results of studies which, to date, do not exist.
*Echinacea is a herb best reserved for short-term administration in cats. Its use in retroviral and autoimmune diseases is controversial. Short-term use (< 2 weeks) for specific situations may be acceptable.
**Cat’s Claw (Una de Gato) that is certified free of tetracyclic oxindole alkaloids (TAOs) stimulates endothelial cells to produce a lymphocyte-proliferation-regulating factor that
prolongs cell-cycle survival of T and B lymphocytes, thereby increasing lymphocyte numbers.
Since production of TH2 inflammatory cytokine IL-6 is stimulated, it is unclear whether the
increase is at the cost of further imbalance of T Helper subsets in a TH2 direction.
***T cell/ B cell “dampening” is a fundamentally different therapeutic approach, seeking to
minimize lymphocyte loss by minimizing activation. Fat-based agents (phytosterols, fish oil,
evening primrose oil, etc), flavonoids (such as quercetin), glucocorticoids or agents that mimic
aspects of glucocorticoid activity (such as licorice or carnitine) tend to be lymphoproliferative
antagonists. Whether or when to embrace this model over the activation model is one of the
major puzzles of FIV therapy (See “Bud’s ‘Second Chance’: Lifetime FIV Therapy”).
Nonspecific Immune Response.
Important cells involved in the nonspecific immune response are neutrophils, dendritic cells,
macrophages (produced from monocytes), and natural killer (NK) cells. Of these, the second and
third are of particular importance in the pathogenesis of HIV and FIV. Neutrophil loss
(neutropenia) is a significant feature of AIDS, but happens by an indirect process, not as a direct
result of viral attack. FIV has been shown to have a detrimental impact on the functioning of the
nonspecific immune response. Some recent research has gone as far as to posit that it is the
impact of HIV on aspects of the nonspecific immune response that causes the majority of
dysfunction in the specific immune response.
Macrophages. Macrophages are important phagocytic cells of the nonspecific immune
response; that is, cells that attack and destroy pathogens outside the cell, thus sparing the cell
from destruction by other agents of the immune-system in order to stop the spread of disease.
Macrophages can seek out and engulf HIV and FIV virus. They are also important
antigen-presenting cells (APCs) which present alien antigens to T cells in order to help configure
cell-mediated response.
● Problem. Along with CD4+ lymphocytes, macrophages, which richly express the CD 134 molecule that the virus binds to, are a primary target of the virus. In fact, infection of macrophages is more central to initial stages of infection in HIV and
FIV than is infection of CD4+ lymphocytes. Along with inactive “Memory”
CD4+ lymphocytes (which store information for future encounters with
pathogens), macrophages become a primary reservoir of virus “hiding out” from
the immune system. They also spread the virus throughout the body, and are
particularly central to HIV and FIV infection of the central nervous system.
● Problem. Among immune cells, activated macrophages are primary producers of pro-inflammatory cytokines, particularly TNF-α,
although many other cells–including B cells and T cells–produce this cytokine as
well. TNF-α creates an environment that encourages viral replication and offers a pathway for T cell apoptosis (programmed cell death), particularly for CD8+ (Cytotoxic) T cells.
Dendritic Cells. An important link between the specific and nonspecific immune systems,
dendritic cells are the major antigen presenting cells (APCs) of the immune system, although
macrophages and B cells also perform this function. Immature dendritic cells (DC) reside in
intraepithelial and submucosal tissue, acting as screens to pathogen entry. They bind pathogen,
activate to become mature cells, then migrate with their captives to the lymph nodes, where they
present them to T cells for pattern recognition.
● Problem. Dendritic cells, in presenting HIV and FIV to T cells, activate them and
expose them to infection. Because they are themselves infected, they are able to
pass on the infection through direct interface with T cells
● Problem. Altered response of dendritic cells due to HIV and FIV infection has
been observed to account for impaired pathogen response. Infected dendritic cells
fail to mature properly and are suspected of playing a major role in T cell
apoptosis and the acquisition of anergic phenotype. HIV interaction with a
particular subset of dendritic cells called plasmacytoid dendritic cells (pDC) sets
off a biochemical chain reaction that may be responsible for chronic T cell
activation and overexpression of anergy-inducing T-regulatory (Treg) cells.
