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Pathogenic Mechanisms of HIV Disease: Further
Pathogenic Mechanisms of HIV Disease: Further
Further
Pathogenic Mechanisms
∗
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Susan Moir,† Tae-Wook Chun,†
and Anthony S. Fauci
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, Maryland, 20892; email: smoir@niaid.nih.gov,
twchun@nih.gov, afauci@niaid.nih.gov
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223
+
INTRODUCTION syndrome. Depletion of susceptible CD4 T
In 1983, the isolation of a T lymphotropic cell targets, together with the evolution of an in-
HIV: oid tissue
human retrovirus (1), later
CCR5: C-
immun named human
chemokine
odeficie receptor 5 immuno- deficiency
ncy virus (HIV), from a
virus
lymph node (LN) of
LN: an individual with
lymph
node lymphadenopathy
marked the
AIDS:
acquir beginning of
ed almost three
immun decades of in- tense
e
research into the
deficie
ncy pathogenesis of the
syndro virus that causes
me acquired immune
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DC
Activated CD4+ T cell
DC
InfectedRegulatory
cellT cells
Macrophage
Lamina propriaLymph node
Figure 1
Phases of infection following exposure to human immunodeficiency virus (HIV). Infection begins with transmission across a mucosal
barrier, either by a cell-free virus, infected cell, or virion attached to dendritic cells (DCs) or Langerhans cells (LCs). Early low-
+ +
level propagation probably occurs in partially activated CD4 T cells, followed by massive propagation in activated CD4 T
cells of the gut-associated lymphoid tissue lamina propria. Dissemination of HIV to other secondary lymphoid tissues and
establishment of stable tissue viral reservoirs ensue. Immune response lags behind the burst of viremia and provides only
partial control of viral replication. Adapted from Reference 5. Abbreviations: CTL, cytotoxic T lymphocyte; PD-1, programmed
death 1.
of cells that may be present at the port of Insight into the transmissibility of HIV
entry, including Langerhans cells (LCs) or has also been gained from epidemiologic
other dendritic cells (DCs) or macrophages studies; some estimates of rates of
(Figure 1), demonstrated that productive transmission (19, 20) have been based on
infection occurs following conjugate frequency of coital acts in discordant
+
formation with target CD4 T cells couples, whereas others (6, 21, 22) have
(reviewed in Ref- erence 15). More recently, examined host factors that appear to in-
investigators (16) studied early events of crease or decrease transmission. The
transmission in organ explants where HIV concept that HIV does not transmit easily is
bound to and protected by LCs can cross based on re- ports that the probability of
the epithelial layers and form complexes transmission ranges from 0.0001 to 0.0040 per
+
with memory CD4 T cells, which then sexual contact (19, 20). Furthermore,
initiate productive viral replication. This circumcision offers a degree of protection
group of investigators as well as others have against HIV infection (21), fur- ther
also proposed a concept of virologic suggesting that cells found in foreskin—
synapse, similar to immunologic synapses, including LCs, DCs, macrophages, and
wherein close proximity, additional virus- +
CD4 T cells—may facilitate transmission
attachment molecules such as integrins (17), (6). There are also indications that
and protective transmission is en-
hanced when the mucosal barrier of the genital
endosomal compartments within LCs and tract is perturbed by inflammation or breached LC: Langerhans cell
DCs help HIV establish a productive by the presence of certain genital-ulcerative DC: dendritic cell
infection (18). sexually transmitted diseases (22).
Acute HIV Syndrome and typically peaks at three to four weeks post
Viral Set Point expo- sure (25, 26), then declines
Approximately two to four weeks following spontaneously for several months before
the transmission of the virus, a majority of reaching a steady state or viral set point
HIV- infected individuals experience an (Figure 2). The level of the viral set point is
acute HIV syndrome (Figure 2), defined as an important determinant of the rate of
flu-like clini- cal manifestations associated disease progression in HIV-infected
with high plasma viremia and often fever and individuals who are not treated with ART
lymphadenopathy (23). Other reported (27).
symptoms also include myalgias, skin rash, The acute phase of HIV infection is usu-
headache, anorexia, and di- arrhea (23), ally accompanied by a dramatic depletion
although there is a high degree of variability +
of CD4 T cells in the peripheral blood,
in the severity of these clinical symp- toms.
