Is this the cure of HIV: Garlic

Current research by some Scientists have shown that there is potential cure for HIV virus
in Garlic. Patients infected with Hiv for 6months when introduced to Garlic Therapy got
their immune system working better by 50% it warded off the viral effect tremenduosly.
Presently this is not official so be on the look out.

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HIV 4

Phylogeny
Phylogenies are used to determine the taxonomic relationship among
pathogens and explain evolutionary mechanisms that produced these
genetic structures (Holmes, 1998). Based upon phylogenetic taxonomy,
HIV is a member of the lentivirus subfamily of retroviruses that
produces chronic infection in the host and gradually damages the
host’s immune system (De Cock et al., 1993; Hu et al., 1996; Grez
et al., 1994; Beer et al., 1999; Hahn, 2000). Three major types of
lentiviruses have been characterized in primates: Simian immunodeficiency
viruses (SIVs); HIV-1, the predominant type in the world;
and HIV-2, primarily found inWest Africa and India (De Cock et al.,
1993; Grez et al., 1994; Beer et al., 1999).
HIV and other infectious diseases conform to the clonal model
where genomes are not easily reshuffled by recombination and mutation.
In the clonal model there is nonrandom association of alleles
(linkage dis-equilibrium) allowing the identification of relationships
among pathogens (Levin et al., 1999). Based on phylogenetic relationships,
HIV-1 viral strains can be divided into three major groups: ‘M’,
‘N’ and ‘O’ (Louwagie et al., 1993; Sharp et al., 1994; Leitner et al.,
1997; Simon et al., 1998; Gao et al., 1999).The predominantMgroup
consists of 11 separate subtypes or ‘clades’ denoted ‘A’ through ‘K’
(Los Alamos National Laboratory, 1998). Multiple strains are found
in many countries but in the United States the majority of isolates
have been subtype B. The occasional presence of HIV-2 and HIV-1
subtypes other than B suggest multiple HIV introductions to North
America because the genomes of the strains are different (Delwart
et al., 1993; Hu et al., 1996). Subtypes found in Africa belong to four
clades (A–D). Subtype C is found mainly along the south and east
coast of Africa (and the west coast of India: Delwart et al., 1993; Stine,
2000). E, B andCare found in Southeast Asia (Louwagie et al., 1993) –
one, subtype E, almost exclusively infects heterosexuals in Thailand
while genotype B and E are found in intravenous drug users (Moore
and Anderson, 1994; Kunanusont et al., 1995).
Nucleic acid sequencing of the N group reveals this appears to be
restricted to Cameroon (Simon et al., 1998).HIV-1 variants outside the
Mand N groups have been provisionally categorized as group O (De
Leys et al., 1990; Gurtler et al., 1994).Within groupO, strains may differ
as much from each other as the variants within groupMsubtypes
differ from each other (Sharp et al., 1994). Group O is also primarily
found in Cameroon (De Leys et al., 1990; Gurtler et al., 1994) but it accounts
for less than 10% of HIV infections there (Gurtler et al., 1994).

It must be recognized that the subtypes identified for HIV are provisional
and reflect those isolates that have been collected and characterised
(Hu et al., 1996) –other subtypes may be identified in the
future.
Phylogenies are thought primarily to be the product of natural
selection operating on genetic diversity. Branches of these phylogenies
are sometimes associated with biological properties such as virulence,
mode of transmission, susceptibility/resistance and tropism
(Holmes, 1998). As such, evolutionary mechanisms such as natural
selection, as discussed earlier in this section, drive these properties.
The following sections of this chapter examine the association between
genetic diversity and these biological properties.
Susceptibility and resistance
A genetic basis for human variation in susceptibility to infectious
diseases has been shown in twin, pedigree, adoptee and candidate
gene studies. These studies show the inheritance of specific genes
and their association with infectious diseases. For instance, there
is a strong genetic association of susceptibility with common variants
of malaria, tuberculosis (Huebner, 1996), Helicobacter pylori infection
(Malaty et al., 1994), hepatitis B (Lin et al., 1989), leprosy
(Chakravari and Vogel, 1973), and HIV infection (see Table 2.1).
Susceptibility or protection can occur in a number of ways. For
example, IL-10 is a cell cytokine that inhibits T cell cytokine secretion
and macrophage growth (Fiorentino et al., 1989, 1991). IL-10 may
limit the number of activated macrophages accessible for HIV-1
replication thereby limiting its duplication. On the other hand, another
genetic polymorphism at that site, IL-10-5’A, is linked to an
accelerated progression to AIDS (Winkler et al., 1998). This indicates
that variants at this IL site can inhibit or promote HIV/AIDS
disease.
Some exposed-uninfected individuals harbour identical mutations
on both chromosomal copies of CC-chemokine receptor 5 (CCR-5:
Hill and Littman, 1996; Samson et al., 1996). A frame shift mutation,
32-base-pair deletion, generates a non-functional receptor that
does not allow membrane fusion or infection by macrophage- and

