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HIV Pathogenesis: Knowledge Gained after Two Decades of Research

J.A. Levy
Adv. Dent. Res. 2006; 19; 10
DOI: 10.1177/154407370601900104

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 HIV Pathogenesis: Knowledge Gained
after Two Decades of Research
J.A. Levy
Director, Laboratory for Tumor and AIDS Research, University of
California, San Francisco, 513 Parnassus Avenue, Suite S1280, San
Francisco, CA 94143-1270, USA; jalevy@itsa.ucsf.edu
Adv Dent Res 19:10-16, April, 2006
G
reat progress has been made in our understanding of
HIV since its initial discovery about 20 years ago.
The ability of HIV to infect CD4+ lymphocytes and a
wide variety of other cells in the body is appreciated,
as is its role in immunologic, gastrointestinal, and brain
disorders. HIV enters cells via the CD4 molecule, chemokine
co-receptors (CXCR4, CCR5), and other cell-surface proteins.
Several accessory virus-associated genes (e.g., Rev, Tat, Nef)
have uncovered unique pathways that can also be observed in
normal cells. Recently, the discovery of natural cellular
resistant factors (APOBEC3G and TRIM5a) has provided
avenues for novel antiviral therapies. Studies of long-term
survivors have given insight into immune responses that
control HIV and can prevent infection. Neutralizing antibodies
and CD8+ cell cytotoxic responses, as well as plasmacytoid
dendritic cells and CD8+ cell non-cytotoxic antiviral responses,
are adaptive and innate immune activities mediating this anti-
HIV effect. HIV vaccine studies have indicated that
conventional approaches do not work against this integrated
intracellular parasite. While much has been learned about HIV,
more details are needed about its infection cycle and its
pathologic effects in the body. The past 20 years have yielded
important information on HIV/AIDS that should lead to
effective anti-HIV therapies and a vaccine.
Introduction
When the acquired immune deficiency syndrome (AIDS) first
appeared in San Francisco, it was initially described in
homosexual men and was called the 'gay-related immune
deficiency syndrome' (GRID). In 1981, it was more appropriately
re-named AIDS, and the San Francisco Chronicle newspaper
published a description of the 'seven deadly symptoms'
associated with the disease: a fever persisting for more than 4 or
5 days; unexplained weight loss of 10 to 20 pounds in a few
months; general aches and pains similar to an acute viral
syndrome for more than 10 days; sore or swollen lymph glands
for more than a week; appearance of blue or purplish spots on
the skin (now recognized as Kaposi's sarcoma); herpes sores that
worsen and persist for more than 5 weeks; and loss of sensory or
motor ability or defects in mental or neurological function. These
clinical features remain today as characteristics of HIV infection.
The confusion that emerged in San Francisco about the
cause of AIDS evolved around whether it was a new agent or a
variant of a previously known one (e.g., hepatitis B virus,
cytomegalovirus, or Epstein-Barr virus). Alternatively, some
considered the possibility that AIDS was caused not by an
infectious agent but by an overdose of drugs or stress to the
immune system. For infectious disease clinicians, the challenge
was to identify the causative microbial agent.
Discovery of HIV
Within 2 years after AIDS was defined, a virus was recovered
from a person with the lymphadenopathy syndrome which
10
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many considered a pre-condition of AIDS. The virus, isolated
by Françoise Barré-Sinoussi et al. (1983), had the unusual
characteristic of infecting peripheral blood mononuclear cells
(PBMC) and causing cytopathic effects within 6 or 7 days.
Examined by electron microscopy, it had the morphology of a
budding retrovirus, later recognized as a lentivirus (Gonda et
al., 1985). This virus was unlike the human T-cell leukemia
virus (HTLV), a previously described human retrovirus that
can cause leukemia (Poiesz et al., 1980). This lympha-
denopathy-associated virus (LAV) did not establish a