which may rebound somewhat after the
During this early phase, HIV often repli-
initial burst of viremia decreases to a set
cates extremely aggressively in the absence
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Viral
106 escape from CD8+ T cells
105
Virus-specific neutralizing antibody
Viral escape from neutralizing antibody
104
100
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Days
Figure 2
Kinetics of immunologic and virologic events associated with human immunodeficiency (HIV) infection during acute and early
chronic phases. The schematic represents the sequence of events, including the appearance of viral antigens, HIV-specific
antibodies, and
+
HIV-specific CD8 T cells during the acute and early chronic phases of infection. HIV reservoirs are established during the acute
phase of infection soon after emergence of plasma viremia. Throughout the acute phase of infection, characterized by
massive virus replication and high levels of plasma viremia, an acute HIV syndrome develops in the majority of infected
+
individuals, and the virus rapidly spreads to various lymphoid organs, causing extensive depletion of CD4 T cells. Although
anti-HIV immunity, including
+
virus-specific CD8 T cells and antibodies, develops during the acute phase of infection, escape viral mutants rapidly emerge.
Abbreviations: ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction. Adapted from Reference 36.
Chronic HIV
Massive HIV infection
infection in GALT
depletion of
CD4+ T cells
HIV-mediated chronic
Destruction of Accelerated virus immune activation
immune system replication via direct and indirect
and disease mechanisms
progression
Figure 3
Key events associated with human immunodeficiency virus (HIV) disease progression. During acute
+
HIV infection, profound depletion of CD4 T cells occurs primarily in the gut-associated lymphoid
tissue (GALT), which is accompanied by high levels of plasma viremia and dissemination of the virus
to other lymphoid organs. During this period, persistent viral reservoirs—such as latently infected,
+
resting CD4 T cells—are established. During the chronic phase of infection, HIV replication also
occurs in all secondary lymphoid tissues, resulting in generalized immune activation, sustained viral
production, increased cell turnover, and ultimately destruction of the host immune system and rapid
disease progression.
consequence of infection and direct killing Studies in SIV and HIV infection have demon- strated that initial
+
as- sociated with the high abundance of depletion of CD4 T cells is less pronounced in peripheral LN
susceptible target cells present in the GALT compared with GALT (11, 28); however, additional stud- ies are
(9), in addi- tion to extensive bystander needed to further delineate the mecha- nisms of depletion in the
killing by apopto- sis (8). The early and high GALT and LNs in humans. The ultimate consequences of mas-
+
level of replication of HIV and SIV in the sive CD4 T cell depletion during the early stages of infection in
GALT is followed by dissemination of the the GALT on HIV disease
virus to peripheral lym- phoid tissue,
especially LNs, and the establish- ment of
persistent lymphoid tissue viral reser- voirs
(see the section entitled Establishment and
Maintenance of HIV Reservoirs, below).
progression also remain individuals, acute HIV infection gives rise
somewhat speculative, to persistent viral repli- cation, and in the
given the lack of absence of ART, plasma viremia remains
longitudinal data and detectable throughout the course of disease
compar- ison between (Figure 2). Several recent studies that aimed
slow and rapid to characterize the trans- mitting virus have
progressors. used single-genome ampli- fication and
mathematical modeling to suggest
(a) that a single “founder” virus (or infected
Failure of cell) is transmitted in a majority of
the individuals and
Immune (b) that HIV begins to evolve or diverge
System to from the founder virus only once a cellular
Clear HIV immune response arises several weeks after
In the vast majority of exposure
+
(29–31). A number of studies have peak of the early HIV-specific CD8 T cell
suggested that transmission represents a response and is characterized by mutations in
+
genetic bottle- neck for the virus, in that
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CD4
HDACi
Purge latent virus SAHA
IL-7
Cell death
Inhibition Benefit Risk
+
Persistent CD4 T Cell Reservoirs Figure 4
In 1995, with the availability of protease in- Therapeutic strategies in human immunodeficiency virus (HIV) infection.
hibitors as a third class of ART (Figure 4), Risks (red boxes) and benefits ( green boxes) associated with antiretroviral and
immune-modulating therapies in HIV-infected individuals are shown.
two important studies on viral dynamics Risks uncertain at present
Abbreviations: HDACi, histone deacetylase inhibitor; IL, interleukin;
demon- strated that potent ART could IRIS, immune reconstitution inflammatory syndrome; SAHA,
suppress plasma viremia to below the limits suberoylanilide hydroxamic acid.