Table 2.1. Host genes and susceptibility to HIV/AIDS
Disease Chromosome/system References
HIV/AIDS HLA-B*35 & Cw*04 Carrington et al., 1999
HLA-A29 & B22 MacDonald et al., 2000
IL10–5’A Winkler et al., 1998
HLA-B*5701 Migueles et al., 2000
HLA- B14 and C8 MacDonald et al., 2000
HLA-A2 MacDonald et al., 2000
HLA-DR1 class II MacDonald et al., 2000
CCR-5 Samson et al., 1996
Hill and Littman, 1996
CCR-2 Smith et al., 1997a; 1997b
Anzala et al., 1998
AIDS-related
non-Hodgkin’s
B cell lymphoma CCR-5 Rabkin et al., 1999
dual-tropic HIV-1 strains (Liu et al., 1996; Samson et al., 1996). The
individual is thereby protected because the protein product is not expressed
on the surface of the cell (Liu et al., 1996; Zimmerman et al.,
1997). Therefore, the virus does not have a receptor to attach to and
enter the cell.
The prevalence of heterozygotes for the CC-chemokine receptor
was lower in anHIV-infected sample compared to the uninfected population
(Hill and Littman, 1996; Samson et al., 1996). Heterozygous
individuals for the normal CCR5+ allele and the CCR5- 32 mutant
allele are not protected against HIV-1 infection although they
progress to AIDS more slowly –about two to four years on average
after HIV-1 seroconversion, relative to CCR5+/+ (homozygote) individuals
(Michael et al., 1997; Zimmerman et al., 1997). This indicates
that CCR5- 32 heterozygotes exhibit reduced viral loads in
vivo and impaired HIV-1 replication in vitro (Vlahov et al., 1991; de
Roda Husman et al., 1997; Bratt et al., 1998). The CCR5- 32/+
genotype also protects against AIDS-related non-Hodgkin’s B cell
lymphoma (Rabkin et al., 1999). So there is a possible partial protection
from infection among individuals with a single copy of the
mutant allele. However, both research groups showed that thoseheterozygous for the CCR5 mutation were susceptible to viral infection
although at reduced levels (Hill and Littman, 1996; Samson et
al., 1996).
The CCR2 gene is within 10 kilobases of CCR5 and the two genes
are in strong linkage dis-equilibrium (Smith et al., 1997a). Seroconverters
(those who test positive for HIV after exposure) with CCR2-64I,
a variant of CCR2, have significantly lower viral loads 9–12 months
after seroconversion (Kostrikis et al., 1998). Like the heterozygote,
CCR5- 32/+, individuals with two copies of CCR2-64I progress
to AIDS more slowly –tw o to four years later than progression observed
among individualswho are homozygous for the normal allele –
although they are still susceptible to infection (Smith et al., 1997a;
Anzala et al., 1998; Kostrikis et al., 1998).
There are statistically significant associations between HLA (the
histocompatibility system) class I homozygotes (HLA-A, HLA-B,
HLA-C: at one or more loci) and accelerated progression to AIDS.
Each locus of HLA Class I loci contribute independently to the association
with AIDS and the effect is greater in individuals homozygous
for two or three loci. Heterozygosity for HLA showed a graded protective
effect with greater protection with HLA-A, -B, and -C with
the least protection against disease progression to AIDS and death.
Heterozygotes at all loci showed the slowest progression (Carrington
et al., 1999). Also, heterozygous advantage suggests that those heterozygous
at the HLA loci present a greater variety of genetic variants
than homozygotes loci, resulting in a more effective immune reaction
to a greater variety of HIV pathogens (Doherty and Zinkernagel,
1975; Zinkernagel, 1996).
In a study of rapid progressors (i.e. those who develop AIDS in
the first two to three years following initial infection) and long-term
non-progressors (i.e. those who remain healthy for 15 or more years) a
variety of alleles were associated with both susceptibility and protection
(Hendel et al., 1999). For instance, HLA-A29 and B22were significantly
associated with rapid progression, B14 and C8 were strongly
associated with protection while B27, B57 and C14 were less strongly
associated with protection (MacDonald et al., 2000). Although HLA
class II associations are less evident in studies of HIV/AIDS (Hill,
2001), HLA-A2 was associated with resistance to disease progression