transformed state in CD4+ cells, but caused cell death after
high-level replication (Barré-Sinoussi et al., 1983).
After this description of LAV by Luc Montagnier's
laboratory (Barré-Sinoussi et al., 1983), two other groups
reported the isolation of retroviruses from AIDS patients. The
first described a virus which they called HTLV III, because they
believed it to be part of the HTLV family of oncogenic
retroviruses (Gallo et al., 1984), and the second, working with
subjects from San Francisco, noted the presence of retroviruses
with characteristics of cytopathic agents such as LAV (Levy et
al., 1984) (Fig. 1). Thus, it was concluded that they could not be
transforming viruses like HTLV and were called AIDS-
associated retroviruses (ARV) (Levy et al., 1984). With time, the
retroviruses isolated by all three research groups were found to
have similar features, although being somewhat distinct—a
characteristic now further appreciated through other research
findings (Levy, 1998). These viruses were renamed the human
immunodeficiency virus (HIV) (Coffin et al., 1986). Shortly
after the identification of HIV, another human retrovirus was
recovered from West African patients with AIDS (Clavel et al.,
1986). It was noted to be sufficiently different genetically from
HIV-1 (by up to 40%) and was named HIV-2.
Cloning and sequencing of HIV
After the isolation of ARV, its molecular cloning was
accomplished (Luciw et al., 1984), followed by sequencing of
the ARV-2 isolate (Sanchez-Pescador et al., 1985). HIV was then
found by several groups to consist of 9 separate genes coding
for 3 structural (Gag, polymerase, Env) and 6 accessory
proteins (Vif, Vpr, Vpu, Rev, Tat, Nef). Similar to other
retroviruses, HIV had a long-terminal repeat (LTR), which
served as the promoter region for transcription of the virus.
The overall structure of the virion with its various components
was defined, and the envelope gp120 and gp41 were found in
knobs projecting from the outside lipid coat. The inner core, a
p24 Gag protein, was described along with the Gag matrix
protein (MA) that helps to maintain the structure of the virion
(Levy, 1998).
The HIV accessory proteins have been very helpful in
revealing functions of not only HIV-1 proteins, but also
biologic activities associated with normal cellular proteins
(Table 1). These accessory proteins define the complex nature
of this lentivirus and offer an understanding of how HIV has
Key Words
HIV, pathogensis, immune response, CD4+ cells, therapy.
Presented at the Fifth World Workshop on Oral Health and Disease
in AIDS, Phuket, Thailand, July 6-9, 2004, sponsored by Prince of
Songkla University, Thailand, the International Association for Dental
Research, the World Health Organization, the NIDCR/National
Institutes of Health, USA, and the University of California-San
Francisco Oral AIDS Center.
Levy
Adv Dent Res 19:10-16, April, 2006
Fig. 1 - Cytopathic changes induced in peripheral blood mononuclear cells by
ARV-2, an early HIV-1 isolate.
evolved ways to infect a variety of different cell types, to
mutate (because of the high error rate of its reverse
transcriptase), and to maintain itself within the infected host
through virus integration and latency (Levy, 1998).
Detection assays for HIV
With the recognition of AIDS, various assays for detection of
HIV needed to be developed (Table 2). Reverse transcriptase
was used for determining the virus' presence in cell culture
(Hoffman et al., 1985), and immunofluorescence assays
(Kaminsky et al., 1985), ELISAs, and the Western blot helped
detect antibodies to HIV (Levy et al., 1984; Levy, 1998). These
tests all formed the basis for confirmatory assays for HIV
infection. Subsequently, based on the polymerase chain-
reaction (PCR), viral RNA levels in the blood could be
determined and measured through RT-PCR procedures (Piatak
et al., 1993). This approach has been particularly useful in
monitoring the effect of antiviral treatment in HIV-infected
individuals (see below).
The effect of HIV on the immune system was greatly helped
