Patogenesis Vih

PM06CH10-Moir ARI 4 December 2010 11:3
ANNUAL
REVIEWS Further
Pathogenic Mechanisms
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Annu. Rev. Pathol. Mech. Dis. 2011.6:223-248. Downloaded from www.annualreviews.org
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Annu. Rev. Pathol. Mech. Dis. 2011. 6:223–48 Keywords

First published online as a Review in Advance on persistent infection, immune activation, immune dysfunction, AIDS
October 25, 2010
The Annual Review of Pathology: Mechanisms of Abstract
Disease is online at pathol.annualreviews.org
Human immunodeficiency virus (HIV) infection is generally char-
This article’s doi:
10.1146/annurev-pathol-011110-130254
acterized by inefficient viral transmission; an acute phase of intense
viral replication and dissemination to lymphoid tissues; a chronic, often
∗
This is a work of the U.S. Government and is not
subject to copyright protection in the United
asymptomatic phase of sustained immune activation and viral replica-
States. tion; and an advanced phase of marked depletion of CD4+ T cells that
†
These authors contributed equally.
leads to acquired immune deficiency syndrome. Major insight into HIV
transmission and each phase of infection has been gained from studies
on blood and tissue specimens obtained from HIV-infected individuals,
as well as from animal and ex vivo models. Not only has the introduc-
tion of effective antiretroviral therapy greatly diminished the morbidity
and mortality associated with HIV disease progression, it has also pro-
vided new avenues of research toward delineating the mechanisms of
HIV-induced pathogenesis. Further advances in therapeutics and in-
formative technologies, combined with a better understanding of the
immunologic and virologic components of HIV disease, hold promise
for new preventative and even curative strategies.
223
INTRODUCTION syndrome. Depletion of susceptible CD4+ T

cell targets, together with the evolution of an in-
In 1983, the isolation of a T lymphotropic
completely effective HIV-specific immune re-
HIV: human retrovirus (1), later named human immuno-
immunodeficiency sponse, leads to the establishment of a plasma
deficiency virus (HIV), from a lymph node (LN)
virus viral set point. As discussed in greater detail be-
of an individual with lymphadenopathy marked
LN: lymph node low, both the host immune system and the na-
the beginning of almost three decades of in-
ture of the rapidly evolving virus contribute to
AIDS: acquired tense research into the pathogenesis of the virus
immune deficiency this set point.
that causes acquired immune deficiency syn-
syndrome drome (AIDS). Even prior to the isolation of
Antiretroviral HIV, other studies provided the first glimpses Events and Contributing Factors
therapy (ART): of how HIV induces immune dysfunction in-
treatment with a of HIV Transmission
volving CD4+ T cells (2, 3), as well as systemic
combination of Because of the difficulty of identifying infected
antiretroviral drugs immune activation and dysregulation, as illus-

individuals very soon after exposure, little is
from different classes trated by simultaneous polyclonal B cell acti-
designed to suppress known regarding the earliest events of HIV
vation and the poor antibody response to neo-
HIV replication transmission in the genital tract or rectal mu-
and recall antigens (4). Given that HIV does not
SIV: simian cosa. However, insight into this rather ineffi-
productively replicate in B cells, the last study
immunodeficiency cient process has been gleaned from in vivo
(4) also provided the first indications of the wide
virus models of simian immunodeficiency virus (SIV)
array of deleterious effects that HIV causes in
GALT: gut- infection (reviewed in Reference 5) and from
virtually every component of the host immune
associated lymphoid epidemiological studies and ex vivo models that
system, predominantly through the process of
tissue aimed to identify cells and factors affecting the
aberrant immune activation. This review ad-
CCR5: C-chemokine transmission of HIV (reviewed in Reference 6).
dresses advancements in our understanding of
receptor 5 One of the first studies to examine early events
the pathogenic mechanisms of HIV disease by
of sexual transmission in the SIV model (7) de-
focusing on the direct and indirect effects of
scribed partially activated CD4+ T cells of the
virus on the major constituents of the immune
genital mucosa as the first targets of productive
system; how these effects arise during the acute
viral replication less than one week after expo-
and early phases of infection, as well as over the
sure (Figure 1); a few days after this event, lo-
course of chronic infection; and how antiretro-
cal propagation of SIV in the less abundant but
viral therapy (ART) affects disease outcome.
more susceptible activated CD4+ T cells takes
place. On the basis of more recent studies of
SIV infection in macaques (8, 9), the virus then
HIV TRANSMISSION AND rapidly migrates, probably via draining LNs,
EARLY INFECTION to the gut-associated lymphoid tissue (GALT),
Sexual transmission of HIV following expo- where it induces massive depletion of memory
sure to cell-free or cell-associated infectious CD4+ T cells in the intestinal lamina propria.
virus in semen or mucosal surfaces represents As discussed further below, similar cellular de-
the most common route of HIV transmission pletion appears to occur in humans (10–12).
globally. Less frequent routes, not discussed The ability of HIV and related simian
here, include transmission via injection drug viruses to establish productive infection is
use, exposure of blood and blood products via dictated by the availability of target CD4+
transfusions, and exposure of fetus or infant T cells that express the chemokine receptor
to HIV from an infected mother. Following CCR5 (13, 14). However, the process whereby
transmission, HIV disseminates rapidly in the the virus penetrates mucosal barriers to es-
absence of preexisting immune pressures, lead- tablish productive infection has been difficult
ing to a burst of viremia manifested in a sub- to evaluate in vivo, even in animal models.
stantial proportion of patients by an acute HIV Early ex vivo models based on cocultures
224 Moir · ·
Chun Fauci
Infected resting Late-responding CTLs
Resting CD4+ T cells

CD4+ T cells PD-1+CD8+
T cells
Establishment Partial
HI V of lymphoid control
virion Dissemination
of virus tissue viral Immune
reservoir activation
DC
Activated
CD4+ T cell
Crossing
the Sustained
barrier HIV
Infected production
activated
DC CD4+ T cell
Infected Regulatory
cell T cells
Macrophage
Lamina propria Lymph node
Hours Days Weeks Years
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 has
entry, including Langerhans cells (LCs) or also been gained from epidemiologic studies;
other dendritic cells (DCs) or macrophages some estimates of rates of transmission (19, 20)
(Figure 1), demonstrated that productive have been based on frequency of coital acts in
infection occurs following conjugate formation discordant couples, whereas others (6, 21, 22)
with target CD4+ T cells (reviewed in Ref- have examined host factors that appear to in-
erence 15). More recently, investigators (16) crease or decrease transmission. The concept
studied early events of transmission in organ that HIV does not transmit easily is based on re-
explants where HIV bound to and protected ports that the probability of transmission ranges
by LCs can cross the epithelial layers and form from 0.0001 to 0.0040 per sexual contact (19,
complexes with memory CD4+ T cells, which 20). Furthermore, circumcision offers a degree
then initiate productive viral replication. This of protection against HIV infection (21), fur-
group of investigators as well as others have ther suggesting that cells found in foreskin—
also proposed a concept of virologic synapse, including LCs, DCs, macrophages, and CD4+
similar to immunologic synapses, wherein T cells—may facilitate transmission (6). There
close proximity, additional virus-attachment are also indications that transmission is en-
molecules such as integrins (17), and protective 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 infection by the presence of certain genital-ulcerative DC: dendritic cell
(18). sexually transmitted diseases (22).
www.annualreviews.org • Pathogenesis of HIV 225