and, another variant, HLA-DR1 class II, was associated with resistance
to HIV infection among African individuals (MacDonald et al.,
2000).
There is other evidence ofHLAassociation with the rate of advance
of HIV infection. For instance, HLA-B*5701 is found in the majority
(11 of 13) of long-term non-progressors with low viral loads. Only
10% of controls (HIV-negative ‘Caucasians’ from the US population)
had this variant (Migueles et al., 2000). In North American AIDS
patients, HLA-DRB1*1501 is associated with increased rate of onset
of disseminated Mycobacterium avium complex disease (an environmentderived
disease (i.e. fromwater, food, animals) that unlike tuberculosis
is systemic and not limited to the lungs: LeBlanc et al., 2000). In a
larger study, haplotypes (combinations of alleles from closely linked
loci) of the HLA such as HLA-B*35 and Cw*04 were associated with
increased rate of progression from HIV-positivity to AIDS disease.
Homozygotes for B*35-Cw*04 haplotype progress to AIDS faster
than heterozygotes and B*35-Cw*04 heterozygotes progress more
rapidly than those without this haplotype (Carrington et al., 1999). A
common mechanism seems to underlie these diseases (Hill, 2001).
Variation in secretion of RANTES and MIP-1β show an inverse
correlation between these chemokines and rate of disease progression.
CD4+ lymphocytes from exposed uninfected individuals secrete
more RANTES than those infected with HIV-1 (Paxton et al., 1998).
A promoter region of RANTES composed of –403A/−28G is associated
with significantly slower rates of CD4+ lymphocyte depletion
relative to other genes (Liu et al., 1996). There is more RANTES secretion
in individuals with −403A/−28G haplotype III than those
without this haplotype. This explains the gene association with slower
CD4+ T cell depletion and protection of this genetic variant against
progression to AIDS (McDermott et al., 2000).
Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine
(secreted by T cells that mediate immune interaction) implicated in
the pathogenesis of auto-immune and infectious diseases (Brennan
and Feldmann, 1996). TNF-α and lymphotoxin (TNF-β) induce HIV
replication through activation of the transcription factor NF-kB (Duh
et al., 1989; Matsuyama et al., 1991). Elevated levels of TNF-α have
been reported in AIDS patients (Brinkman et al., 1997).

Properties discussed here, i.e. susceptibility and resistance, are likely
to be the product of evolutionary forces with natural selection being
the driving force behind these polymorphisms. Acting on variation
from high mutation rates and recombinogenic effects, the pathogen
evolves. As a species, Homo sapiens is also changing at the genetic level
in response to these infectious agents. It is the interaction between genetic
diversity of the host and pathogen that determines susceptibility
or protection from HIV infection and the rate of progression to AIDS.