by the development of flow cytometry in the 1970s (Cantor et al.,
1975). This technology enabled clinical and research laboratories,
via selective monoclonal antibodies, to determine the number of
CD4+ and CD8+ cells in people. While the CD4+/CD8+ cell
ratio is usually 2:1, it was very soon recognized that the ratio in
infected individuals often was reduced to less than 1 (Gottlieb et
al., 1981; Mildvan et al., 1982). The number of CD4+ cells, usually
in the range of 600 to 1200 cells/␮L, became reduced over time,
particularly in progressors, to the low hundreds (e.g., < 300
cells/␮L). These findings supported the observation that the
CD4+ lymphocyte was a major target for HIV replication and
cell death (Klatzmann et al., 1984a). Shortly thereafter, the
receptor on CD4+ cells was found to be the major attachment
site for the virion (Klatzmann et al., 1984b).
HIV heterogeneity
Despite the great progress made in understanding HIV/AIDS
TABLE 1 - HIV Accessory Proteins and Their Functions
Protein Size (kDA) Function
Tat p14 Transcriptional activator
Rev p19 Regulation of viral mRNA expression
Nef p27 Pleiotropic, can increase or sometimes decrease
virus replication
Vif p23 Increases virus infectivity and cell-to-cell transmission
Vpr p15 Helps in virus replication; transactivation
Vpu p16 Helps in virus release
Vpx p15 Helps in virus infectivity
Adv Dent Res 19:10-16, April, 2006 Twenty Years of HIV Research
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Fig. 2 - Virus-infected cells in seminal fluid as detected by in situ hybridization.
From Levy (1988); reprinted with permission.
in the early 1980s, some observations challenged certain
findings at the time: All CD4+ cells were not susceptible to the
virus, and CD4-negative cells could be infected by HIV. These
findings led groups to recognize that galactosylceramide (Gal-
C) could be another receptor for HIV, particularly in brain and
bowel cells (Harouse et al., 1989; Fantini et al., 1993).
Importantly, the virus itself was noted to have two major
differences in its replicative ability in host cells. While all HIV
isolates grew well in most primary CD4+ cells, some isolates
grew very well in primary macrophages, whereas others
productively infected established CD4+ T-cell lines (Cheng-
Mayer et al., 1988a). These cellular host range differences
defined two biologic phenotypes. The macrophage-tropic
viruses were found not to induce multi-nucleated syncytia in
T-cell lines (e.g., MT-2), whereas the T-cell-line tropic viruses
did. They subsequently became known biologically as non-
syncytia-inducing (NSI) and syncytia-inducing (SI) viruses
(Fenyo et al., 1988; Tersmette et al., 1988).
The reason for these host range differences was
appreciated much later, when it was recognized that these
viruses used different chemokine co-receptors for entry into
target cells (Berger et al., 1999). After attachment to CD4 on
CD4+ cells, further binding occurred via the viral envelope V3
loop to a chemokine co-receptor, and then entry took place.
The NSI virus used the CCR5 chemokine receptor (R5 isolates),
whereas the SI virus used the CXCR4 receptor (X4 isolates).
The processes leading to viral entry are still not fully defined.
For example, after virus attachment, fusion takes place but the
fusion receptor on the cell has not been defined. We also do not
know how the viral capsid enters the cells. Conceivably,
separate biologic events are involved in these events (Levy,
1996).
HIV transmission and cellular host range
An important consideration in understanding HIV transmission
was the role of the virus-infected cell in transmitting HIV not
only to immune cells but also to macrophages and mucosal-
lining cells (Levy, 1988). These infected cells (lymphocytes and
macrophages) are found in genital fluids (Fig. 2). Several
TABLE 2 - Assays for Detection of HIV Infection
Reverse transcriptase activity
Immunofluorescence (IFA)
ELISA
Western blot
PCR
11
Fig. 3 - Virus-infected cells detected by in situ hybridization in mucosal lining
cells of the bowel. From Nelson et al. (1988); reprinted with permission.

