Transmission, acute HIV-1 infection and the quest for strategies to prevent infection.

Abstract

By the acute stage of HIV-1 infection, the immune system already faces daunting challenges. Research on mucosal barriers and the events immediately after heterosexual transmission that precede this acute stage could facilitate the development of effective microbicides and vaccines.

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NATURE MEDICINE VOLUME 9 | NUMBER 7 | JULY 2003
NATURE MEDICINE VOLUME 9 | NUMBER 7 | JULY 2003
847847
HIV SPECIAL
The AIDS epidemic has exacted a terrible toll in terms of loss of life
and decreased quality of life worldwide, especially in Africa, where
70% of deaths from HIV-1 infection have occurred1. AIDS increas-
ingly has a woman’s face; almost 60% of individuals infected with
HIV-1 are women2. There is therefore a great urgency to develop vac-
cines, microbicides and other preventive strategies to blunt the
progress of the epidemic and,in particular,to stop the transmission of
HIV-1 to women.
This review focuses on studies of this predominant route of hetero-
sexual transmission, as well as the acute stage of infection by HIV-1
and the closely related simian immunodeficiency virus (SIV).Because
transmission and the earliest stages of infection cannot be investigated
systematically in humans, the in vivo studies that we discuss are con-
ducted in rhesus macaques inoculated intravaginally and atraumati-
cally with SIV. Although far from perfect, the many parallels in
anatomy,physiology,immunology and nature and course of infection
make this model,in our view,the most relevant for in vivo study3,4.
The main lesson to be learned from the HIV-1 and SIV studies is
how quickly the virus establishes persistent infection in a lymphatic
tissue reservoir and compromises host defenses. Because of this, we
conclude that microbicides and vaccines that elicit durable mucosal
immunity, thereby targeting the earliest stages of infection, have the
best prospects for preventing or containing infection.
Acute HIV-1 infection: the die is cast
By the acute stage of HIV-1 infection, the immune system is already
facing un uphill struggle. In the 2- to 3-week incubation period that
follows sexual mucosal transmission (or transmission by oral or par-
enteral routes), the virus becomes well established in a lymphatic tis-
sue reservoir5. This reservoir6–12is the principal site of virus
production,storage,persistence (Fig.1) and pathology13(CD4+T-cell
depletion and destruction of follicles and the lymphatic tissue archi-
tecture).By the time the infection becomes symptomatic in the clinical
illness associated with seroconversion14,15most commonly fever,
skin rash, oral ulcers and lymphadenopathy16–19the lymphatic tis-
sues teem with productively,chronically and latently infected cells,and
with virions (Fig.1).
From this acute stage until the late stages of infection,billions of viri-
ons are produced daily, mainly by activated CD4+T cells20. About
10–100 million of the infected activated CD4+T cells die each day21in a
dynamic process22,23in which each infected cell in the acute stage of
infection generates about 20 infected progeny during its lifetime24.Once
acute infection is established, a cellular immune response to HIV-1 is
generated that partially controls viral replication25. It has been esti-
mated,however,that a vaccine ofat least 95% efficacy would be required
to extinguish productive infection ofthis magnitude in the acute stage24.
In addition to the general loss of CD4+T cells, the virus preferen-
tially infects and eliminates HIV-1-specific CD4+T cells26,which fur-
ther compromises the virus-specific immune response. In addition,
the error-prone viral replication process generates mutants that can
escape neutralizing antibodies27,28and virus-specific cytotoxic T lym-
phocytes (CTLs) in both HIV-1 and SIV infections29–32, further con-
tributing to the continuing difficulties that the immune system
encounters in containing infection.
The lymphatic tissues also contain a population of infected resting
CD4+T cells20,variously estimated at 1–100 million11,20,33,and a large
pool of 5–50 billion virions in immune complexes bound to follicular
dendritic cells (FDCs)9–12,34in the acute and subsequent stages of
infection. The infected resting CD4+T cells either produce small
quantities of virus or are latently infected.Infectious virus can be pro-
duced by the activation of latently infected cells and by the reactivation
of virus in immune complexes by FDCs.Thus,there are two long-lived
reservoirs and sources of virus that persist despite host defenses and
current antiretroviral therapy (ART) and that can refuel infection35,36.