Acute HIV Syndrome and Viral typically peaks at three to four weeks post expo-
Set Point sure (25, 26), then declines spontaneously for
Approximately two to four weeks following the several months before reaching a steady state
transmission of the virus, a majority of HIV- or viral set point (Figure 2). The level of the
infected individuals experience an acute HIV viral set point is an important determinant of
syndrome (Figure 2), defined as flu-like clini- the rate of disease progression in HIV-infected
cal manifestations associated with high plasma individuals who are not treated with ART
viremia and often fever and lymphadenopathy (27).
(23). Other reported symptoms also include The acute phase of HIV infection is usu-
myalgias, skin rash, headache, anorexia, and di- ally accompanied by a dramatic depletion of
arrhea (23), although there is a high degree of CD4+ T cells in the peripheral blood, which
variability in the severity of these clinical symp- may rebound somewhat after the initial burst
toms. During this early phase, HIV often repli- of viremia decreases to a set point. This de-
cates extremely aggressively in the absence of pletion of peripheral-blood CD4+ T cells may
an immune response, reaching levels of plasma be associated with the massive depletion of
viremia as high as 10 million copies per milliliter CCR5+ memory CD4+ T cells in the GALT
(24, 25). In the abence of ART, plasma viremia (Figure 3). In SIV infection, this depletion is a
Acute phase Early chronic phase

108
Acute HIV syndrome
Wide dissemination of virus
Seeding of lymphoid tissues
107 Destruction of gut-associated lymphoid tissue
Plasma viremia (copies of HIV RNA per ml)
Establishment of HIV reservoirs

HIV-specific CD8+ T cells
106
Viral escape from CD8+ T cells
105
Virus-specific neutralizing antibody
Viral escape from neutralizing antibody
104
HIV-specific antibody+ (Western blot)

103
HIV-specific antibody+/- (Western blot)
Viral set point
HIV-specific antibody+ (ELISA)
102
HIV p24+ (ELISA) Limit of detection
101 HIV RNA+ (PCR)
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.
226 Moir · · Chun Fauci

Chronic HIV
Massive HIV infection
infection in GALT
High levels of plasma

Primary viremia and wide
infection dissemination of virus to
lymphoid organs
Lymph
node
Establishment of
persistent viral reservoir
Massive and progressive

depletion of
CD4+ T cells
HIV-mediated chronic
Destruction of
Accelerated virus immune activation via
immune system
replication direct and indirect
and disease progression
mechanisms
Rapid CD4+ T cell

turnover
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 as- progression also remain somewhat speculative,
sociated with the high abundance of susceptible given the lack of longitudinal data and compar-
target cells present in the GALT (9), in addi- ison between slow and rapid progressors.
tion to extensive bystander killing by apopto-
sis (8). The early and high level of replication
of HIV and SIV in the GALT is followed by Failure of the Immune System
dissemination of the virus to peripheral lym- to Clear HIV
phoid tissue, especially LNs, and the establish- In the vast majority of individuals, acute HIV
ment of persistent lymphoid tissue viral reser- infection gives rise to persistent viral repli-
voirs (see the section entitled Establishment cation, and in the absence of ART, plasma
and Maintenance of HIV Reservoirs, below). viremia remains detectable throughout the
Studies in SIV and HIV infection have demon- course of disease (Figure 2). Several recent
strated that initial depletion of CD4+ T cells studies that aimed to characterize the trans-
is less pronounced in peripheral LN compared mitting virus have used single-genome ampli-
with GALT (11, 28); however, additional stud- fication and mathematical modeling to suggest
ies are needed to further delineate the mecha- (a) that a single “founder” virus (or infected cell)
nisms of depletion in the GALT and LNs in is transmitted in a majority of individuals and
humans. The ultimate consequences of mas- (b) that HIV begins to evolve or diverge from
sive CD4+ T cell depletion during the early the founder virus only once a cellular immune
stages of infection in the GALT on HIV disease response arises several weeks after exposure

(29–31). A number of studies have suggested ESTABLISHMENT AND

that transmission represents a genetic bottle- MAINTENANCE OF
Latently infected
neck for the virus, in that certain traits, espe- HIV RESERVOIRS
cells: resting CD4+ T cially those of the viral envelope, appear to be
The rapid establishment and persistence of var-
cells carrying preferentially selected. Such early viruses tend
ious HIV reservoirs remain two of the most
unintegrated or to be characterized by an increased sensitiv-
important impediments to achieving complete
integrated HIV DNA ity to neutralization and a paucity of glycosy-
that can give rise to eradication of the virus in infected individu-
lation sites in the exposed areas of the HIV
infectious virus upon als, even in an era of clinically effective ART.
cellular stimulation envelope gp120 (32). Approximately 12 weeks
Nonetheless, strategies to eradicate the virus
after transmission, neutralizing antibodies be-
and cure HIV infection in at least some indi-
gin to arise and evolve (Figure 2); however,
viduals remain a topic of considerable interest
this response appears to be too little, too
within the HIV scientific community (38). HIV
late, as well as too narrow, as neutralization-
reservoirs can be divided into two main cate-

sensitive virus is quickly replaced in succes-
gories: (a) lymphoid tissues that provide HIV
sion by neutralization-resistant variants (33,
with an abundance of target cells, close con-
34). The envelopes of the escaping populations
tacts for efficient cell-to-cell propagation, and
of HIV tend to be more highly glycosylated; this
reduced drug penetration; and (b) cellular reser-
finding has led to the notion of a so-called gly-
voirs that consist mainly of CD4+ T cells that
can shield that prevents binding of neutralizing
are highly susceptible to HIV replication when
antibodies and promotes viral persistence (33).
activated but can also carry latent virus.
Several other mechanisms regarding the failure
of antibodies to neutralize the virus have been
proposed, but they are beyond the scope of this
discussion (see Reference 35 for a review). Lymphoid Tissue Reservoirs
There is reasonable evidence, albeit cir- As discussed in the previous section, the GALT
cumstantial, that early HIV-specific CD8+ provides HIV with its first abundant source of
T cell responses contribute to the decline in targets for intensive replication (Figure 3). The
HIV plasma viremia during the acute phase massive depletion of GALT-associated CCR5+
of infection (Figure 2) (see Reference 36 memory CD4+ T cells in early HIV infection
for a review). Rapid evolution of the initially is often cited as evidence for high levels of HIV
homogeneous virus begins at the peak of the replication; however, bystander cytopathic ef-
early HIV-specific CD8+ T cell response fects also contribute to cell death (8), and there
and is characterized by mutations in epitopes is evidence that CD4+ T cells in the GALT
recognized by CD8+ T cells (30). Similar to disappear before peak viremia (39). Nonethe-
the phenomenon of escape from neutralizing less, on the basis of the detection of virus in
antibodies, selection of sequential viral variants tissue sections and single cells isolated from
with mutations in CD8+ T cell epitopes has biopsied tissue, the GALT remains a major
been described in HIV-infected individuals early site for active HIV and SIV replication (8,
(31). This evolution occurs very early in the 9, 40). In addition, the GALT remains a ma-
course of infection, before the appearance jor reservoir for HIV throughout the course of
of neutralizing antibodies, and continues disease, again on the basis of virus detection ei-
throughout the course of disease, thus also ther in tissue sections or in isolated single cells
contributing to viral persistence. There is (41, 42). Several of these studies, among others,
also recent evidence from animal models that, also demonstrate the presence of HIV in GALT
although the timing of the HIV-specific T cell after several years of ART (41, 43), suggesting
response is important, other factors such as the that the GALT is a persistent HIV reservoir.
location and magnitude of the response are also It is unclear what accounts for the persistence
likely to contribute to disease outcome (37). of the virus. Long-lived latently infected cells
228 Moir · ·
Chun Fauci
and/or CD4+ T cells undergoing low levels Induce viral replication