Natural Killer (NK) Cells. NK cells are lymphocytes of the non-specific immune system that,
like macrophages, can directly attack pathogens, which they destroy by secreting an enzyme
called perforin that breaks down cell walls. They are activated not by antigen-presenting cells, but by toll-like receptors (TLRs) specific to molecules that characterize infective organisms. They are important components of antiviral activity and tumor surveillance.
● Problem. NK cells can also be infected by HIV and FIV virus. In addition to activation by IL-12 produced by
macrophages, NK cells are also activated by IL-2 produced by CD4+ and CD8+
lymphocytes. HIV and FIV suppresses these activators. Defective NK function
has been observed with both HIV and FIV infection, involving, among other things, reduced ability to destroy virus upon binding.
Possible Therapeutic Response.
1. Supplement with agents that build NK cell numbers and enhance NK function without
encouraging CD4+ TH2 expression or B cell antibody production: PRPs/transfer factors, Type 1 interferons,
lactoferrin, IP6, echinacea, astragalus, thymus peptide, phytosterols (such as Moducare), melatonin, zinc,
vitamin C read more. Aloe derivatives and mushrooms supplements are potent NK cell
enhancers, though their stimulation of TNF-α may be a problem. DMG is also suspect in this
regard. See item 4 for further information.
2. Supplement with agents that block binding of virus to DC. Lactoferrin binds a receptor called DC-SIGN on DC cells –and on B cells, as well– preventing both from becoming infected and, in
turn, affecting the T cells with which they interface. Interferon alpha (omega?) and
glucocorticoids do likewise. Feline DC-SIGN has not yet been cloned, but indications are that
what works for HIV should work for FIV. Recent research involving plasmacytoid dendritic
cells (pDC) at least raise questions about the advisability of choosing interferon alpha. Glycyrrhizin in licorice inhibits HIV infection of DCs through inhibition of HMGB1 activity, thereby preventing NK-dependent HIV-1 replication in DCs. Curcumin (and to a lesser extent resveratrol and omega-3 fatty acids) binds and activates the PPAR-gamma receptor, whose activation inhibits retroviral capture by DCs
3. Much ambiguity shrouds the question of whether and how to target macrophages therapeutically. Most of what is known about how macrophages react to retroviral infection is derived from HIV research, and some of it may not be fully applicable to FIV. While a strong phagocytic response is necessary to a healthy immune system, activation of macrophages by HIV appear to contribute to its pathogenesis. This activation occurs by multiple pathways and multiple macrophage activating factors (MAPs), which may individually either enhance or suppress HIV-1 replication. Some factors/cytokines, such as TNF-α, enhance virus production; others, such as both type 1 and type 2 interferons, inhibit virus production. While activation results in production of pro-inflammatory cytokines such as TNF-α, activated macrophages also secrete IL-12 necessary to CD8+ T cell maturation. Many natural and pharmaceutical agents activate the macrophage network, but it is generally unclear whether benefit or harm results in the long term. Healthy caution would not be misplaced. Immune and parammune stimulators such as Acemannan, Baypammune, Immunoregulin, and Staphylococcus Protein A all activate and stimulate production of macrophages (as well as augment NK cell activity and increase circulating interferon). Like aloe products, beta glucans in mushroom supplements enhance macrophage function in cats, but also stimulate production of TNF-α. A number of botanicals (licorice, astragalus, gingseng, etc) activate macrophages largely through the presence of lipoproteins and lipopolysaccharides belonging to endophytes (bacterial or fungal symbiants) that live within the plants. Some drugs and supplements have shown evidence of positive effect on macrophages with lesser or no known downside. Interferons reduce HIV-infected macrophages and may have a worthwhile role in antiviral programs. Blue-green algae (Spirulina) and some probiotics enhance macrophage function in cats, much as lactoferrin enhances neutrophil and dendritic cell function. Supplementing with Vitamin B12 has been shown to enhance resistance of macrophages (and the monocytes from which circulating macrophages derive) to HIV infection.