Thus,by the time there is any indication of infection,the immune sys-
tem,vaccines or ART are already faced with huge obstacles to the erad-
ication or full control of infection.
The early stages of HIV-1 transmission
The litany of difficulties that host defenses confront in acute infection
points to the importance of analyzing even earlier events in infection
to discover where the virus may be more vulnerable to sterilizing
immunity or to other means of preventing infection.Below,we discuss
Transmission, acute HIV-1 infection and
the quest for strategies to prevent infection
Melissa Pope1& Ashley T Haase2
By the acute stage of HIV-1 infection, the immune system already faces daunting challenges. Research on mucosal barriers and
the events immediately after heterosexual transmission that precede this acute stage could facilitate the development of
effective microbicides and vaccines.
1Center for Biomedical Research, Population Council, 1230 York Avenue, New
York 10021, USA. 2Department of Microbiology, University of Minnesota, 420
Delaware Street SE, Minneapolis, Minnesota 55455, USA. Correspondence
should be addressed to A.T.H. (ashley@mail.ahc.umn.edu)
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some of the issues relevant to the early stages of pathogenesis, from
infection at the portal of entry to dissemination and establishment of a
persistent infection in the lymphatic tissues (Fig. 2). Our discussion
focuses on the transmission of cell-free virus because so much more is
known about the transmission in vivo of cell-free as opposed to cell-
associated virus, but there are probably inherent differences in how
cell-associated viruses are transmitted.
Viral dose and transmission. The probability of transmission for each
encounter with HIV-1 is quite small (about 0.001) and is related,in part,
to dose37.There is a direct relationship between viral load in peripheral
blood and transmission, with a cutoff of around 1,500 copies of viral
RNA per ml of blood, below which there is no evidence of transmis-
sion38.The extent to which the concentration of virus in semen mirrors
that in peripheral blood is unknown,but this dose dependency in trans-
mission suggests that ART and vaccines that lower viral load might have
a significant impact in reducing transmission at the population level.
The relationship between dose and transmission highlights one of
the principal imperfections of the nonhuman primate models: the
dose of SIV required to infect macaques consistently by the intravagi-
nal route,about 105TCID50(50% tissue culture infectious doses)3,4,is
probably far greater than that required to infect humans and may skew
the appraisal of vaccine (and microbicide) candidates in the macaque
model towards an underestimation of their potential efficacy.
R5 and X4 viruses.Transmission of HIV-1 to CD4+T cells is mediated
by interactions between the viral envelope glycoproteins gp120 and
gp41, the T-cell receptor CD4 and the chemokine coreceptors CCR5
(ref. 39) and CXCR4 (ref. 40). During the course of HIV-1 infection,
the error-prone viral polymerase generates genetically diverse quasi-
species, including the strains designated R5 and X4, which use the
CCR5 and CXCR4 coreceptors,respectively,to infect cells41.
Mainly R5 strains are transmitted, for reasons discussed below,
whereas X4 strains emerge later and are associated with a rapid pro-
gression to AIDS42. A deletion of 32 base pairs in CCR5 prevents
HIV-1 infection43–45,which indicates that there is strong selection for
the R5 strain during transmission and early infection.
Crossing the mucosal barrier
Inflammation, menstrual cycle and hormones. The idealized intact
vaginal epithelium contains stratified squamous cells, several layers
thick, and an intact single layer of columnar epithelium in the endo-
cervix that may be more easily traversed by HIV-1 and SIV (Fig.2).In
reality, the vaginal epithelial barrier changes markedly during the
menstrual cycle and in response to exogenously administered hor-
mones such as progesterone46. Pre-existing inflammatory conditions
such as sexually transmitted diseases, bacterial vaginosis and some
microbicides (such as nonoxynol-9) also cause microulcerations and
breaks in the epithelium.
Thinning and breaches in the mucosal barrier, created in the above
ways,could quickly expose susceptible cells in the submucosa to virus.