Stimulate cellular immunity IL-7/IL-15 Toxicity
of viral propagation through cell-to-cell spread
could contribute to persistent HIV infection
in the GALT (see the section entitled Persis-
tent CD4+ T Cell Reservoirs, below). The lat- Suppress virus
Increase CD4+ T cells CD8 CD4
ter scenario is feasible, given the abundance of
activated and proliferating CD4+ T cells in the
GALT even after several years of ART (41, 42). Fusion/entry
In HIV-infected individuals, the level of HIV inhibitors
proviral DNA in tissue-derived CD4+ T cells Integrase

has been directly correlated to the level of ac- inhibitors
tivation on GALT-derived CD8+ T cells, an
indication that the level of immune activation Reverse CD4
transcriptase
plays a role in the persistence of HIV in the inhibitors
GALT (43).
Protease
The GALT is not the only lymphoid tissue inhibitors
to serve as a site for active HIV and SIV repli-
cation (Figure 3). As described several years
Side effects
ago before the era of effective ART and sensi- Drug-resistant virus
tive assays for measuring HIV plasma viremia, IRIS
large amounts of virus can be detected in tis- Incomplete immunologic restoration
sue sections isolated from peripheral LNs of

clinically asymptomatic HIV-infected individ- HDACi
uals (44, 45). These studies revealed HIV in SAHA
close proximity to the follicular dendritic cell IL-7 Cell death
(FDC) network, which was later shown to har-
bor infectious virus (46). Such FDC reservoirs CD4
are established early in HIV-infected individ-
uals and show resistance to the effects of ART
(47, 48). However, the level of persistence of Purge latent virus Risks uncertain at present
HIV in peripheral LNs following several years
of effective ART remains to be determined.
Inhibition Benefit Risk
Figure 4
Persistent CD4+ T Cell Reservoirs
Therapeutic strategies in human immunodeficiency virus (HIV) infection.
In 1995, with the availability of protease in- Risks (red boxes) and benefits ( green boxes) associated with antiretroviral and
hibitors as a third class of ART (Figure 4), two immune-modulating therapies in HIV-infected individuals are shown.
important studies on viral dynamics demon- Abbreviations: HDACi, histone deacetylase inhibitor; IL, interleukin; IRIS,
immune reconstitution inflammatory syndrome; SAHA, suberoylanilide
strated that potent ART could suppress plasma hydroxamic acid.
viremia to below the limits of detection within
a few weeks of initiation of therapy (49, 50).
These studies also demonstrated the existence first evidence of HIV latency at the cellular level
of a biphasic decay in plasma viremia, begin- was described in resting CD4+ T cells of in-
ning with a rapid decay that reduced the ma- fected individuals (Figure 5) (51). This study
jority of replicating virus in short-lived cells was followed a few years later by a detailed anal-
and followed by a second, slower phase of de- ysis of the frequency of infectious virus in such
cay thought to involve a minor population of latently infected cells in lymphoid tissues (154).
longer-lived infected cells. That same year, the The latter study estimated the pool of latently

HIV
infection Unintegrated HIV DNA
Resting
CD4+ T cell
HIV Activation
virion
Integration
of HIV DNA
Cell death
Lymph node GALT Productively

infected
CD4+ T cell
Latently infected
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 virus the majority of individuals studied, HIV plasma
to be small: fewer than 10 million cells in the viremia returned to detectable levels within two
body. However, three subsequent studies (52– weeks of the interruption of their drug regimen.
54) demonstrated that this latent HIV reservoir Although there is no consensus in the field on
was resistant to the ART regimens that were the precise half-life of latently infected, resting
employed at that time, which cast doubt on the CD4+ T cells, a number of studies have pro-
implication that HIV could be eradicated after jected that it will take 7 to more than 60 years
two to three years of effective ART (55). These to eliminate HIV in this viral reservoir (57, 58),
studies did, however, indicate that its estimate which has led to the prediction that eradication
was based on the two aforementioned slopes of based on these numbers and current treatment
decay and did not take stable reservoirs into ac- strategies may not be feasible (38).
count (55). The importance of stable reservoirs In addition to the persistence of HIV in
and other mechanisms of persistence was fur- the latent viral reservoir, there is also evidence
ther demonstrated when HIV-infected individ- for low levels of ongoing viral replication in
uals whose plasma viremia had been fully sup- HIV-infected individuals whose viremia was
pressed by ART for a minimum of 12 months otherwise well suppressed by ART (57, 59, 60).
and up to three years interrupted their ther- One source of viral replication was identified
apy and experienced rapid viral rebound (56). In in the activated CD4+ T cells of HIV-infected
230 Moir · ·
Chun Fauci
individuals whose plasma viremia had been sup- References 38 and 64). Furthermore, given the
pressed below the limits of detection for up to early establishment of the latently infected,
nine years; this finding suggests that virologic resting CD4+ T cell reservoir (65), adding a
Increased cell
cross talk occurs between activated and rest- drug that blocks cellular activation, such as cy- turnover: an in vivo
ing CD4+ T cells in the absence of detectable closporin A, to ART may reduce the initial process whereby cells
viremia (61). The trigger of such events could burst of viremia in activated CD4+ T cells and respond to activating
be the occasional activation of the immune thereby limit the establishment of a latent viral stimuli by undergoing
increased proliferation
system by (a) random triggering events and reservoir (66).
and cell death
(b) specific events such as secondary infections
or vaccination; the latter induces HIV replica-
tion (62). Continual replenishment of CD4+ IMMUNE DYSFUNCTION
T cell viral reservoirs could also be associated CAUSED BY HIV INFECTION
with trafficking of cells between the peripheral The previous sections described how HIV
blood and tissues, such as the GALT, where rapidly establishes a persistent infection that is
(as described in the previous section) there are accompanied by high levels of viral replication
an abundance of activated CD4+ T cells and in lymphoid tissues, together with massive de-
a persistent HIV reservoir (Figure 5). In ad- pletion of memory CD4+ T cells in the GALT.
dition to occasionally activated CD4+ T cells By targeting a major constituent of the immune
contributing to the low level of persistence of system, HIV destroys and dysregulates CD4+
virus, the latent CD4+ T cell viral reservoir may T cells. However, HIV also induces immuno-
be expanded by homeostatic proliferation of logic dysfunction of CD8+ T cells, B cells,
these latently infected cells in CD4+ T cell lym- natural killer (NK) cells, and nonlymphoid cells
phopenic HIV-aviremic individuals (63). The through mechanisms that include increased
findings of this latest study also suggest that cell turnover, activation, differentiation, and
in healthier HIV-aviremic individuals, the size homeostatic responses. Together, these vari-
of the HIV reservoir is increased by subsets of ous factors lead to qualitative changes within
CD4+ T cells that are expanded during the im- each immune cell population that ultimately
mune reconstituting effects of ART. affect overall immunologic competence. As
There is increasing belief, although amid in the previous section, immune dysfunction
some controversy, that new insight into residual and dysregulation are considered in terms
viral replication and long-lived persistent reser- of both the major lymphoid organs and the
voirs will come from new therapeutic strategies, cellular compartments that are affected in
including new classes of antiretroviral drugs and HIV-infected individuals, with an emphasis
drugs aimed at either purging the latent reser- on individuals whose plasma viremia is not
voir or preventing its establishment (38, 64). controlled by ART.
For example, if intensification of ART with a
new class of drugs can further reduce the resid-
ual pool of infectious virus, it would indicate Lymphoid Tissue Dysfunction
that low levels of ongoing viral replication in Massive CD4+ T cell depletion in the GALT
the absence of detectable viremia contribute to occurs soon after transmission of HIV in hu-
viral persistence (64). In addition, several strate- mans and pathogenic SIV in the nonhuman
gies have been proposed for purging HIV from primate model by cytopathic effects that prob-
latently infected reservoirs (Figure 4). Such ap- ably include both direct and indirect mecha-
proaches include the use of inhibitors of histone nisms (8–12). In nonpathogenic natural SIV
deacetylases, a group of chromatin-remodeling infections, similar levels of CD4+ T cell de-
enzymes that restrict HIV expression in la- pletion occur early after infection but are
tently infected cells, to decrease the latent followed by a period of recovery that is not ob-
viral reservoir through purging (reviewed in served in HIV and pathogenic SIV infections

