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HIV Medicine 2007
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4. Pathogenesis of HIV-1 Infection
Since the initial description of the human immunodeficiency virus type I (HIV-1) in 1983 (Barre-Sonoussi 1983, Gallo 1983) and HIV-2 in 1986 (Clavel 1986), these two viruses have been identified for almost 20 years as the primary cause of the acquired immunodeficiency syndrome (AIDS). As HIV-1 is the major cause of AIDS in the world today, our discussion will be primarily limited to HIV-1 infection. Worldwide, the number of HIV-1 infected persons exceeds 40 million, the majority of whom live in the developing countries of Sub-Saharan Africa, Asia and South America.
The introduction of protease inhibitors and non-nucleotide reverse transcriptase inhibitors (NNRTIs) to antiretroviral treatment regimens in 1995 began the era of highly active antiretroviral therapy (HAART), and resulted in dramatic improvements in the mortality and morbidity of HIV disease, as determined by a decreased incidence of opportunistic infections, tumors, and deaths. Despite all the therapeutic advantages achieved during the last decade, including the development of HAART, once an individual has become infected, eradication of the virus still remains impossible.
In addition, new problems relating to the short- and long-term toxicity of drug treatments and the
occurrence of resistance mutations in both circulating and transmitted viruses are emerging. In most
countries in South East Asia and Africa, the incidence and prevalence of HIV-1 infection continues
to increase and surpass that of Europe and North America. However, due to the high costs of drug
regimens and the lack of a healthcare infrastructure in these developing countries, the widespread
use of HAART is currently still difficult. The further course of the HIV-1 pandemic, therefore,
mainly depends on how and to what degree the developing countries with a high HIV-1 prevalence are
able to take advantage of the medical pro-gress achieved in Europe and North America, and whether an
effective prophylactic vaccine becomes available in the near future.
An understanding of the immunopathogenesis of HIV-1 infection is a major prere-quisite for
rationally improving therapeutic strategies, developing immunotherapeutics and prophylactic
vaccines. As in other virus infections, the individual course of HIV-1 infection depends on both
host and viral factors.
The course of infection with HIV-1 in HIV-infected humans may vary dramatically, even if the primary
infections arose from the same source (Liu 1997). In some individuals, with a long-term
non-progressive HIV-1 infection (i.e., lack of decline in CD4+ T-cell counts, or chronic infection
for at least 7 years without the development of AIDS), a defective virion was identified (Kirchhoff
1995). Thus, infection with a defective virus, or one that has a poor capacity to replicate, may
prolong the clinical course of HIV-1 infection. However, in most individuals, HIV-1 infection is
characterized by a replication-competent virus with a high daily turnover of virions.
Host factors may also determine whether or not an HIV-1-infected individual rapidly develops
clinically overt immunodeficiency, or whether this individual belongs to the group of long-term
non-progressors, who represent about 5 % of all infected patients. The identification and
characterization of host factors contributing to the course of HIV infection, including
immunological defense mechanisms and genetic factors, will be crucial for our understanding of the
immunopathogenesis of HIV infection and for the development of immunotherapeutic and prophylactic
1. The structure of HIV-1
HIV-1 is a retrovirus and belongs to the family of lentiviruses. Infections with lentiviruses
typically show a chronic course of disease, a long period of clinical latency, persistent viral
replication and involvement of the central nervous system. Visna infections in sheep, simian
immunodeficiency virus infections (SIV) in monkeys, or feline immunodeficiency virus infections
(FIV) in cats are typical examples of lentivirus infections.
Using electron microscopy, HIV-1 and HIV-2 resemble each other strikingly. However, they differ with
regard to the molecular weight of their proteins, as well as having differences in their accessory
genes. HIV-2 is genetically more closely related to the SIV found in sootey mangabeys (SIVsm) rather
than HIV-1 and it is likely that it was introduced into the human population by monkeys. Both HIV-1
and HIV-2 replicate in CD4+ T-cells and are regarded as pathogenic in infected persons, although the
actual immune deficiency may be less severe in HIV-2-infected individuals.
1.1. The morphologic structure of HIV-1
HIV-1 viral particles have a diameter of 100 nm and are surrounded by a lipoprotein membrane. Each
viral particle contains 72 glycoprotein complexes, which are integrated into this lipid membrane,
and are each composed of trimers of an external glycoprotein gp120 and a transmembrane spanning
protein gp41. The bonding between gp120 and gp41 is only loose and therefore gp120 may be shed
spontaneously within the local environment. Glycoprotein gp120 may also be detected in the serum as
well as within the lymphatic tissue of HIV-infected patients. During the process of budding, the
virus may also incorporate different host proteins from the membrane of the host cell into its
lipoprotein layer, such as HLA class I and II proteins, or adhesion proteins such as ICAM-1 that may
facilitate adhesion to other target cells. The matrix protein p17 is anchored to the inside of the
viral lipoprotein membrane. The p24 core antigen contains two copies of HIV-1 RNA. The HIV-1 RNA is
part of a protein-nucleic acid complex, which is composed of the nucleoprotein p7 and the reverse
transcriptase p66 (RT). The viral particle contains all the enzymatic equipment that is necessary
for replication: a reverse transcriptase (RT), an integrase p32 and a protease p11 (overview in:
Gelderblom 1993) (Fig. 1).