electron microscopy studies have shown that, whereas HIV Fig. 4 - Differences in replication of HIV-1 recovered from an individual early in
infection (●● ) and later, when he had progressed to disease (▲ ▲ ) (Cheng-Mayer
alone may not directly infect cultured cervical-lining cells or et al., 1988b). Note that the early virus replicates at low titer, and peaks after
mucosal cells from the bowel, infected T-cells and macrophages a longer period of time than the faster-replicating virus, recovered later at the
can efficiently deliver virus to these infected cells (Phillips, time of disease.
1994). Time-lapse photography has shown that the infected cells,
remaining viable, can move from one mucosal-lining cell to the
other, delivering virus, and thus emphasizing this important
means of transmission. Infection of the bowel mucosae through virus expression in the lymphoid tissues (Pantaleo et al., 1993).
HIV-infected cells in genital fluid could account for the infected
HIV replication and latency
cells noted in mucosal-lining cells of the bowel (Fig. 3) as well as
the cervix (Nelson et al., 1988; Levy, 1998). Observations in many laboratories defined the nature of the
Other work in this field during the late 1980s and early HIV replicative cycle, which involved reverse transcription,
1990s indicated the wide cellular host range of HIV, infecting integration, and proteolytic activities of the three enzymes
several cell types of the brain, as well as the bowel, heart, encoded by the virus. The HIV reverse transcriptase, integrase,
kidney, liver, testes, prostate, and other organs (Table 3) (Levy, and protease have become targets for antiviral therapies. With
1998). Virus replication in the lymphoid tissues mirrors the these observations in HIV replication came the recognition that
progression of HIV infection in individuals—destruction of the this retrovirus, as had been seen with other retroviruses, can
germinal centers in the lymph node, accompanied by increased infect and replicate to very low levels or remain latent (Table
4). The mechanism for this latency, or 'silent virus' state, has
not been elucidated but could be related to DNA methylation
TABLE 3 - Human Cells Susceptible to HIV or direct activity of the host cellular products on the integrated
Hematopoietic Bowel
HIV genome (Levy, 1998).
These differences in virus replication also indicated that an
T-lymphocytes Fetal adrenal cells HIV isolated early in the infection, when the infected
B-lymphocytes Columnar and goblet cells individual was asymptomatic, replicated more slowly and to a
Macrophages Enterochromaffin cells lower level than the virus recovered later, when the individual
NK cells Colon carcinoma cells progressed to disease (Asjo et al., 1986; Cheng-Mayer et al.,
Megakaryocytes
Dendritic cells Other 1988a) (Fig. 4). These biologic features emphasized what we
Promyelocytes now recognize as a change from the R5 NSI type virus to an X4
Stem cells Myocardium SI virus, which is associated with increased destruction of
Thymic epithelium Renal tubular cells CD4+ lymphocyes. Essentially, the replicative cycle, which can
Follicular dendritic cells Synovial membrane lead to the emergence of up to 10 mutations per replication
Bone marrow endothelial cells Hepatocytes
cycle, can give rise to highly cytopathic strains and viruses that
Hepatic sinusoid endothelium
Skin Hepatic carcinoma cells can infect other tissues, such as the brain, the bowel, and the
Kupffer cells kidney (Levy, 1998).
Langerhans cells Pulmonary fibroblasts
Fibroblasts Adrenal carcinoma cells
Retinal cells Host Immune Responses to HIV
Brain Cervix-derived epithelial cells What can the infected individual do to control this HIV
Cervix
infection? Now that viral RNA levels in the blood can be
Capillary endothelial cells Prostate
Astocytes Testes
Macrophages (microglia) Osteosarcoma cells TABLE 4 - Retrovirus Latency and Persistence
Oligodendrocytes Rhabdomyosarcoma cells
Choroid plexus ganglia cells Fetal chorionic villi • Cellular - lack of viral RNA and protein expression after integration
Neuroblastoma cells Trophoblast cells • Clinical - interval between infection and onset of symptoms
Glioma cell lines (Neurons) • Abortive infection - lack of virus integration (e.g., resting cell)
Dental pulp fibroblasts • Low persistent infection - only low levels of virus production are
detected. Often, co-cultivation with other target cells is needed to
Adapted from Levy, 1998. demonstrate virus replication.