(reviewed in Reference 67). It is unclear why nonpathogenic and pathogenic SIV infections
recovery of CD4+ T cells in the GALT suggest that these events may not necessarily
occurs in nonpathogenic natural SIV but predict disease outcome (68).
not in HIV and pathogenic SIV infections, Early reports on GALT depletion and gas-
although differences in levels of chronic im- trointestinal damage in HIV and SIV infection
mune activation may be an important determi- were based largely on histological findings at
nant of pathogenicity (see the section entitled necropsy (reviewed in Reference 69), with little
Role of Immune Activation in the Pathogene- emphasis on the functional consequences of
sis of HIV, below). Although it is also unclear these alterations. More recently, loss of mucosal
whether early depletion of CD4+ T cells in the integrity in HIV and SIV infection has been
GALT of HIV-infected individuals leads to ir- reported to be associated with translocation
reversible damage to the immune system, sim- of microbial products (70) from the intestinal
ilar levels of early CD4+ T cell depletion in mucosa into the circulation, thus contributing
to HIV-induced systemic immune activa-

HIV infection tion and dysregulation, as discussed below
(Figure 6). Gene-expression profiles of
GALT-derived cells from HIV-infected indi-
viduals are also consistent with a disruption
of the mucosal epithelial barrier and of the
metabolic and digestive functions (71). Specific
losses in mucosal immune function have
also been associated with (a) the preferential
depletion of IL-17-secreting (Th17) CD4+ T
HIV replication Microbial translocation Host immune responses cells, which are a subset of T helper cells that
and viral proteins in GALT to HIV infection
are involved in mucosal host defense against
extracellular bacteria, and (b) the consequent
Stimulation inability to control systemic dissemination of
of innate and adaptive Salmonella in pathogenic SIV infection (72).
immune cells
Preferential depletion of Th17 cells in the
GALT has also been reported in HIV-infected
Release of proinflammatory
cytokines, increased cell individuals (73), although the functional
turnover, and exhaustion implications remain unknown.
As first described over 25 years ago (re-
Chronic immune activation
viewed in Reference 74), HIV infection has
a profoundly deleterious effect on peripheral
lymphoid tissues, causing extensive follicular
Enhanced HIV replication and
destruction of immune system and germinal-center hyperplasia during the
clinically early stages of infection and invo-
Figure 6
lution during the advanced stage of disease
Factors associated with human immunodeficiency virus (HIV)-induced
immune activation. During the establishment of persistent HIV viremia, cells (Figure 3). These alterations begin to occur
from both the innate and adaptive arms of the immune system become soon after initial infection (47, 48) and are
activated by factors such as viral proteins, microbial products translocated from associated with ongoing viral replication in
the gut-associated lymphoid tissue (GALT), and host responses. Activated cells the untreated patient. However, both direct
produce a swarm of proinflammatory cytokines, such as tumor necrosis factor
and indirect effects of the virus are prob-
α, interferon-α, and interleukin-1 and -6, which in turn cause chronic immune
activation. In addition, ongoing HIV replication and host immune responses to ably responsible for the changes described
infection contribute to immune activation. These events promote enhanced above, especially given that germinal-center
levels of HIV replication and ultimately lead to the exhaustion and destruction B cells, which are not targets for productive
of immune system. HIV replication, are largely responsible for
232 Moir · ·
Chun Fauci
the hyperplasia observed in these lymphoid of these observations include the suggestion
tissues (75). As with the GALT, it remains that there is an increased relative proportion of
difficult to establish the precise immunologic activated CD8+ to CD4+ T cells due to a higher
consequences of HIV-induced alterations in death rate in the latter population (77, 84).
peripheral lymphoid tissues. However, given There is also evidence that residual ongoing
the critical role of these tissues in mount- viral replication in infected individuals receiv-
ing effective cellular and humoral immune ing ART is associated with an inverted ratio of
responses, any disruption probably has dele- CD4+ to CD8+ T cells (83). Interestingly, B
terious consequences. In this regard, recent cells, which are not targets for HIV replication,
studies suggested that collagen deposition in T behave more similarly to CD4+ than to CD8+
cell zones of LNs of HIV-infected individuals T cells before and after initiation of ART in
(76), possibly resulting from HIV-induced im- terms of cellular dynamics (85). These obser-
mune activation and inflammation, may disrupt vations further support the concept that HIV-
normal lymphocyte trafficking and contribute induced changes in CD4+ T cell dynamics are
to decreased immunologic function (77). more likely to be driven by indirect rather than
direct effects of ongoing viral replication (77).
The consequences of ongoing HIV repli-
HIV-Induced Immune Dysfunction cation on lymphocyte dynamics include qual-
at the Cellular Level itative alterations within each population that
The massive depletion of CD4+ T cells that probably contribute to the progressive loss of
occurs early after HIV infection in the GALT, cellular and humoral responses. Lymphocytes
and to a lesser extent in the peripheral blood of the B cell and T cell lineage can be divided
and LNs, is offset by increased CD4+ T cell into two main categories: naı̈ve (antigen-naı̈ve)
turnover (Figure 3) (78). Given that other cell and memory (antigen-experienced) cells. Both
populations, including CD8+ T cells, B cells, memory CD4+ cells and memory CD8+ T cells
and NK cells, also exhibit increased turnover can be divided further into central memory and
during HIV viremia (79), immune activation effector memory cells, in addition to several
(see the section entitled Role of Immune additional subpopulations on the basis of the
Activation in the Pathogenesis of HIV) rather expression of various phenotypic markers (re-
than homeostatic responses to CD4+ T cell viewed in Reference 86). Whereas acute HIV
depletion may explain increased lymphocyte infection is associated with preferential infec-
turnover (Figure 3) (77). Regardless of the tion and depletion of effector memory CD4+
mechanism, increased cell turnover is induced T cells at mucosal sites (12), the chronic phase
soon after HIV and pathogenic SIV infection of HIV infection in untreated individuals is as-
and, in the absence of control of virus replica- sociated with a relative expansion of short-lived
tion, persists throughout the chronic phase of effector memory CD4+ and CD8+ T cells (87).
infection (31, 80). The initiation of ART leads Possible reasons for such skewing of T cell sub-
to a significant decrease in the rate of turnover populations include loss of regenerative poten-
in CD4+ and CD8+ T cells (81), and similar tial resulting from reduced thymic function,
changes are thought to occur for B cells and NK excessive differentiation, and progressive de-
cells on the basis of cross-sectional studies in struction of LN architecture (see Reference 77
SIV infection (82). The similarly high turnover for a review). Similar skewing of NK cell and B
rates for both CD4+ and CD8+ T cells have cell subpopulations has also been reported and
led investigators to question why CD8+ T cell probably contributes to dysfunction in both the
numbers increase, whereas CD4+ T cell num- innate (reviewed in Reference 88), and adap-
bers decrease in HIV-viremic individuals, lead- tive (humoral) arms (reviewed in Reference 89),
ing to only partial normalization of their ratios respectively, of the immune system in HIV-
in ART-treated individuals (83). Explanations infected individuals. Overall, the alterations in