3. “Killing” Virus"
In order to kill virus directly, you must interrupt the process of its replication at one or more
points. Trying to maximize the immune system’s antiviral capacity is one approach. Another is
to administer agents that directly affect the replication cycle. This may be done in several ways.
One is to select agents that act upon some part of the virus itself or upon some protein or enzyme
that it produces. Another is to select an agent that deprives the virus of the use of some
substance that is already part of the natural chemistry of the host and that the virus makes use of
in order to replicate. In the case of FIV, this strategy is complicated by the fact that many agents
that have been tested and have been found to have some level of effectiveness against HIV have
not also been tested against FIV. A further complication is that even many of the agents that
have been tested on HIV have been tested “in vitro” in cultured cell lines, not in a living being.
Some agents that produce spectacular results in the laboratory produce none in a living being
either because they never reach the place where they need to go or because bodily processes alter
them by the time they get there. Yet another complication is that HIV and FIV, though similar,
are still different viruses, and cats and people, though genetically similar (cats are more similar
genetically to humans and simians than is any other creature), are different beings with variations
in cellular chemistry.
The replication cycle of the Feline Immunodeficiency Virus comprises the following stages: (1)
Attachment and Entry, (2) Reverse Transcription and DNA Synthesis, (3) Transport to the
Nucleus of the Host Cell, (4) Integration into the Host DNA, (5) Activation and Transcription
back to RNA, (6) Viral Protein Synthesis Using Cellular Synthesizing Machinery (called
Ribosomes), (7) Assembly of the Virus at the Cell Wall, (8) Cleaving of the protein chains of the
viral core and release of the virus from the cell wall. Each of these stages is a potential point for
interdiction of the replication process. The rationale of Highly Active Anti-Retroviral Therapy
(HAART), known familiarly as the “triple cocktail,” is to interdict replication at several points in
the process simultaneously and/or at the same point by different biochemical routes.
Some of the agents in the following breakdown have not, so far as I have been able to discover,
actually been given to cats; most have. I make no pretense of completeness to the list. Activity
against HIV does not guarantee activity against FIV or safety in cats. Unavailable agents have
not been listed.
Attachment and Entry. The viral envelope protein binds to a receptor on the CD4+ immune cell surface (to a
protein called CD134, in the case of FIV) and undergoes a change as a result, increasing affinity
for a co-receptor that normally binds to a specific chemokine responsible for attracting the cell to sites of infection. The binding of the chemokine co-receptor activates another viral
protein, gp40, which secretes an enzyme causing fusion with the cell membrane and growth of a
penetrating filament network. The virus unzips itself and releases its genome and accessory proteins and enzymes
into the cell. Action. Block the bond between viral envelope and the CD4+ surface: St. Johnswort
(hypericin), coumarin, licorice (glycyrrhizin), green tea (catechin EGCG), black tea (theaflavins), white mulberry leaf (N-butyldeoxynojirimycin), green coffee bean (chicoric acid), spirulina / blue-green algae (cyanovirin), lactoferrin
(nonspecific inhibitor), procaine hydrochloride (membrane cholesterol inhibitor), iodine (hypoiodous acid), propolis (unknown mechanism). Action. Block viral binding with CXCR4 co-receptor: birch bark (betulinic acid),
green tea (EGCG), curcumin (curcuminoids), prunella and forsythia (tannic acid). Inhibition of CCR5, an occasional secondary co-receptor, is less significant: licorice (glycyrrhizin), CM4 (patented extract of eleuthero root). Action. Block fusing action of gp40 and cell transmembrane: olive leaf (oleuropein), prunella (tannic acid) green tea (EGCG). Elderberry leaf inhibits fusion by unknown means not involving gp40 binding. The HIV fusion inhibitor Fuseon is not effective against FIV.
Reverse Transcription and Synthesis. The viral enzyme reverse transcriptase converts viral
RNA into DNA. Action. Terminate DNA chain by substituting phosphorylated nucleoside
analogues for nucleosides: HIV nucleoside reverse transcriptase inhibitors. Action. Inhibit
phosphorylation* of RT by Casein Kinase II.. Chrysin, Quercetin, Licorice, Chrysanthemum
multifolium. Action Uncertain. Possible activity against polymearase or RNase H, enzymes
essential to the process. Baikal Scullcap (flavonoid baicalin), SPV-30 (triterpenoid alkaloids),
olive leaf (oleuropein), shiitake mushrooms (lentin), prunella vulgaris (anionic polysaccharides), green tea (catechin
EGCG).