of detection within a few weeks of initiation
of therapy (49, 50). These studies also
demonstrated the existence of a biphasic first evidence of HIV latency at the cellular
+
decay in plasma viremia, begin- ning with a level was described in resting CD4 T cells
rapid decay that reduced the ma- jority of of in- fected individuals (Figure 5) (51). This
replicating virus in short-lived cells and study was followed a few years later by a
followed by a second, slower phase of de- detailed anal- ysis of the frequency of
cay thought to involve a minor population infectious virus in such latently infected cells
of longer-lived infected cells. That same in lymphoid tissues (154). The latter study
year, the estimated the pool of latently
HIV
infection
Unintegrated HIV DNA
Resting CD4+ T cell
HIV Activation
virion
Integration of HIV DNA
Cell death
Lymph nodeGALT
Latently infected
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CD4+ T cell
Figure 5
+
Establishment and maintenance of the resting CD4 T cell reservoir in human immunodeficiency
+
virus (HIV)-infected individuals. HIV infects resting CD4 T cells and completes reverse
transcription. In the absence of cellular activation and prior to the integration of a provirus into the
+
nuclear DNA of the cell, infected resting CD4 T cells “cure” themselves of virus as a result of the
short half-life of the HIV preintegration complex. Following activation of the infected cells, the vast
majority of these cells die from HIV-induced cytopathic effects and the host immune response.
However, a very small fraction of productively infected cells revert to a resting memory state. In the
+
presence of effective antiretroviral therapy, these latently infected, resting CD4 T cells can persist for
prolonged periods of time in infected individuals. Some of these cells reactivate in lymphoid tissues and
may further contribute to the persistence of viral reservoirs in infected individuals by cell-to-cell spread
of virus, even in the absence of detectable viremia. Abbreviation: GALT, gut-associated lymphoid
tissue.
+
infected CD4 T cells carrying infectious for a minimum of 12 months
virus to be small: fewer than 10 million cells and up to three years
in the body. However, three subsequent interrupted their ther- apy
studies (52– and experienced rapid viral
54) demonstrated that this latent HIV rebound (56). In
reservoir was resistant to the ART regimens
that were employed at that time, which cast
doubt on the implication that HIV could be
eradicated after two to three years of
effective ART (55). These studies did,
however, indicate that its estimate was based
on the two aforementioned slopes of decay
and did not take stable reservoirs into ac-
count (55). The importance of stable
reservoirs and other mechanisms of
persistence was fur- ther demonstrated when
HIV-infected individ- uals whose plasma
viremia had been fully sup- pressed by ART
the majority of individuals studied, HIV plasma viremia In addition to the persistence of HIV in
returned to detectable levels within two weeks of the the latent viral reservoir, there is also
interruption of their drug regimen. Although there is no evidence for low levels of ongoing viral
consensus in the field on the precise half-life of latently replication in HIV-infected individuals
+ whose viremia was otherwise well
infected, resting CD4 T cells, a number of studies have pro-
jected that it will take 7 to more than 60 years to eliminate suppressed by ART (57, 59, 60). One source
HIV in this viral reservoir (57, 58), which has led to the of viral replication was identified
+
prediction that eradication based on these numbers and in the activated CD4 T cells of HIV-infected
current treatment strategies may not be feasible (38).
individuals whose plasma viremia had been either purging the latent reser- voir or References 38 and
sup- pressed below the limits of detection preventing its establishment (38, 64). For 64). Furthermore,
for up to nine years; this finding suggests example, if intensification of ART with a given the early
that virologic cross talk occurs between new class of drugs can further reduce establishment of the
+ the resid- ual pool of infectious virus, it latently
activated and rest- ing CD4 T cells in the infected,
absence of detectable viremia (61). The would indicate that low levels of +
resting CD4 T cell
trigger of such events could be the ongoing viral replication in the absence
reservoir (65),
of detectable viremia contribute to viral
occasional activation of the immune system adding a drug that
persistence (64). In addition, several strate-
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nonprogressors (LTNPs), and within this there has been much debate and some
group, patients who maintain a viral burden evidence that low viral fitness may contribute
be- low the limits of detection are referred to to the suppression of HIV replication in a
as elite controllers. Studies on the natural certain percentage of LTNPs (147), there are
control of HIV disease progression in strong indications that host factors also play
LTNPs and other HIV-infected individuals an im- portant role in restricting HIV
have focused on cel- lular restriction factors replication and disease progression (Tables
1 and 2). Among the host genetic factors
and viral fitness, as well as host genetics and
most consistently
its impact on the ability to
a
Abbreviations: CTL, cytotoxic T lymphocyte; HLA, human leukocyte antigen.
a
Abbreviations: APOBEC3G, apolipoprotein B editing complex
3G; CCR5, C-chemokine receptor 5; HLA, human leukocyte
antigen.