various lymphocyte populations observed in described for B cells well over 25 years ago (4).
persistent viral infections such as HIV are most Although the underlying causes of HIV-
likely associated with chronic antigenic stimu- induced cellular hyperactivity remain some-
IFN: interferon
lation that induces increased turnover and dif- what obscure and a source of intense debate,
Exhaustion: elusive
ferentiation, ultimately culminating in progres- the pathogenic consequences of such activity
consequence of
immune activation sive loss of the potential to regenerate, which is are fairly well understood. These consequences
whereby effector key to maintaining a competent immune system include increased cell turnover; the skewing of
immune cells lose their (90). lymphocytes toward more activated and dif-
proliferative and In addition to contributing to overall im- ferentiated subpopulations; and the induction
functional capacities
mune competence, the quality of CD4+ and of cellular exhaustion, senescence, and low re-
CD8+ T cells also appears to be important newal potential. In addition, several recent av-
for mounting and sustaining an effective re- enues of research on the GALT and animal
sponse against HIV itself. Although several models have provided important insight into
earlier studies suggested that there is no differ- the pathogenesis of chronic HIV infection.
ence in the frequency of HIV-specific T cells
across various groups of HIV-infected individ-
uals (91, 92), recent findings suggest that cer- Role of Soluble Factors in
tain functional capabilities of responding cells HIV-Induced Immune Activation
are more important than the number of cells Modulators of the immune system that
that are available. In untreated patients, the are thought to play a significant role in
HIV-specific CD4+ and CD8+ T cells of in- HIV-induced immune activation include
fected individuals who control HIV replication proinflammatory cytokines (e.g., TNF-α,
and disease progression tend to proliferate bet- IL-1, IL-12, IL-6) and chemokines (e.g.,
ter ex vivo than do those of infected individu- CXCL10), lipopolysaccharide (LPS), and type
als who experience disease progression (93, 94). I IFN (IFN-α). Many of these factors arise
Furthermore, defective HIV-specific CD8+ T during acute infection, and several are main-
cell responses against HIV have been associated tained during the chronic phase of infection
with decreased function, including cytolytic ca- (Figure 6) (see Reference 36 for a review).
pacity (95) and the capacity to secrete multiple Increased levels of LPS, a particularly potent
cytokines (96). The paucity of multifunctional activator of the immune system because of its
CD4+ T cells also appears to correlate with ability to bind to and trigger the release of
HIV disease progression; HIV-infected indi- proinflammatory factors from macrophages
viduals with advancing disease have an increas- and DCs, have been associated with certain
ing proportion of HIV-specific CD4+ T cells changes that occur during acute HIV infec-
that secrete only interferon (IFN)-γ, whereas tion. These changes include disruption of
those of individuals who control HIV disease the intestinal mucosal barrier, which causes
with or without ART secrete IL-2 along with microbial translocation in the form of LPS
IFN-γ (97, 98). Thus, polyfunctionality and into circulation (70), and periods of intense
proliferative capacity of T cells are probably secretion of cytokines and chemokines (36).
two important correlates of the control of HIV Levels of LPS in the plasma are maintained at
disease progression. increased levels throughout the chronic phases
of both HIV and pathogenic SIV infection (70),
leading to the speculation that virus-induced
ROLE OF IMMUNE ACTIVATION destruction of the GALT and the associated
IN THE PATHOGENESIS OF HIV leaking of microbial products are central to
One of the most widely recognized hallmarks the induction and maintenance of the immune
of the chronic phase of HIV infection is gen- activation observed throughout the course of
eralized immune activation, which was first disease (99). However, several other potential
234 Moir · ·
Chun Fauci
(and probably multifactorial and intercon- recent indications that TLR triggering of pDCs
nected) mechanisms of HIV-induced immune modulates levels of cellular activation (see the
activation have been proposed (36, 67). section entitled Consequences of HIV-Induced
ISG: IFN-α-
A role for IFN-α in the pathogenesis Immune Activation at the Cellular Level, be- stimulated gene
of HIV infection was first suggested over low) in HIV-infected individuals (105).
Toll-like receptors
20 years ago on the basis of ultrastructural (TLRs): a family of
analyses of lymphoid tissue sections (100). receptors that
More recently, DNA microarray analyses have Consequences of HIV-Induced recognize conserved
demonstrated that induction of a wide array of Immune Activation at the molecular patterns
IFN-α-stimulated genes (ISGs) occurs in all Cellular Level expressed by
pathogens and play an
major lymphocyte populations isolated from One of the most widely reported correlates of important role in
chronically viremic individuals (reviewed in HIV disease progression is the increased fre- innate immunity
Reference 101). Although a direct association quency of activated lymphocytes, which is man-
pDC: plasmacytoid
between ISGs and HIV-induced immune acti- ifested especially by upregulation of the acti- dendritic cell
vation has been difficult to establish in humans, vation marker CD38 on CD8+ T cells (106).
recent data from animal models have provided Increased expression of activation markers has
a possible link. The absence of immune acti- also been described for all major lymphocyte
vation in the setting of natural nonpathogenic populations and is largely associated with on-
SIV infection in sooty mangabeys despite going HIV replication (77, 88, 89). Further-
chronic high levels of plasma viremia provided more, HIV-induced immune activation that oc-
one of the earliest concrete indications of a role curs during ongoing viral replication has been
for immune activation in pathogenic HIV and associated with other manifestations, includ-
SIV infections (102). More recent studies have ing increased turnover of lymphocytes, as de-
pursued this line of investigation by focusing scribed in the previous section (Figure 6);
on the differences between pathogenic and hypergammaglobulinemia, which probably re-
nonpathogenic SIV infections. One such sults from increased terminal differentiation of
difference is in the triggering of two Toll-like B cells (89); increased activation-induced apop-
receptors (TLRs), TLR7 and TLR9, and the tosis of CD4+ and CD8+ T cells as well as B
induction of downstream adaptor molecules cells (107); and increased susceptibility to the
and ISGs. IFN-α is secreted in copious development of HIV-related malignancies, es-
amounts by plasmacytoid dendritic cells pecially of the B cell type (108). Notably, the
(pDCs), which express TLR7 and TLR9 increased susceptibility to apoptosis is proba-
and appear to be differentially regulated in bly induced by several factors, including the in-
pathogenic versus nonpathogenic SIV infec- duction of ISGs involved in cellular death path-
tions (103). When the two types of infections ways, namely TNF-related apoptosis-inducing
were compared, pDC activation was muted ligand and its receptor, as well as Fas (reviewed
in the acute phase of nonpathogenic but not in References 107 and 109).
pathogenic SIV infection, and the latter setting One of the numerous oddities associated
led to strong induction of IFN-α via TLR7- with HIV infection and chronic immune ac-
and TLR9-mediated signaling in pDCs. tivation is the appearance of HIV-specific T
Although these findings have raised questions cells and B cells that show signs of exhaustion or
about the role of TLR signaling and whether senescence (Figure 6) (see References 89 and
acute events are important in determining dis- 110 for reviews). These cells arise from the in-
ease outcome in SIV infection (67, 104), there duction of inhibitory pathways, which would
remains a strong consensus for a prominent role be expected to attenuate the state of systemic
for pDCs and IFN-α responses in determining hyperactivation, as has been proposed (68) as
outcome during the chronic phase of SIV and, a potential mechanism for the lack of patho-
by extension, HIV infection. There are also genesis in natural SIV infections. However,