12 Levy
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Adv Dent Res 19:10-16, April, 2006
 TABLE 6 - Autoantibodies Detected in HIV Infection
TABLE 5 - Neutralization Subtypes of HIV
Antibodies to: Associated Clinical Condition:

Proposed Serum Lymphocytes Loss of CD4+ CD8+ B-lymphocytes

Subtype HIVSF Source 1 2 3 Platelets Thrombocytopenia
Neutrophils Neutropenia
A 2 PBMC (SFa, 1983) > 1000 100 10 Red blood cells Anemia
4 PBMC (SF, 1984) > 1000 100 100 Nerves (Myelin) Peripheral neuropathy
13 PBMC (SF, 1984) > 1000 100 10 Nuclear protein (ANA) Autoimmune symptoms
33 PBMC (Ph, 1984) > 1000 100 10 Thyroglobulin Thyroid disease

B 97 PBMC (SF, 1985) 80 20 -

171 PBMC (Af, 1985) 20 10 -
C 98 CNS (SF, 1985) 20 - -
128A CNS (SF, 1985) 20 - -
161B CNS (SF, 1985) 100 - -
162 CNS (SF, 1985) 100 - -
D 170 PBMC (Af, 1985) - - - As an infected individual advanced to disease, the
a SF, San Francisco; Ph, Philadelphia; Af, Africa. From Cheng-Mayer et al., 1998b
(reprinted with permission).
measured by PCR techniques, the observation was made that,
within 8 to 12 weeks after infection, HIV reaches levels as high
as several million RNA molecules/mL, and then is reduced to
much lower levels (5000 to 15,000 molecules/mL), or even to
an undetectable level. The lower the viral set point, the better
the long-term prognosis for the infected person (Mellors et al.,
1996). These observations led to the suggestion that some
immune responses were controlling the infection, at least for
this period of time.
Anti-HIV neutralizing antibodies
One of the first anti-HIV immunologic responses recognized
was the presence of neutralizing antibodies that, initially,
seemed to be able to inactivate several HIV strains (Robert-
Guroff et al., 1985; Javaherian et al., 1990). Based on serum from
three different individuals, our laboratory suggested a
potential classification of HIV according to their sensitivity to
neutralization by three different sera (Cheng-Mayer et al.,
1988b): Some viruses were very sensitive (A), some moderately
sensitive (B), and some completely resistant to neutralization
(D) (e.g., SF170) (Table 5). Subsequent work has shown that this
virus neutralization is rarely broad enough to handle the
variety of different envelope antigens present in different virus
isolates. That challenge faces us with vaccine development.
During the evaluation of virus neutralization, Jacques
Homsy, in my group, noted that antibodies from some sera
enhanced virus replication through interaction with the Fc
receptor (Homsy et al., 1989). Essentially, when followed over
time, healthy individuals showed antibody neutralization of
the virus strain obtained at the time of the serum sample. As
that person advanced to disease, however, the serum obtained
from that individual enhanced, by up to 300%, the HIV
recovered at that same time (Homsy et al., 1990). This antibody-
mediated enhancement thus appeared to be a detrimental
effect of the humoral response. Similar observations have been
made with complement-mediated antibody enhancement of
HIV infection (Robinson et al., 1990).
Other harmful effects of antibodies, not currently given