This would increase the likelihood of establishing and rapidly dissem-
inating infection,and would decrease the opportunities for a microbi-
cide to inactivate the virus or for a vaccine-induced recall response to
contain the infection at the portal of entry.In SIV infection,this could
be the basis for the reported resistance to inactivation of the inoculated
virus within 1 h and rapid dissemination beyond the portal of entry
within 24 h (ref.47),and may also be responsible for enhanced intrav-
aginal transmission in monkeys pretreated with progesterone. In
HIV-1 infection, thinning and breaches may underlie the increased
transmission associated with sexually transmitted diseases, bacterial
vaginosis and nonoxynol-9 use48–51,as well as the association between
cervical ectopy and increased HIV-1 transmission52.
It may be easier for viruses to traverse the single layer of epithelium
that lines the endocervix than the multilayer squamous epithelium of
the ectocervix and vaginal mucosa. This would account for both the
association between cervical ectopy and increased HIV-1 transmis-
sion52,and the higher concentration of SIV-infected cells found in the
cervical submucosa after intravaginal inoculation20. The fact that the
virus crosses the mucosal barrier so rapidly and gains access to den-
dritic cells (DCs) and CD4+T cells to facilitate virus production and
dissemination limits opportunities for a vaccine-induced anamnestic
response to HIV-1 that could prevent or fully control infection.
Mechanisms for crossing an intact mucosal barrier. HIV-1 could tra-
verse the intact stratified squamous epithelium of the vaginal mucosa
and the simple columnar epithelium ofthe cervix by the modes oftrans-
mission and dissemination shown in Fig. 3. Transcytosis by a vesicular
pathway is one mechanism by which HIV-1 could cross an intact barrier
to infect susceptible host cells in the underlying tissues53,but it is also a
stage at which the virus is vulnerable to mucosal antibody responses
because secretory antibodies neutralize the infectivity of transcytosing
virus54,55.In addition,SIV bound by neutralizing antibodies specific for
the viral envelope is also significantly less effective than is unbound virus
at infecting macaques through the vaginal route56.
Epithelial cells selectively capture R5 HIV-1 and then transfer infec-
tion to CCR5-expressing target cells underneath the epithelia, which
could account for the preferential transmission of HIV-1 strain R5 (ref.
57).Dendritic cells positioned in the stratified squamous
Neutraliza
escape mu
virus
CD4 T-cell
depletion
(HIV-specific)
Reactivatable HIV in
immune complexes bound
to FDCs
CTL escape
mutants
Germinal center
Resting
CD4+ T cell
Latently infected
Dead/killed
I
I
I*
I
Productively
infected
* * * *
+
Figure 1 HIV-1 lymphatic tissue reservoirs and the potential obstacles that
the immune system faces. In HIV-1 (and SIV) infections, the lymphatic
tissues are the reservoir where virus is produced and stored in immune
complexes bound by FDCs, and where virus persists in latently infected
resting CD4+T cells. Viral replication generates antigenic escape mutants and
depletes CD4+T cells (including HIV-1-specific CD4+T cells) either directly
or indirectly. FDCs can also reactivate infectious virus from the large FDC
stores. Collectively, these obstacles to the elimination or control of infection
by host defenses are already established in the acute stages of infection.
Katie Ris
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epithelium of the vaginal mucosa (with processes that extend to the
lumenal surface to sample contents and to trap pathogens) and in the
underlying tissues of the vagina and cervix are also prime targets for
HIV-1 (Fig. 3). Dendritic cells express CD4, CCR5, DC-SIGN58and
other C-type lectin receptors (CLRs) that facilitate capture and infec-
tion by HIV-1 and SIV59,60. Different subsets of DCs express unique
members of the CLR family,but the virus can use specific CLRs on each
subset to ensure capture and dissemination.For example,DCs in vagi-
nal epithelium express langerin (also known as CD207) but lack DC-
SIGN (CD209) and mannose receptor (CD206), whereas DCs in the
lamina propria express DC-SIGN and mannose receptor but not lan-
gerin,and yet both subsets bind virus in a CLR-dependent manner61.
Evidence indicates that in vivo,both intraepithelial and submucosal
DCs and CD4+T lymphocytes are the predominant cell populations
first targeted by SIV and HIV-1.After intravaginal inoculation of SIV,
viral DNA and RNA are detected within 24–72 h of exposure in
DCs47,62, intraepithelial lymphocytes and CD4+T cells (mainly rest-
ing, but also activated) in the endocervical submucosa20. In female
genital organ cultures ex vivo, the first HIV-1-infected cells that could
be detected were intraepithelial memory CD4+T cells63,64.