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Trim-5α and SIV Gag escapes the effects of most simian enhancing in- nate immune responses must
Trim-5α, whereas the inability of HIV to in- fect nonhuman be balanced with the potential deleterious
primates is at least in part due to the inhibitory effects of effects of inducing ex- cessive immune
simian Trim-5α on HIV. If simian Trim-5α could be activation, as can occur with
IFN-α and ISGs in chronically HIV-infected innate immunity are considered important for
individuals (see the section entitled Immune stimulating adaptive responses against HIV
Activation). Nonetheless, efforts to improve for both infected and vaccinated individuals
(153).
SUMMARY POINTS
1. HIV transmission occurs primarily at mucosal sites during sexual contact and is
followed by a period of intense viral replication, first in the GALT and then
systemically in all lymphoid tissues.
2. The consequence of acute HIV infection is massive depletion in the GALT of
+
CCR5- expressing memory CD4 T cells, which are the major targets of HIV
replication.
3. The early events of intense HIV replication and dissemination lead to the
establishment of stable viral reservoirs in lymphoid tissues and, at the cellular
+
level, in the form of latently infected resting CD4 T cells. These stable reservoirs
are major impediments to eradication of the virus.
4. Cellular and humoral immune responses are generated against HIV during the
acute and early phases of infection, yet they fail to restrict HIV replication in the
majority of infected individuals. There is strong evidence for selection of viral
mutants that escape these cellular and humoral responses.
5. Immune cell dysfunction, manifested by poor immune responses against HIV and
other pathogens, is observed in the majority of untreated HIV-infected individuals.
Chronic HIV viremia leads to increased cell turnover and changes in cellular
phenotype and function that are consistent with increased immune activation,
differentiation, and exhaustion.
6. There is strong evidence from animal models and human studies that HIV-
induced immune activation is a major determinant of HIV pathogenesis that is
likely to be driven by multiple factors.
7. Effective ART has greatly reduced HIV-related morbidity and mortality by
+
dramatically reducing HIV plasma viremia, which results in increased CD4 T cell
counts. How- ever, incomplete immune restoration persists to varying degrees in
most HIV-infected individuals.
8. Studies on host genetic determinants, as well as on adaptive and innate immune
responses and restriction factors associated with HIV disease progression, are
providing insight into new avenues of treatment and prevention.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings
that might be perceived as affecting the objectivity of this review.
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ACKNOWLEDGMENTS
This work was funded by the Intramural Research Program of the National Institute of
Allergy and Infectious Diseases at the National Institutes of Health.
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Annual Review of
Pathology:
Mechanisms of
Contents Disease
Volume 6, 2011
v
The Pathobiology of Arrhythmogenic Cardiomyopathy
Jeffrey E. Saffitz............................................................................................................299
Mechanisms of Leukocyte Transendothelial Migration
William A. Muller........................................................................................................323
Retinoids, Retinoic Acid Receptors, and Cancer
Xiao-Han Tang and Lorraine J. Gudas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Biomedical Differences Between Human and Nonhuman Hominids:
Potential Roles for Uniquely Human Aspects of Sialic Acid Biology
Nissi M. Varki, Elizabeth Strobert, Edward J. Dick Jr., Kurt
Benirschke,
and Ajit Varki............................................................................................................365
A Glimpse of Various Pathogenetic Mechanisms
of Diabetic Nephropathy
Yashpal S. Kanwar, Lin Sun, Ping Xie, Fu-you Liu, and Sheldon Chen. . . . . . . . . . . . . . . 395
Pathogenesis of Liver Fibrosis
Virginia Hernandez-Gea and Scott L. Friedman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
Mesenchymal Stem Cells: Mechanisms of
w.annualreviews.org by Stanford University - Main Campus - Green Library on 06/21/12. For personal use only.
Indexes
Errata
vi Contents