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HIV 3

Genetic epidemiology
Genetic variability is found in most host–parasite associations (Borst, 1991; Antia et al., 1996) and this is a major reason for the re-emergence of infectious diseases (Ewald, 1993; Morse, 1995; Stephens et al.,
1998). The capacity for the genetic structure of the pathogen to change enables it to escape immunological protective mechanisms, creates functional diversity, and can change tissue or host tropism.
High mutation rates among pathogens also allow them to evade antimicrobial or antibiotic selective pressures. For instance, microbes may acquire an expanded host range through mutations (Stephens et al., 1998).
Genetic diversity
HIV has a high mutation rate (Dimmock and Primrose, 1987;
Dougherty and Temin, 1988; Saag et al., 1988; Nowak, 1990; Ho et al., 1995) but the mechanisms for producing HIV mutations are not completely understood. Reverse transcriptase, which copies the virus’ RNA strand into DNA, makes 1–10 errors on average during the replication of the HIV genome (Dougherty and Temin, 1988; Nowak, 1990). In other words, there is a nucelotide mistransmission
(such as substitution, addition and deletion) when reverse transcriptase composes proviralDNA. Other ways inwhich HIV genetic diversity is produced can involve any additional steps in the reproductive
cycle (Stine, 2000).
HIVhas a highmutation rate and small genome size (Temin, 1989). The genetic structure for HIV is LTR-gag-pol-vif-vpr-tat-rev-env-nef-LTR
(long terminal repeats: Greene, 1993; Stine, 2000; see Figure 2.2). Gag and pol genes are less variable than the env gene which has a high mutation
rate. Within the env gene there are five hyper-variable regions, V1 to V5. Changes of one amino acid in the V3 region alone can restrict recognition by neutralizing antibodies (Nowak, 1990; Shaper and Mullins, 1993).
Collections of genetically distinct HIV variants can evolve from the initial infection. Populations of these closely related genomes are called quasi-species (Shioda et al., 1991) that vary increasingly over time (Hahn et al., 1986) and are the products ofmutation and selection (Bonhoeffer et al., 1995). Different mutants within these quasi-species can exhibit very different biological properties such as cell tropisms (affinity), cytopathic properties, surface antigen traits, and replication

rates (Shioda et al., 1991). Quasi-species can also migrate into new cellular populations by acquiring mutations that facilitate adaptation (Doms and Moore, 1997).
The genetic diversity of the HIV virus results in drug resistance, evasion from immune responses and makes the development of a vaccine challenging (Bonhoeffer et al., 1995;Korber et al., 1998). HIV mutants can evade the immune response and thrive (Stine, 2000). As
such the immune response is a major force in positive selection pressure generating genetic diversity (Nowak, 1990). The high mutation
rate also results in the production of viral strands that are not susceptible to drug therapy. This process explains why single drug therapies such as AZT tend to be only temporarily efficacious (Greene, 1993; Korber et al., 1998) and why some HIV strains are not reliably detected by all antibody screening tests currently in use (Loussert-Ajaka et al., 1994; Schable et al., 1994). In addition, since HIV is diploid (carries 2 RNA molecules) there can be genetic recombination (exchange of parts) between these strands and other strands in the area (Levy, 1988; Stine, 2000).Recombination in HIV is facilitated by co-infection with different strains orsubtypes of HIV or in cells with different susceptibilities for various subtypes, and by geographic intermixing of subtypes (Laurence, 1997). Recombination is probably involved in genetic diversity and selection pressures at every level although it is only detected when distinct strains are present, for example two distinct strains in the same person (Korber et al., 1998).
Both mutation and recombination produce genetic diversity in HIV and other infectious diseases. Mutation can cause pathogens to acquire new tissue tropisms, change their virulence and mode of transmission and cause a shift from endemic to epidemic. Genetic diversity provides variation upon which natural selection can act. As such, high mutation rates accelerate evolutionary change.
Variation in the rate of HIV evolution may be determined by differences in host-mediated selection pressures (Nowak, 1995; Wolinsky et al., 1996). For instance, upon infection the individual has a homogeneous viral population (Bonhoeffer et al., 1995; Nowak, 1995; Wolinsky et al., 1996). Stable viral population equilibrium is found when the initial viral strain is relatively fit and replicating in a relatively constant environment. In this environment a particular genetic variant, regardless of it pathogenic ability, would be preferentially increased (Wolinsky et al., 1996). Early in the infection the immune response reacts quickly and strongly against common viral variants (Boyd et al., 1993). As HIV infects different cells and tissues, rare mutants escape surveillance and increase in frequency (Wolinsky et al.,
1996). This provides strong selection pressure for HIV viral diversification (Saag, 1988; Boyd et al., 1993; Bonhoeffer et al., 1995). After the virus generates many variants with specific cell tropisms there is a decline in the immune response, and selection pressures are weaker (Boyd et al., 1993; Bonhoeffer et al., 1995). Individuals who have progressed to AIDS usually have a more homogeneous viral population. Slow evolution may represent the apparent predominance of an optimally adapted variant (Wolinsky et al., 1996).