*Phosphorylation is an important cellular process of particular relevance to HIV and FIV.
Protein function is regulated by donation of phosphate groups through the mediation of enzymes
called kinases. After activation by the HIV (and FIV?) Rev gene, the cellular enzyme CKII
phosphorylates both viral reverse transcriptase and viral protease; it also phosphorylates
cellular proteins which inhibit cellular transcriptional factors, allowing the latter to translocate
to the nucleus of the cell and bind to sites on the viral LTR, thereby boosting viral production.
Integration into the Host DNA. The viral components move from the cell cytoplasm to the
nucleus. The viral enzyme integrase unzips the host DNA so that the viral DNA can insert itself.
The virus is now called a “provirus.” Action. Block binding of viral and host DNA by integrase
inhibition: Type 1 interferon, quercetin, olive leaf (oleuropein), turmeric (dicaffeoylquinic acids), rosemary
or oregano extract (rosmarinic acid), green coffee bean (l-chicoric acid), bitter melon (MAP30
protein), St. Johnswort (hypericin). Action. Inhibit catalysing necessary to integration:
niacinamide (PARP-1 inhibition) read more. An HIV integrase inhibitor, raltegravir, has
recently been approved. It may inhibit FIV.
Activation and Transcription. Proteins on cell receptors stimulate host DNA to make RNA
copies of the DNA. The “Messenger” RNA (mRNA) is transported back out of the nucleus and
into the cytoplasm through the offices of a viral protein. Action. Inhibit transactivating proteins.
Chrysin, quercetin, licorice, chrysanthemum multifolium. (See note on phosphorylation.). Action.
Inhibition of the proviral LTR, the “on-switch”: Turmeric (curcuminoids), bitter melon. Action.
Inactivate mRNA. Type 1 Interferons. Bitter melon may inactivate mRNA.
Viral Protein Synthesis. Another form of RNA, “Transfer” RNA (tRNA), weds the mRNA to a
cellular copying machine called a “ribosome,” which uses it as a template to translate its coding
into proteins. Action. Inhibit interaction of ribosome and mRNA/tRNA: trichosanthes root
(trichosanthin), bitter melon (MAP30 protein).
Viral Assembly. Viral protein chains move to the cell wall and fuse with viral envelope proteins
within the cell wall, which then surround the immature viral core. Action. Inhibit interaction of
assembling core with cell wall: St. Johnswort (hypericin), Type 1 interferons.
*In HIV studies, Alpha Interferon has usually shown significant antiviral benefit when used in
conjunction with antiviral agents, not when used as monotherapy.
Release and Maturation. The core protein-chains are cut by the viral enzyme protease into the
three viral enzymes, reverse transcriptase, protease, and integrase. The mature virus pinches off
from the cell wall. Action. Protease inhibition. No available HIV protease inhibitors are directly
effective against FIV. Reishi and agaricus (triterpenes), turmeric (curcuminoids), prunella
vulgaris (ursolic acid). Action. Inhibit release from cell wall. HIV protease inhibitors do inhibit
a host substance called proteasome, creating a deficiency of another substance called “ubiquitin,”
the absence of which causes the “budding” virus to fail to detach from the cell membrane. It is
unclear whether the viral inhibition is significant enough to justify use of such a drug. (See also
note on phosphorylation.)
4. “Boosting” Immunity Vs “Killing” Virus
The divide between the general approaches of traditional and alternative medicine toward HIV
therapy is substantially defined by the weight given to one or the other of these strategies. As for
FIV therapy, the great divide tends to be between vets willing to try something and those content
to do nothing. Among the former, the inclination is almost entirely in the direction of immune
enhancement.