functional immune cell exhaustion is a phe- of receptors associated with homing to and
nomenon that has been observed in the set- within LNs (e.g., CD62L, CCR7, CXCR4,
ting of numerous persistent viral infections (90), CXCR5) and increased expression of recep-
including HIV infection. Furthermore, several tors associated with homing to inflammatory
animal studies have demonstrated that block- extralymphoid tissues (e.g., CXCR3, CCR6,
ing the interaction between programmed death CD11c). Given the importance of the LN en-
1 (PD-1), one of the major inhibitory receptors vironment for generating optimal cellular and
associated with virus-specific exhausted T cells, humoral immune responses (Figure 3), these
and its ligand (PDL-1) reverses the exhaustion findings suggest that the dysregulated hom-
and improves cellular and humoral responses ing to extralymphoid tissues may contribute
against the persisting virus (111, 112). Although to the ineffective immune responses against
it may appear difficult to reconcile the nega- HIV observed in chronically viremic individ-
tive effects of PD-1 in HIV and pathogenic SIV uals. Finally, recent gene-expression analyses
infections with its proposed positive effects in suggest that inflammatory markers contribute
nonpathogenic SIV infection, early induction to the hyperactivation profile associated with
of PD-1 in the latter setting may contribute to pathogenic but not nonpathogenic outcomes of
the favorable outcome (113). SIV infection (104). These findings further sug-
Much emphasis has been placed on the role gest that the inflamed-tissue homing receptor
of PD-1 in virus-specific CD8+ , and to a lesser profiles observed on exhausted lymphocytes in
extent, CD4+ T cell exhaustion in HIV and chronic HIV–infected individuals represent a
SIV infections. However, there are indications consequence of HIV-induced immune activa-
that other inhibitory receptors may be involved tion and that these dysregulated cells contribute
in virus-induced immune cell exhaustion. This to HIV pathogenesis.
hypothesis is based on (a) the relatively mod-
est effects of blocking PD-1 ex vivo (114, 115),
(b) the involvement of the inhibitory receptor LONG-TERM CONSEQUENCES
CTLA-4 (cytotoxic T lymphocyte–associated OF HIV INFECTION
antigen 4) in HIV-specific CD4+ T cell exhaus- In the absence of ART, the vast majority
tion (116), and (c) evidence that the combined of HIV-infected individuals experience pro-
effect of multiple inhibitory receptors may be gressive loss of CD4+ T cells and increased
more important than that of any one recep- immunodeficiency that ultimately lead to
tor (117). In addition, although the effects of the opportunistic diseases characteristic of
blocking PD-1 have been proposed to relieve AIDS (reviewed in Reference 121). With
its inhibitory effects (114, 115), there is also ev- the increasing availability of ART, there has
idence that the triggering of PD-1+ CD8+ T been a dramatic reduction in the number of
cells induces apoptosis of cells expressing high people who progress to AIDS and subsequently
levels of PD-1 (118). Thus, blocking the trig- die from AIDS-defining illnesses. However,
gering of PD-1 on these cells leads to enhanced long-term pathogenic consequences of living
survival and effector responses against HIV. with HIV persist in most infected individuals
In addition to the increased expression of in- who receive ART, although the effects are, for
hibitory receptors, exhausted CD4+ and CD8+ the most part, far less severe than those arising
T cells, as well as B cells that arise during in untreated individuals. Some of these effects
chronic immune activation in the setting of per- may arise from incomplete immunologic
sistent viral infections, are characterized by loss recovery that is manifested by persistently low
of proliferative capacity and effector functions CD4+ T cell counts and that may be associated
(reviewed in References 89 and 110). These with incomplete suppression by ART of low
cells also tend to express distinct receptor pro- levels of cell-to-cell spread of virus, even in the
files (119, 120), including decreased expression absence of detectable viremia.
236 Moir · ·
Chun Fauci
Consequences of Low CD4+ However, more recent findings (128) suggest

T Cell Counts that levels of IL-7 increase in lymphopenic in-
dividuals as a result of reduced utilization of
A progressive depletion of CD4+ T cells oc-
the cytokine stemming from the loss of cells
curs in the majority of HIV-infected individu-
expressing the IL-7 receptor CD127, which
als who remain untreated and can also occur in
serves as regulator of IL-7 production under
individuals receiving ART. Although the initi-
normal physiologic conditions. Given the im-
ation of effective ART typically leads to a dra-
portance of IL-7 in the expansion and mainte-
matic increase in CD4+ T cell counts, there
nance of T cells (reviewed in Reference 129),
are individuals whose CD4+ T cell counts re-
as well as evidence of incomplete restoration
main low despite long-term and virologically
of CD4+ T cells and immune competence of
suppressive ART (Figure 4). A very low CD4+
both CD4+ and CD8+ T cells in HIV-infected
T cell count at initiation of ART is one of the
individuals, several studies have explored the
most important predictors of incomplete CD4+