Local propagation and dissemination
After crossing the epithelial barrier, HIV-1 and SIV can infect CCR5-
expressing DCs, macrophages and T cells in the underlying mucosal
tissues (Figs.2 and 3) to initiate infection.Dendritic cells capture HIV-
1 through CLRs61and are productively infected by a CCR5-dependent
mechanism65,66.Captured virus can be internalized (without produc-
tive infection) and then rapidly transmitted to nearby CD4+T cells
within an hour,in the form of an ‘infectious synapse’67(S.G.Turville et
al., unpublished data). Productive infection in CD4+T cells is facili-
tated in these DC–T cell conjugates68,69and can spread infection to
more CD4+T cells, most efficiently to the memory subset59, which is
the chief producer of virus in vivo20. In carrying out their normal
function of conveying pathogens and antigens to the draining lym-
phatic tissues to induce an immune response,virus-carrying DCs can
also disseminate infection to large numbers of CD4+T cells to amplify
and further disseminate the infection.
Transmitted strains of HIV-1 and SIV were originally referred to as
macrophage- or M-tropic because the viruses replicated in vitro in
monocyte and macrophage cultures but not in T-cell lines70. The tro-
pism was subsequently shown to be a consequence of selection for R5
viral strains.In fact,there is no correlation in vivo between M-tropism
and intravaginal transmission of SIV4. But infection of macrophages
and DCs may be important in transmission by recruiting and enhanc-
ing virus production in T cells in ways that circumvent the activation
of antiviral T-cell responses.Viral replication and viral gene products
(including Nef, Tat and Vpx)71–76induce macrophages and DCs to
forge contacts with T cells and to drive the productive infection of rest-
ing and activated CD4+T cells. This may
partly explain the predominance of infection
in resting CD4+T cells during early SIV infec-
tion after intravaginal inoculation20and in
genital organ cultures in vitro63,64.
HIV-1 transmission in vivo
Understanding which coreceptors and other
molecules are involved in virus-host cell
interactions and how these interactions occur
helps to identify the kinds of cells that HIV-1
(or SIV) can infect. But it does not tell us
which types of cells,and in what proportions,
will actually be infected either at transmission
or in the acute and later stages of infection in
an affected individual. These factors may be
determined by substrate availability77.
The types and proportions of cells infected
in vivo may be determined by substrate avail-
ability and spatial proximity.In predator-prey
models78, the likelihood of infecting a cell is
Cervix
Vagina
Viral
quasi
speciesR5
CD4+ T cell
Dendritic
cell
Efferent
lymphatics
Thoracic duct
Spleen
Brain
Liver
Transmission and acute infection
Host
Mucosal
Barrier
Submucosa
Draining
lymph-node
Innate and
adaptive
immune
defenses
Lymphoid and
other organ
systems and
peripheral
tissues
Virus
Crossing the
mucosal barrier
Virus–host cell
interactions and
local propgation
of infection
Dissemination
to draining
lymph nodes
Establishment
of lymphatic
tissue reservoir
Systemic dissemination
of virus and infected cells
Afferent
lymphatics
Lung
Lymph
node
GALT
Macrophage
Figure 2 Overview of sexual transmission to
women and acute infection. Shown are the major
stages and events in transmission relevant to
development of microbicides, vaccines and other
preventive measures. R5 viruses from a viral
quasispecies of R5 and X4 viruses are selectively
transmitted. After crossing the cervicovaginal
mucosal barrier, DCs, CD4+T cells and
macrophages in the underlying submucosa are
infected. Infection is subsequently propagated
and disseminated, thereby establishing the
lymphatic tissue reservoir that spreads infection
to other organs and peripheral tissues. Innate and
adaptive host defenses (left column) are directed
at the different stages to prevent transmission
and contain infection.
Katie Ris
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determined by the density of a particular type of cell and its proximity
to a virus-producing cell. Such a model can account for both the pre-
dominance of infection of CD4+T cells at transmission and in acute
and later stages of SIV and HIV-1 infection12,20,and the predominance
of productive infection in ostensibly resting CD4+T cells in the first
two weeks of SIV infection, during which more than 80% of the cells
containing SIV RNA are resting CD4+T cells20.