In HIV medicine, the proponents of immune enhancement regard the direct killing of virus as a
losing strategy. It is true that reduction of viral burden does not solve all HIV- and FIV-related
dysfunction. HIV and FIV has shown a capacity to overcome almost any single antiviral agent
put in their path because of the adaptive capacity made possible by its extraordinary random
mutation. HAART, the strategy of simultaneous use of a number of antivirals, can extend the
depth and period of viral suppression, but will still lose ground to the virus. The cost of such
combination therapy in dollars and unwanted side effects is considerable. Moreover, it has been
observed that with HAART, substantial increases of CD4+ cells have not always prevented
opportunistic infections. Some proponents ask, should we be concentrating on the immune
reconstitution that comes from radical reduction of viremia alone, a simple increase in the
number of CD4+ cells; or should we concentrate on manipulating the immune response to
increase the cells that are really needed, those that produce the TH1 cytokines that the virus
suppresses?
Proponents of antiviral agents in traditional medicine rightly point to the great complexity of
immune response and the uncertainties involved in trying to manipulate it, especially to fight a
disease that has so many interlocking effects on immune response, many of them still poorly
understood. They argue the great difficulty in gaining actual immune enhancements without also
acquiring unintended deficits in the bargain. They will tell you that the graveyards are full of
people who thought they could lick HIV with immune-enhancing gimmicks and that killing virus
remains the most reliable strategy for trreating the disease.
This divide is by no means absolute. A number of experts in traditional HIV medicine have
acknowledged a growing body of research indicating that viral reduction correlates only loosely
with individual clinical pictures. Many HIV sufferers with their virus well under control with
antiviral drugs continue to suffer significant effects of the disease because of CD4+ lymphocytes
that refuse to return to functional levels for reasons rooted in immune dysfunction set in motion
by the virus but now operating semi-independently of it. Those who achieve effective viral suppression when their CD4+ lymphocytes are at a very low level have particular difficulty in reattaining more healthy counts. There is no reason to think that the situation is any different for cats with FIV. One study of AZT in FIV+ cats showed substantial
reduction of viral burden in plasma, peripheral blood lymphocytes, and thymus, yet decline in
CD4+ lymphocytes was not reversed. On the other hand, eliminating a substantial portion of the
virus that would otherwise be present is the single most significant step that can be taken to
improve the health of an infected individual, and antiviral agents, whether natural or manmade,
are a proven way to do that, even if the effect on the disease process is not decisive.
Employing both immunomodulating and antiviral approaches on cats with FIV in a judicious
way makes sense . Immune stimulation or immune modulation that is very broad in its action
probably should be reserved for circumstances requiring a substantial “boost” in immune
capacity: notably, episodes of secondary infection when bloodwork shows clear immune deficit.
Otherwise, antioxidants and immune modulators that can preserve cells, reduce inflammation,
and help gain or maintain a TH1 cytokine profile seem most desirable. Early intervention during the asymptomatic phase of
infection is particularly important in this regard. Many natural anti-viral agents, for a variety of
reasons, probably need to be reserved for cats who (1) are showing signs of becoming
symptomatic or who (2), by reason of age and duration of positive status, seem prime candidates
for the onset of symptoms. Experience suggests that herbal and other supplements are capable of
exerting considerable antiviral effect; only further experience with them will tell whether any or
all are liable to the same resistance as HIV antiviral drugs. If not, along with immune
enhancement, antiviral therapy might become an effective long- term strategy for treating FIV.
HIV antiviral drugs, by reason of their ability to rapidly impact viral load–which is the greatest
predictor of FIV mortality– deserve to have a place in the veterinary arsenal that, mostly, they do
not currently have. Because of their limited duration of effectiveness and expense, they must be
used primarily as rescue drugs. .
5. What’s Missing
A number of studies have established that HIV has a powerful impact on the ability to uptake and
use important nutrients. There is no reason to think that FIV is any different. Equally important,
though, is the revelation by one recent study that supplementing at the RDA level (Required
Daily Allowance) is inadequate–that, in fact, many times the RDA level of a number of vitamins,
minerals, and amino acids were necessary in order to achieve “normal” cellular levels in the
HIV+ males participating in the study. Clearly, in some cases, the effectiveness of large doses of
substances stems not merely from replacing what is missing but from creating artificially large
intercellular concentrations.
Following are a list of some of the most significant “missing” nutrients.