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HIV 2

The human immune system and HIV Specific immune responses, antibodies such as IgG, IgA and IgM,
fight viral or intracellular bacterial organisms before they attach to host cells (Yang and Hill, 1996). Killer T cells (cytotoxic T lymphocytes/CD8+), along with the major histocompatibility complex Class I antigen, kill host cells that display foreign characteristics (i.e. antigenic
characteristics) on their surface.Tcells and macrophages augment the ‘killer T cells’ by producing cytokines (secreted by T and B cells and monocytes, which act as messengers in the immune system) such as IL-2, gamma-interferon (IFN-gamma) and IL-12. After the virus enters the cell, specific lymphocyte-mediated cellular immunity induces cytokines that restrain viral replication or evoke cellular cytotoxicity
against virus-infected cells (Proffitt and Yen-Lieberman, 1993; Yang and Hill, 1996). Most microbial infections can be eliminated through this process within 10 days to 2 weeks (Yang and Hill, 1996).

HIV-1 mainly targets CD4+ T lymphocytes (white blood cells that recognize and remember foreign antigens) and CD4+ cells of monocyte/ macrophage lineage which search and destroy foreign agents (Dimmock and Primrose, 1987; Connor and Ho, 1994). T4 cells may be lost through HIV infection by a number of processes. For instance, defects in T4 cells caused by HIV infection may produce activation-induced cell death or normal cell death (apoptosis; Pantaleo
et al., 1993). HIV may also trick the immune system into attacking itself (Kion and Hoffmann, 1991). For instance, syncytia formation involves the massing of healthy T cells around a single-HIV infected T4 cell that results in loss of immune function (Gelderbloom et al., 1985; Hoxie et al., 1986; Sodroski et al., 1986; Stine, 2000). Also, death of
cells could be due to direct membrane disruption involving calcium channels (Gupta and Vayuvegula, 1987) and/or phospholipid synthesis (Lynn et al., 1988). A build-up of un-integrated proviral copies of HIV DNA may cause cytopathology since it is associated with
cell death in other retroviral systems (Levy, 1988). However, it is believed that depletion of T4 cells is insufficient to cause AIDS because not enough T4 cells are destroyed. Equally important may be T4 cell infection of monocytes and macrophages that engulf and destroy antigens (Bakker et al., 1992).
HIV usually puts a portion of its virus on the surface of the cell that it infects. Killer cells, cytotoxic T lymphocytes (CTL), search out and destroy infected cells. But HIV escapes detection by CTLs because Nef, an HIV gene, makes infected cells difficult to identify (Cohen,
1997). There is also a temporal change in viral tropism (affinity) during the course of HIV infection. Early in infection, HIV strains with an affinity for macrophages (macrophage tropic (M-tropic) viruses) have the ability to infect macrophages and are non-syncytium inducing
(NSI) due to their inability to form syncytia on T-cell lines
(Fenyo et al., 1988; Schuitemaker et al., 1992; Connor et al., 1993; Zhu et al., 1993). Usually about four to five years after infection, virus strains evolve in some individuals (about 50%) that can infect T-cell lines in addition to primary T cells (Tersmette et al., 1989; Shioda et al., 1991; Milich et al., 1993). In this change in tropism the viral strains sometimes lose their ability to infect macrophages but more often they retain this property and are referred to as ‘dual tropic’ (Collman et al., 1992). HIV strains that can infect T-cell