therapeutic potential of IL-7 in HIV infection
T cell restoration following ART (122). This
(130, 131). Similar attention is being paid to
observation, among others, has led to a reassess-
IL-15, another cytokine with important T cell
ment of recommendations on when to initiate
immunomodulating features (Figure 4) (see
ART (123, 124). The incomplete restoration of
Reference 129 for a review).
CD4+ T cell counts in individuals who delay
therapy may result from incomplete virologic
suppression, as evidenced by ongoing immune Consequences of Initiating Therapy in
activation, even in individuals with a sustained the Setting of Advanced HIV Disease
virologic response to HIV as measured by sup- Individuals who initiate ART when their CD4+
pression of plasma viremia (125). As discussed T cells counts are low and/or who have an
above, other potential reasons for incomplete underlying opportunistic infection are at in-
restoration of CD4+ T cells may include loss of creased risk of developing a potentially dev-
regenerative potential, senescence, exhaustion, astating complication referred to as immune
and destruction of lymphoid tissue architecture reconstitution inflammatory syndrome (IRIS)
and mucosal integrity of the GALT. In addi- (reviewed in References 132 and 133). This
tion, thymic dysfunction may also contribute syndrome has been particularly prevalent in
to incomplete restoration of CD4+ T cells in resource-poor countries, where ART is gen-
HIV-infected individuals (77, 84). erally started late in the course of HIV dis-
During the early stages of HIV infection, ease in patients who usually present with one
CD4+ T cell depletion is balanced by increased or more opportunistic infections. The clini-
immune activation, whereas during the ad- cal manifestations of IRIS are diverse, and the
vanced stages of infection, the immune system underlying causes are not completely under-
gradually loses the ability to replenish itself. stood; however, the phenomenon involves a
During the latter phase of progressive CD4+ strong inflammatory response after initiation of
T cell lymphopenia, homeostatic pressures rise, ART. IRIS typically reflects a dysregulated re-
as evidenced by increased serum levels of the T sponse to a pathogen that was present prior to
cell homeostatic cytokine IL-7. Several studies ART, such as tuberculosis, herpes zoster, cryp-
have demonstrated a strong inverse correlation tococcus, toxoplasmosis, or bacterial pneumo-
between CD4+ T cell counts and serum levels nia (132, 133). Initiation of ART in severely im-
of IL-7 in HIV infection and other settings in munosuppressed individuals may cause a rapid
CD4+ T cell lymphopenia (126, 127). These activation of the immune response against the
observations were initially interpreted as re- secondary pathogen as the immune system is
sulting from an increased homeostatic produc- partially reconstituted, leading to an inflamma-
tion of IL-7 in response to the lymphopenia. tory response that is specific to the pathogen but

that can cause substantial tissue damage (134). risk of cardiovascular manifestations. There is
In addition to low CD4+ T cell counts, condi- evidence for a role of HIV-induced IFN-α
tions that favor IRIS include a rapid decrease in on one of the main risk factors for cardio-
NADM: non-AIDS-
defining malignancy HIV plasma viremia upon initiation of ART and vascular disease, namely increased triglycerides
a high antigenic burden of secondary pathogen, (135). In addition, a landmark study compar-
which serves as trigger of the dysregulated im- ing the effects of continuous and intermittent
mune response (134). Treatment options for ART on HIV disease outcome (138) identi-
cases of IRIS are complicated and controversial, fied cardiovascular disease as one of the sig-
although most experts agree that deferring the nificant events associated with individuals who
initiation of ART for more than the short inter- interrupted ART intermittently, which led to
val that is required to initiate therapy against the increased exposure to replicating virus. Fur-
opportunistic infection(s) is almost always more ther analyses from this study found an asso-
life-threatening than the clinical manifestations ciation between cardiovascular events in the
of IRIS (132–134). ART interruption arm and inflammatory mark-

ers (139), which have been proposed as impor-
tant factors in HIV-induced immune activation
Consequences of Long-Term (see previous section).
Antiretroviral Therapy and Living One area that has received considerable at-
Longer with HIV tention and controversy is the incidence of ma-
The increasing availability and use of ART have lignancies in the era of ART. Although ART has
greatly reduced the incidence of opportunis- dramatically reduced the incidence of AIDS-
tic infections and AIDS-related malignancies. defining malignancies such as Kaposi’s sarcoma
The increasing availability of different classes and non-Hodgkin lymphoma, the effect of ART
of antiretroviral drugs to treat HIV-infected on the incidence of non-AIDS-defining ma-
individuals has also reduced concerns regard- lignancies (NADMs) has been more difficult
ing the emergence of viral resistance and has to evaluate. Confounding factors in assessing
provided physicians with more options to min- changes in NADMs in the era of ART include
imize drug-related toxicities and complications longer survival time, age and other risk fac-
(Figure 4). Nonetheless, several areas of con- tors, and variables associated with HIV status
cern remain; some are associated with the ART (108, 140, 141). There has been little agreement
regimens themselves, and others are associated on whether HIV-infected individuals continue
with the fact that people are living longer with to experience diminished immune surveillance
HIV. Within the latter category, there are con- that would affect the incidence of NADMs,
ditions that suggest premature aging and con- despite effective immunologic and virologic
ditions that are exacerbated by the fact that responses to ART. However, HIV-infected
most HIV-infected individuals never achieve individuals may be more likely than HIV-
complete immunologic reconstitution; in ad- uninfected individuals to develop NADMs that
dition, there are conditions that combine ele- are caused by infectious agents, including hu-
ments of both aging and HIV infection. Cardio- man papillomavirus and hepatitis B and C
vascular disease represents one such condition; viruses (142). It remains unclear whether an
it also involves risks associated with prolonged impaired ability to suppress coinfecting onco-
use of ART itself (reviewed in Reference 135). genic viruses explains the increased incidence of
Both nonnucleoside reverse transcriptase in- corresponding cancers, although coinfections
hibitors and protease inhibitors have been asso- themselves continue to be highly prevalent in
ciated with increased risk of cardiovascular dis- HIV-infected individuals in the era of ART
ease (136, 137), part of which can be explained (143). These observations underscore the need
by effects of the drugs on lipid metabolism. to find better therapeutic strategies for treating
However, HIV infection itself increases the coinfections such as hepatitis B and C (144), as
238 Moir · ·
Chun Fauci
well as to develop vaccines against these viruses. control HIV infection through innate, cellular,
These are important considerations, given that and humoral immunity.
both age and HIV infection (with or without
LTNP: long-term
ART) are associated with reduced responsive- nonprogressor
ness to immunization (145).
Insight from Long-Term
Nonprogressors and Elite Controllers
EFFECTS OF HOST AND VIRAL LTNPs were first described in the 1990s, when
FACTORS IN HIV INFECTION sensitive testing for HIV plasma viremia made
Both host and viral factors are thought to in- it possible to begin to identify the approxi-
fluence the natural course of HIV infection and mately 5–15% of HIV-infected individuals who
disease progression. Considerable insight has fall into the broader nonprogressor category
been gained over the past 25 years from studies (146). The subgroup of elite controllers com-
of HIV-infected individuals who maintain low prises less than 1% of HIV-infected individuals
to undetectable HIV plasma viremia and stable (146). In this group, certain human leukocyte
CD4+ T cell counts in the absence of ART. As a antigen (HLA) class I haplotypes, particularly
group, these individuals are referred to as long- HLA-B57–01, are overrepresented (Table 1).
term nonprogressors (LTNPs), and within this Although there has been much debate and some
group, patients who maintain a viral burden be- evidence that low viral fitness may contribute to
low the limits of detection are referred to as elite the suppression of HIV replication in a certain
controllers. Studies on the natural control of percentage of LTNPs (147), there are strong
HIV disease progression in LTNPs and other indications that host factors also play an im-
HIV-infected individuals have focused on cel- portant role in restricting HIV replication and
lular restriction factors and viral fitness, as well disease progression (Tables 1 and 2). Among
as host genetics and its impact on the ability to the host genetic factors most consistently
Table 1 Characteristics of long-term nonprogressors (LTNPs)a

Key characteristics
Infected >10 years
Maintain low (LTNP) to undetectable plasma viremia (elite LTNP, <50 copies per milliliter)
Maintain normal and stable CD4+ T cell counts
Maintain high levels of human immunodeficiency (HIV)-specific and functional CD4+ T cells
Maintain strong innate immunity against HIV
Maintain strong anti-HIV immunity, particularly CD8+ CTLs
Carry certain genetic traits
Genetic features
HLA B∗ 5701
HLA B∗ 5703
HLA B∗ 2705
Heterozygosity for CCR532
Antiviral CD8+ T cell immunity
High frequency of polyfunctional HIV-specific CD8+ T cells
High capacity to produce perforin upon exposure to HIV antigens
High capacity to proliferate upon exposure to HIV antigens
Secretion of antiviral factors (C-chemokines)
a
Abbreviations: CTL, cytotoxic T lymphocyte; HLA, human leukocyte antigen.