Vitamins A, C, & E. All important antioxidants. Vitamin C has long been recognized as
anti-viral, as well–at least in vitro. Cats create their own Vitamin C, but supplements are likely
beneficial. Vitamin E has been shown to lower viral loads when used in conjunction with
antiviral agents and when used alone. Vitamin A does have toxic levels, and there is some
suspicion that it might raise rather than lower viral loads when given at levels higher than those
needed to overcome deficiency read more.
Vitamins B2, B6, B9 (Folic Acid), and B12. B12, for example, has a specific capacity to aid
monocytes and macrophages in avoiding HIV infection. It may also serve neuroprotective
functions. B9 is important for resistance to HIV-associated anemia and is necessary for effective
utilization of B12.
Selenium. Nutrient whose depletion is known to be related to HIV mortality rates. An important
component of the glutathione support system that reduces oxidative stress. The
proportion of loss directly tracks disease progression. Does have toxic levels and recent research
has shown positive antiviral and CD4+-enhancing activity. read more
CoQ10. Plays a key role in producing adenosine triphosphate (ATP), which is needed for energy
production within individual cells. Also an antioxidant. Found to be depleted in many chronic
diseases, including HIV.
Zinc. Most prevalent micronutrient deficiency seen in HIV infection. Low plasma levels predict
a tripling of mortality rate. Although the role of zinc deficiency in disease progression is
controversial, zinc deficiency is known to lead to a reduction of circulating T Cells, both CD4+
and CD8+. Toxic threshold is fairly high, but less than toxic concentrations can still inhibit use
of other minerals such as iron and copper.
Carnitine. L-Carnitine is an amino acid. Acetyl-L-Carnitine, a related substance, is produced in
the body. Carnitine is responsible for transporting fatty acids and is particularly important for
holding weight. It also protects against apoptosis of healthy cells. A number of studies have
shown carnitine deficiencies in HIV infected individuals. read more
Glutathione. Has cell-protective and -regenerative functions. An important antioxidant and
enhancer of immune function through enabling of amino acid uptake. Glutathione is a peptide
created in the body from precursor substances such as N-Acetyl-Cysteine (NAC) read more. One
study found an average plasma concentration in HIV+ individuals of 30% normal. A recent FIV
study has likewise found decreased concentrations in CD4+ and CD8+ lymphocytes.
Superoxide Dismutase. A host antioxidating enzyme found in short supply in HIV+ individuals.
Supplying reduces inflammation, protects mitochondria and CNS cells from oxidative stress, and
improves CD4+ counts. A recent study in FIV+ cats showed that SOD (supplied as the
proprietary supplement Oxstrin) improved CD4:CD8 ratio in asymptomatic cats.
Lactoferrin. One study found decreased levels of plasma lactoferrin in HIV-1 infected patients
in relation to disease progression, another that the lack of lactoferrin in the oral cavity correlated
strongly with the AIDS-related infections of the oral cavity.
Tryptophan. A recent study found that cats with FIV, like humans with HIV, have markedly
reduced levels of serum tryptophan, an amino acid. It concludes, “ Dietary or pharmacologic
intervention to support serum tryptophan concentrations has been shown to be clinically useful in
humans with AIDS and might be applicable to cats with FIV infection.” Tryptophan deficiency
has been linked to depressed niacin and serotonin levels, immune incompetence, polyneuropathy,
dementia, dermatitis, and diarrhea. Direct supplementation with tryptophan is controversial, but
has had some success in HIV medicine. Niacinamide supplementation has been shown to raise
tryptophan levels 40% in humans with HIV read more.
Melatonin. The body’s own production of melatonin declines as HIV disease
progresses. Exogenous melatonin restores levels, regenerates thymic tissue, and increases
native production of IL-2 and IL-12, necessary to T-cell maturation and proliferation.
It is necessary to resist jumping to easy conclusions based on these findings. Research findings
aren’t always borne out by clinical experience, and some damage is more easily done than
undone. This having been said, it is hard to see the logic of indifference to replacement of
substances important to disease resistance. Many veterinarians have put off cat owners inquiring
about something as basic as a daily multivitamin on the grounds that there is no “known” or
“likely” benefit. Yet veterinary studies in this area are conspicuous by their absence. Prudence is
a virtue; inertia isn’t.
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