In the acute stage of HIV-1 infection, roughly equal proportions of
the predominant population of CD4+T cells positive for HIV-1 RNA
were typed as resting or activated20.At later stages,most of the infected
CD4+T cells were activated, consistent with the greater availability of
activated CD4+T cells, owing to chronic immune activation, to be
infected. In addition, the clustering of SIV-infected cells one and two
cell diameters away from a ‘parent’infected cell79and the clustering of
SIV genotypes80are consistent with the spatial proximity tenet of such
a predator-prey model.
Virus production by resting and activated CD4+T cells
Resting CD4+T cells infected with SIV or HIV-1 have about five times
fewer copies of viral RNA than do infected activated CD4+T cells20,
consistent with the low amount of virus production in this type of
cell. But because CD4+T cells predominate at transmission and dur-
ing the first days of SIV infection,they could have key roles in spread-
ing infection and in maintaining an unbroken chain of transmission
from one infected cell to the next. The function of the infected acti-
vated cell may be to act as an amplifier,propagating infection to more
cells at greater distances.
Staged versus rapid spread beyond the portal of entry
The answers to questions of how and when infection is disseminated
from the portal of entry have important implications for vaccine
development.On the one hand,if the virus replicates locally for several
days at the portal of entry in small numbers of cells with low levels of
virus production, a vaccine-induced memory response will have the
best chance of containing and perhaps eliminating infection.If,on the
other hand,the virus quickly reaches large numbers of CD4+T cells in
the draining lymph nodes and large amounts of virus are produced to
disseminate infection systemically throughout the lymphatic tissues,
the immune system will face an uphill battle, even with a rapid recall
response. In addition, immune defenses will be further weakened by
the loss of CD4+T cells to infection. In SIV infection, these losses are
very substantial, particularly in gut-associated lymphoid tissues81
where the largest populations of lymphocytes are located, but also at
the portal of entry82.
Evidence from the SIV macaque model supports both schemes.
There are reports that SIV replication is restricted to small foci in the
cervical submucosa in the first week after intravaginal inoculation20,
and that local amplification and ‘stepwise’ dissemination occurs after
intrarectal transmission of SIV71.By contrast,within 24 h of intravagi-
nal exposure, SIV-infected cells have been detected in the draining
lymph nodes of SIV-infected rhesus macaques47, and within 48 h in
pig-tailed macaques inoculated intravaginally with SIV/HIV-1 (ref.
83). These two observations might reflect, for example, a pre-existing
inflammation that facilitates the rapid spread of virus. Whatever the
mechanisms,they need to be understood if we are to devise countering
strategies against rapid viral spread.
The race between virus and immune defenses: Too little, too late
Figure 2 characterizes the fight between virus and host as a struggle in
part for dominance in what we call the ‘in vivo effector-to-target ratio’
(the ratio of virus-specific CD8+T cells to productively infected cells).
The host defenses will win if virus-specific CTLs quickly outnumber
infected target cells, particularly at the portal of entry, whereas the
virus will win if this is not the case.In both published and unpublished
studies of the natural history of sexual mucosal transmission,it seems
likely that the virus usually wins because the host is unable to mount a
cellular immune response of sufficient magnitude,breadth and rapid-
ity to contain infection.
After intrarectal or intravaginal inoculation of SIV,significant num-
bers of SIV-specific CD8+T cells are not detected until the second to
third week of infection, and the CD8 response is largely focused on
immunodominant epitopes in Gag and Tat84. By this stage, there are
large numbers of productively infected cells throughout the lymphatic
tissues and an effector-to-target ratio of <1 at most sites (calculated as
the ratio of Gag and Tat tetramer–positive CD8+T cells to SIV
RNA–positive cells; M. Reynolds et al., unpublished data). The rela-
tively unchecked replication also quickly spawns the above-mentioned
Vagina
Infected DC
DC and T-cell
conjugate
captured vi
CD
Cervix
1
rent
lymphatics
Draining
lymph node
M
a
c
Crossing
the barrier
Propagation
of infection
Dissemination
Figure 3 Close-up view of virus crossing the barrier and initial propagation
and dissemination of infection. Viruses cross the barrier by capture or
infection of DCs (1), transcytosis (2) or infection of intraepithelial
lymphocytes (3). After R5 virus is ferried across the barrier or produced by
DCs or intraepithelial lymphocytes, it infects resting and activated CD4+T
cells, DCs, DC and T-cell conjugates, macrophages, and macrophage and T-
cell conjugates. There is also enhanced transmission to T cells by viruses
captured by DCs through CLRs. Virus produced by T cells, DCs,
macrophages and infected cells spread the infection to the draining lymph
nodes. Infection may be initially confined to the portal of entry with
subsequent dissemination, or virions and infected cells may rapidly spread
infection to the draining lymph nodes and beyond.