lines are referred to as T-tropic, syncytium-inducing (SI). Strains that can grow on transformed cell lines by continual passage are called T-cell line adapted (TCLA: Doms and Moore, 1997). Others display tropism differently with macrophages being infected efficiently and T cell lines less efficiently (Moore and Ho, 1995; Sullivan et al., 1995; Fenyo et al., 1997). This switch may be related to the colonization
of different types of cells by HIV variant strains or a product of natural/host selection in which certain HIV strains (and
their phenotypes) are selected for and escape the immune response (Weiss, 1996).
CD4 receptors alone are sufficient for binding HIV to T4 lymphocyte membranes but co-receptors are required to mediate entry of HIV-1 into cells (see Figure 2.1). The best known HIV co-receptors are CXCR4 and CCR5 members of the CXC and CC chemokine (also called cytokine) receptor subfamilies, respectively (Dragic et al., 1996; Doms and Moore, 1997; Fenyo et al., 1997). CCR5 is the primary
co-receptor for HIV-1 isolates with the NSI phenotype (Deng
et al., 1996; Dragic et al., 1996; Fenyo et al., 1997) while SI phenotypes are associated with the use of CXCR4 alone or in conjunction with
CCR5 (Simmons et al., 1996; Zhang et al., 1996; Fenyo et al., 1997).
Studies show that in the presence of CD4 and the appropriate coreceptor both SI and NSI strains can induce syncytium formation.
Therefore the terms SI and NSI are not absolute but are related to co-receptor expression levels on target cells (Deng et al., 1996; Fenyo et al., 1997).
CD8 T lymphocytes partly control HIV infection by the release of HIV-suppressive factors, beta chemokines that are active on monocytes and lymphocytes. Beta-chemokines MIP-1α, MIP-1β and RANTES are most active against HIV-1 in combination and
inhibit infection of CD4+ T cells by primary, NSI HIV-strains at the virus entry stage. But TCLA/SI HIV-1 strains are insensitive to beta-chemokines. Therefore some CD4+T-helper cells from HIV-1 exposed uninfected individuals resist infection with NSI strains (by secreting high levels of beta-chemokines) but are infected by TCLA/SI strains. It is unknown if high levels of these chemokines can delay HIV disease progression (Cocchi et al., 1995).

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The Human Immunodeficiency Virus (HIV)

The human immunodeficiency virus (HIV)

The HIV virus is roughly spherical and about one ten-thousandth of a millimetre across. Its outer envelope or coat is composed of a double layer of lipid envelope that bears numerous spikes (see Figure 2.1).

Each spike is composed of four molecules of ‘gp120’ and the same number of ‘gp41’ embedded in the membrane. Beneath the envelope is a layer ofmatrix protein that surrounds the core (capsid).The capsid has a hollow, truncated cone shape and is composed of another protein ‘p24’ within which lies the genetic material of the HIV virus –two strands of RNA consisting of about 9 749 nucleotide bases, integrase,

a protease, ribonuclease and two other proteins, ‘p6’ and ‘p7’ fit inside the viral core (Fauci, 1988; Greene, 1993; Stine, 2000).

HIV reverses the usual direction of genetic information within the host cell to produce protein.The process of protein synthesis in regular gene expression results from theDNA being copied intoRNA and the RNA is translated into specific proteins. With retroviruses like HIV, the RNA is copied using its reverse transcriptase (RT) enzyme. In the cytoplasm RT migrates along the RNA to produce a complementary strand of DNA. After completion of the first DNA strand the RT

begins constructing a second strand, using the first one as a template (Dimmock and Primrose, 1987; Fauci, 1988; Greene, 1993; Stine, 2000).

The double-stranded retroviral HIV DNA moves into the nucleus where it inserts into the host DNA and becomes a ‘provirus’. Infection of the cell is then permanent. The provirus can remain dormant for a long time. Its genes cannot be expressed until RNA copies are made by the host cell’s transcription machinery. Transcription starts when genetic switches at the ends of the provirus’ long terminal repeats

activate the cell’s RNA polymerase II. Regulatory proteins known as NF-kB/Rel (which are found in almost all human cells) bind with the long terminal repeats at the ends of the proviral RNA to activate the cell’s RNA polymerase and thereby cause transcription of the provirus to RNA (Greene, 1993). Some long terminal repeats possess regulatory genes (genes that control structural genes which produce

proteins) that contain a sequence for NF-kB and Sp1 binding sites that are shared by cellular regulator genes. Sequences recognised by NF-kB promote replication of HIV, cytomegalovirus, human Igk chain, and major histocompatibility antigen complex (MHC) classes

I and II, interleukin 1 (IL-1), and IL-2 (Chang, 1991). NF-kB/Rel regulatory proteins increase in production when the cell is exposed to foreign proteins or through hormones that control the immune system (Dimmock and Primrose, 1987; Fauci, 1988; Greene,1993; Stine, 2000). In essence, HIV uses our own biological machinery, NF-kB/Rel, to replicate itself and this co-option of human physiology  is initiated by foreign substances such as HIV infection.

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