enough attention, are auto-antibodies circulating in the blood
of individuals with HIV infection (Table 6). These auto-
TABLE 7 - Mechanisms for CD4+ Cell Loss
Direct infection by HIV
Chronic immune activation: apoptosis
ADCC killing of CD4+ cells carrying gp120
CTL activity against normal CD4+ cells
Bone marrow toxicity: lack of lymphocyte regeneration
antibodies can lead to several clinical conditions involving the
loss of certain peripheral blood cells (e.g., neutropenia,
thrombopenia) and to neuropathies (Levy, 1998).
Cellular immunity
predominant immune response went from type 1 (cell-
mediated immunity) to type 2 (antibody production) (Clerici
and Shearer, 1993). While these observations have not been
noted consistently in all studies, they form a framework by
which clinicians and researchers can begin to evaluate whether
the presence of a type-1- or type-2-dominant response is found
in healthy individuals compared with those advancing to
disease. It would appear that a type-1 response (i.e., cellular
immunity) is most beneficial in HIV infection.
In studies of clinically healthy infected men in the early
1980s, a new mechanism for CD8+ cell control of HIV infection
was discovered: suppression of virus replication without
killing the infected cell (Walker et al., 1986). This CD8+ cell
non-cytotoxic antiviral response (CNAR) was the first cellular
immune response against HIV described, and it was associated
with a clinically healthy state. CNAR appears to be mediated
by a novel soluble protein, the CD8+ cell anti-HIV factor (CAF)
(Walker and Levy, 1989), that has not yet been identified.
Subsequently, classic adaptive cytotoxic T-cell anti-HIV
responses were noted in infected individuals (Plata et al., 1987).
Thus, in HIV infection, two functions of the CD8+ cell antiviral
response can be found: the conventional cytotoxic response
and a novel non-cytotoxic suppression that had not previously
been recognized in any microbial infections.
CD4+ Cell Loss
The mechanism for CD4+ cell loss still is not explained.
Various reasons have been presented (Table 7). The most likely
cause for the greatest reduction in these cells is activation-
induced cell death by apoptosis (Ameisen, 1992). This
programmed cell death occurs following HIV infection of
macrophages or CD4+ cells, with the production of various
cytokines that can induce this normal mechanism for cell
death.
Long-term survivors
Long-term survivors (LTS), who have been infected for 10
years or more with normal CD4+ cell counts and are clinically
healthy without treatment, have certain characteristics
reflecting a beneficial anti-HIV immune response (Table 8): the
presence of neutralizing antibodies and a lack of enhancing
antibodies; the presence of anti-HIV CTL and certain innate
immune responses, such as CNAR; and high levels of
TABLE 8 - Characteristics of Long-term Survivors
Ongoing infection by an NSI (R5) virus
Lack of enhancing antibodies
Presence of anti-HIV CTL
Presence of innate immune responses
- CD8+ cell non-cytotoxic antiviral response
- High levels of plasmacytoid dendritic cells