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CTL escape mutants29–32, further compounding the difficulties of
controlling infection.
Microbicide and vaccine success stories
These natural history studies paint a rather depressing picture of how
quickly conditions become unfavorable for host defenses to prevent or
clear infection, but there are success stories of prevention and reports
of resistance to infection that provide proof of principal that sexual
mucosal transmission can be stopped.
First,although antibodies are generated too late in the natural his-
tory of acute infection to contribute to host defenses, they might be
more effective if induced by a vaccine or supplied locally in sufficient
concentration to block entry and spread.Antibodies can block infec-
tion, as substantiated by the report that antiviral antibodies in a
microbicide prevent infection by SIV56. Second, there are reports
that vaccines can prevent transmission of intravaginally and
intrarectally inoculated SIV85–90. Finally, some individuals who have
been repeatedly exposed to HIV-1 remain seronegative and appar-
ently uninfected, although the virus may be present at extraordinar-
ily low levels;this resistance is correlated with a virus-specific cellular
immune response91,92. Although the resistance may not be sus-
tainedfor example,exposed and uninfected women who leave and
then return to commercial sex work can become infectedit sug-
gests that a vaccine-induced durable local mucosal immune response
may prevent infection.
Future research
When we look at the overview of transmission and acute infection
(Figs. 1 and 2) and consider the great difficulties that host defenses
encounter once the lymphatic tissue reservoir is established, we are
persuaded that the primary focus of future studies for preventive
strategies needs to be at the beginning of transmissionthat is,at the
mucosal barrier and the initial interaction of virus with host cells and
host defenses. As far as the mucosal barrier is concerned, we need to
understand the causes of pre-existing inflammation and how to treat
it, and to develop effective microbicides that inactivate virus without
destroying the integrity of the barrier.At and beyond the mucosal bar-
rier, we need to examine the role of innate defenses in preventing or
controlling infection in vivo.
Greater knowledge of these first-line defenses might lead to new
measures to inactivate or inhibit replication of the virus before or
immediately after it crosses the barrier. For effective vaccine develop-
ment, we need to know how to elicit a durable cellular and humoral
mucosal immune response comprising persistent antibodies in cervi-
cal vaginal fluids and virus-specific memory CD8+T cells, both of
which are needed to generate a rapid recall response at the portal of
entry.Finally,we need a widely available nonhuman primate model of
SIV infection that more closely resembles HIV-1 transmission by
repeated low-dose exposure, to look for correlates of protection and
critical vaccine components.
In this review,we have focused on the early events of mucosal spread
in women, but future studies will clearly also need to address par-
enteral, rectal, oral and mother-to-child transmission. Collectively,
such studies will advance in important ways the urgent quest to
develop effective microbicides and vaccines to reduce the spread of
HIV-1 around the world.
ACKNOWLEDGMENTS
We thank C.O’Neill and T.Leonard for help with editing and preparing the
manuscript and figures,and J.V.Carlis,T.Schacker and P.J.Southern for
comments.M.P.is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric
AIDS Foundation and is supported by grants AI52060,AI40877,HD41752 and
AI52048 from the National Institutes of Health (NIH),and by the Rockefeller
Foundation and the Elizabeth Glaser Pediatric AIDS Foundation.A.T.H.is
Regents’Professor and Head of the Department of Microbiology at the University
of Minnesota and is supported by grants CA 79458,AI28246,HD37356,AI48484
and RR00167 from the NIH,and by the University of Minnesota.
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