Table 2 Host restriction factors of human immunodeficiency virusa (Table 2) (see Reference 151 for a review).
Host restriction factors One such restriction factor is APOBEC3G,
CCR532 a member of the apolipoprotein B editing
CCL3L1-CCR5 genotypes complex (APOBEC) cellular deaminase family
APOBEC3G that modifies cytidine and restricts HIV repli-
Trim-5α
cation by at least two different mechanisms.
APOBEC3G is packaged within viral particles
Tetherin
and, upon subsequent entry into a new target
MicroRNA
cell, induces dG-to-dA hypermutations in the
Coexpression of KIR3DS1 (on natural killer cells) and HLA Bw4–08I
nascent proviral DNA. The potentially crip-
Coexpression of KIR3DL1 (on natural killer cells) and HLA Bw4
pling effect of APOBEC3G on HIV DNA is
a
Abbreviations: APOBEC3G, apolipoprotein B editing complex 3G; greatly diminished by the action of the HIV ac-
cessory protein Vif. In addition, APOBEC3G
CCR5, C-chemokine receptor 5; HLA, human leukocyte antigen.

may be active in resting but not activated CD4+
T cells and may restrict HIV postentry events
associated with LTNP status are certain alle- in a deaminase-independent mechanism (152).
les within the HLA class I loci that are thought A second intrinsic cellular restriction factor is
to help control viral replication via CD8+ T Trim-5α, a member of the tripartite protein
cell–mediated immunity. Given that HLA class family that targets the retrovirus capsid protein
I molecules present processed viral antigens on for degradation (reviewed in Reference 151).
the surface of infected cells to CD8+ T cells, The activity of Trim-5α is highly dependent
it is assumed, although not proven, that HLA on species-specific compatibility, such that HIV
molecules associated with nonprogression are Gag escapes the effects of human Trim-5α and
the most effective at enabling CD8+ T cells SIV Gag escapes the effects of most simian
to recognize and lyse infected cells and/or se- Trim-5α, whereas the inability of HIV to in-
crete antiviral cytokines. Also, CD8+ T cells fect nonhuman primates is at least in part due
of LTNPs may be superior to those of HIV- to the inhibitory effects of simian Trim-5α on
infected progressors in terms of proliferation HIV. If simian Trim-5α could be modified to
(93), cytolytic capacity (148), ability to secrete allow HIV replication, it could lead the way to
multiple cytokines (see previous section) (96), better animal models for HIV infection.
and capacity to respond to viral variants (149). Both APOBEC3G and Trim-5α are consid-
Other mechanisms of immune-mediated viral ered to be part of the innate immune response,
control in LTNPs include a role for HLA which could be harnessed in order to restrict the
molecules that recognize certain regulatory re- early deleterious effects of HIV infection (see
ceptors on NK cells, which kill infected cells via above) and enable a more effect adaptive im-
innate mechanisms; enhanced survival and ef- mune response against HIV to develop. Among
fector functions of CD4+ T cells; and a possible other elements of innate immunity that have
role for neutralizing antibodies and antibodies been implicated in slower disease progression
that facilitate cell-mediated killing (reviewed in are (a) receptors and HLA molecules associ-
Reference 150). ated with NK cell function and (b) members
of the TLR family of pattern-recognition re-
ceptors expressed on pDCs and associated with
Cellular Restriction Factors the myriad of antiviral IFN-α-based pathways.
Replication of HIV and other retroviruses may However, any strategy aimed at enhancing in-
be restricted at the intracellular level by intrin- nate immune responses must be balanced with
sic host factors that function in a virus-specific the potential deleterious effects of inducing ex-
and, in many cases, species-specific manner cessive immune activation, as can occur with
240 Moir · ·
Chun Fauci
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 for
Activation). Nonetheless, efforts to improve 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.
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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• Top downloaded articles

Annu. Rev. Pathol. Mech. Dis. 2011. 6:223–48 Keywords

INTRODUCTION syndrome. Depletion of susceptible CD4+ T

antiretroviral drugs immune activation and dysregulation, as illus-

Infected resting Late-responding CTLs

Resting CD4+ T cells

Hours Days Weeks Years

www.annualreviews.org • Pathogenesis of HIV 225

Acute phase Early chronic phase

Establishment of HIV reservoirs

HIV-specific antibody+ (Western blot)

101 HIV RNA+ (PCR)

226 Moir · · Chun Fauci

High levels of plasma

Massive and progressive

Rapid CD4+ T cell

www.annualreviews.org • Pathogenesis of HIV 227

(29–31). A number of studies have suggested ESTABLISHMENT AND

reservoirs can be divided into two main cate-

and/or CD4+ T cells undergoing low levels Induce viral replication

proviral DNA in tissue-derived CD4+ T cells Integrase

sue sections isolated from peripheral LNs of

www.annualreviews.org • Pathogenesis of HIV 229

Lymph node GALT Productively

www.annualreviews.org • Pathogenesis of HIV 231

to HIV-induced systemic immune activa-

www.annualreviews.org • Pathogenesis of HIV 233

www.annualreviews.org • Pathogenesis of HIV 235

Consequences of Low CD4+ However, more recent ﬁndings (128) suggest

most important predictors of incomplete CD4+

www.annualreviews.org • Pathogenesis of HIV 237

of IRIS (132–134). ART interruption arm and inﬂammatory mark-

Table 1 Characteristics of long-term nonprogressors (LTNPs)a

www.annualreviews.org • Pathogenesis of HIV 239

CCR5, C-chemokine receptor 5; HLA, human leukocyte antigen.

www.annualreviews.org • Pathogenesis of HIV 241

29. Performs genetic

www.annualreviews.org • Pathogenesis of HIV 243

infected, resting CD4+ 1:1284–90

Nat. Med. 14:421–28

www.annualreviews.org • Pathogenesis of HIV 245

tially maintain highly functional HIV-speciﬁc CD8+ T cells. Blood 107:4781–89

speciﬁc CD8+ T cell survival in HIV infection. J. Exp. Med. 203:2281–92

www.annualreviews.org • Pathogenesis of HIV 247

with and without a known infectious cause. AIDS 23:2337–45

Starting in Immunology by Way of Immunopathology

The Pathobiology of Arrhythmogenic Cardiomyopathy

and Ajit Varki p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 365

Cumulative Index of Contributing Authors, Volumes 1–6 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 539

An online log of corrections to Annual Review of Pathology: Mechanisms of Disease articles

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