Adv Dent Res 19:10-16, April, 2006 Twenty Years of HIV Research
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13
TABLE 9 - Natural Cellular Resistance to HIV Replication TABLE 10 - Future Directions

Cellular Protein Mechanism of Action • Understanding HIV latency

• Recognizing the emergence of recombinant viruses
APOBEC-3G Cytosine deaminase • Targeting the virus-infected cell
TRIM5␣ (LV-1) Blocks HIV capsid uncoating (?) • Appreciating the role of innate immunity
Ref-1 Blocks reverse transcription, ? related to TRIM5␣ • Instituting immune-based therapies
Murr-1 Inhibits degradation of I␬B␣ • Developing an effective vaccine
Unknown Inhibits virus assembly, countered by Vpu

approaches to anti-HIV therapies. These cell resistances are

interferon-producing cells or plasmacytoid dendritic cells recognized because they are sometimes countered by HIV
(PDC) (Levy, 1993; Levy et al., 1996; Soumelis et al., 2001). These proteins. For example, APOBEC-3G, a cytosine deaminase that
latter innate responses, not previously given much attention in creates mutations in the HIV genome at the DNA template level,
HIV infection, can influence the disease course (Levy, 2001). is countered by the Vif protein, which prevents the APOBEC-3G
Obviously, the host immune response is a major determinant in protein from functioning in the infected cell (Sheehy et al., 2002;
the course of HIV infection. Mangeat et al., 2003). Restriction of HIV in monkey cells has
been shown to be related to the presence of a cellular protein,
TRIM5␣, that appears to limit the opening of the HIV capsid
Antiviral Therapy within the cell (Stremlau et al., 2004). A gene product Murr-1
The fact that we can measure HIV RNA levels in the blood inhibits degradation of I␬B␣ and therefore can play a role in
permits us to evaluate treatments that could directly attack the creating and/or maintaining latency within the cell (Ganesh et
virus and reduce its ability to replicate in the host. These viral al., 2003). Finally, still to be identified is a human cellular
dynamics were used to examine, initially, mono-therapy and, restriction factor for HIV particle production that is counteracted
later, combined therapy, now known as highly active anti- by Vpu (Varthakavi et al., 2003).
retroviral therapy (HAART), which is generally given as a
three-drug combination. Over 20 anti-HIV drugs are now
available for treatment (Fauci, 2003). Future Directions
Some novel therapies under consideration include the use While HAART has, for many years, facilitated the control of
of RNA interference, which targets specific viral genes HIV infection in individuals who are suffering from disease
(Lieberman et al., 2003), and drugs that block virus interaction and even AIDS, the long-term control of this virus will require
with the chemokine co-receptors (Trkola et al., 2002) or fusion new directions (Table 10). Besides consideration of latent
at entry into cells (e.g., Fuzeon) (Cammack, 2001). infections, the emergence of recombinant viruses may
challenge therapies, if strains resistant to immune responses or
Natural cellular resistance HAART evolve (Thomson et al., 2002). The virus-infected cell
A major potentially beneficial observation made over the last remains a mechanism for HIV transfer, since anti-retroviral
two years is the presence within cells of natural mechanisms for drugs do not directly eliminate this source of the virus.
limiting HIV replication (Table 9). These findings offer novel Further work should be done toward boosting the
immune response via both the
adaptive and the innate immune
TABLE 11 - Constantly Changing Concepts systems and, of course, the
development of an effective
Initial Conclusion New Observation
vaccine. Innate immune
AIDS is caused by one virus. HIV-1 and HIV-2 lentiviruses and quasi-species are discovered. responses are particularly
important at mucosal sites of HIV
HIV infects only CD4+ lymphocytes. HIV infects a wide range of cells in the body. transmission (Levy, 2001). One
emphasis for future therapies is
HIV uses CD4 as its cell-surface receptor. Other receptors, including the chemokine co-receptors, have to restore the immune system to
been recognized.
that of long-term survivors who
HIV is a conventional retrovirus. HIV has accessory genes with pleiotropic activities. can control HIV infection. This
approach would include a variety
HIV remains stable after infection. HIV, by replicating in the host, can mutate and become of cytokines, including IL-2, IL-
more virulent over time. 15, IFN-alpha, IL-7, and, when
fully identified, CAF. In vaccine
Loss of CD4+ cells is by direct HIV killing. Other processes, particularly chronic immune activation and
apoptosis, appear to be primarily involved. development, these same
cytokines can act as beneficial
HIV/AIDS has no survivors. Long-term survivors have been identified who have been adjuvants along with CpG
infected for more than 25 years. (Dumais et al., 2002), G-CSF, and
Flt-3 (Pulendran et al., 2000) that
Classic adaptive immune responses HIV can escape neutralizing antibodies, can take advantage
can protect against AIDS. of enhancing antibodies, can escape CTL activity.
help elicit innate immune
responses.
Adaptive immune responses Innate immune response may be very important.
are needed for HIV control.
Constantly Changing
Superinfection cannot take place Individuals can be infected following an initial HIV trans- Concepts
if host immune response is effective. mission. Superinfection is common in other viral infections. In the past 20 years, the
identification of AIDS and the
All HIV-exposed individuals become infected. Certain highly exposed individuals are protected from characterization of its causative
infection (e.g., ⌬CCR5; mucosal IgA; CTL; innate immunity).
agent, HIV, have been progressing
An AIDS vaccine will become available Science has never been faced with the challenge of at a very rapid rate. According to
in a short period of time. preventing infection by an infected cell. many experts, this virus is the

14 Levy
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Adv Dent Res 19:10-16, April, 2006
best-understood agent that causes human disease. Importantly,
what we have learned over these two decades is that concepts
that were initially considered conclusive were subsequently
shown to be incorrect (Table 11).
New discoveries have provided novel avenues for
improvement in prevention, vaccine development, and care.
Above all, we need to emphasize the approaches that target
not only the causative agent, HIV, but also the host immune
response. In this regard, with sufficient attention to this
objective by researchers in public and private institutions, we
should be able to see immune control of HIV to the state
achieved by long-term survivors.
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