1.2. The organization of the viral genome
Most replication competent retroviruses depend on three genes: gag, pol and env: gag means
"group-antigen", pol represents "polymerase" and env is for "envelope" (overview in: Wong-Staal
1991) (Fig. 2). The "classical" structural scheme of a retroviral genome is: 5'LTR-gag-pol-env-LTR
3'. The LTR ("long terminal repeat") regions represent the two end parts of the viral genome, that
are connected to the cellular DNA of the host cell after integration and do not encode for any viral
proteins. The gag and env genes code for the nucleocapsid and the glycoproteins of the viral
membrane; the pol gene codes for the reverse transcriptase and other enzymes. In addition, HIV-1
contains six genes (vif, vpu, vpr, tat, rev and nef) in its 9kB RNA. Nef, vif, vpr and vpu were
classified as accessory genes in the past, as they are not absolutely required for replication in
vitro. The accessory genes, nef, tat and rev, are all produced early in the viral replication cycle.
Tat and rev are regulatory proteins that accumulate within the nucleus and bind to defined regions
of the viral RNA: TAR (transactivation-response elements), found in the LTR; and RRE (rev response
elements), found in the env gene, respectively. The tat protein is a potent transcriptional
activator of the LTR promoter region and is essential for viral replication in almost all in vitro
culture systems. Cyclin T1 is a necessary cellular cofactor for tat (Wei 1998). Tat and rev
stimulate the transcription of proviral HIV-1 DNA into RNA, promote RNA elongation, enhance the
transportation of HIV RNA from the nucleus to the cytoplasm and are essential for translation. Rev
is also a nuclear export factor that is important for switching from the early expression of
regulatory proteins to the structural proteins that are synthesized later.
Figure 1: Structure of an HIV virion particle. For detailed explanations see text.
Figure 2: HIV and its genes. For detailed explanations see text.
Nef has been shown to have a number of functions. Nef may induce downregulation of CD4 (Aiken 1994)
and HLA class I molecules (Collins 1998) from the surface of HIV-1-infected cells, which may
represent an important escape mechanism for the virus to evade an attack mediated by cytotoxic CD8+
T-cells and to avoid recognition by CD4+ T-cells. Nef may also interfere with T-cell activation by
binding to various proteins that are involved in intracellular signal transduction pathways
(Overview in: Peter 1998). In SIV-infected rhesus macaques, an intact nef gene was essential for a
high rate of virus production and the progression of disease. HIV-1, with deletions in nef, was
identified in a cohort of Australian long-term non-progressors. However, more recent reports
indicate that some of these patients are now developing signs of disease progression together with a
decline of CD4+ T-cells. Thus, although, deletions of the nef gene may slow viral replication, they
cannot always prevent the development of AIDS.
Vpr seems to be essential for viral replication in non-dividing cells such as macrophages. Vpr may
stimulate the HIV-LTR in addition to a variety of cellular and viral promoters. More recently, vpr
was shown to be important for the transport of the viral pre-integration complex to the nucleus
(Overview in: Miller 1997) and may arrest cells in the G2 phase of the cell cycle.
Vpu is important for the virus "budding" process, because mutations in vpu are associated with
persistence of the viral particles at the host cell surface. Vpu is also involved when CD4-gp160
complexes are degraded within the endoplasmic reticulum and therefore allows recycling of gp160 for
the formation of new virions (Cullen 1998 ).
Some recent publications have highlighted a new and important role for vif in supporting viral
replication (Mariani 2003). Vif-deficient HIV-1 isolates do not replicate in CD4+ T-cells, some T
cell lines ("non-permissive cells") or in macrophages. Vif-deficient isolates are able to enter a
target cell and initiate reverse transcription, but synthesis of proviral DNA remains incomplete. In
vitro fusion of "permissive" and "non-permissive" cells leads to a "non-permissive" phenotype,
suggesting that the replication of HIV depends on the presence or absence of a cellular inhibitor.
This endogenous inhibitory factor was recently identified as APOBEC3G (Sheehy 2002). APOBEC3G
("apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G") belongs to a family of
intracellular enzymes that specifically de-aminate cytosine to uracil in mRNA or DNA resulting in an
accumulation of G-to-A mutations that lead to degradation of viral DNA. By forming a complex with
APOBEC3G, vif blocks the inhibitory activity of APOBEC3G (Figure 3a).
Figure 3: HIV wild-type infection: vif interacts with APOBEC3G, binds to APOBEC3G and prevents its
incorporation in newly formed viruses (Fig 3a). Vif-deleted HIV isolates fail to inhibit
intracellular APOBEC3G, which is then incorporated into new viruses and interferes with reverse
transcription in the target cell.
Of interest, the antiviral activity of APOBEC3G is highly conserved among various species, whereas
the blockade of APOBEC3G by vif is highly specific for HIV. HIV-1 vif does not complex to murine or
rhesus APOBEC3G. In the absence of vif, APOBEC3G is incorporated into newly formed viral particles
and in subsequently infected target cells, synthesis of proviral DNA is blocked (Figure 3b). In
contrast, in the presence of vif, APOBEC3G is complexed, degraded and not incorporated in newly
formed virions. APOBEC3G is expressed in lymphocytes and macrophages representing the primary target
cells of HIV infection.
Currently, there are still a lot of open questions regarding the regulation of intracellular
APOBEC3G: for example, whether there is a critical amount of intracellular APOBEC3G that restricts
HIV infection in the presence of vif, or whether genetic polymorphisms of APOBEC3G exist that may
potentially affect the course of disease. It has been shown that dendritic cells upregulate APOBEC3G
upon maturation (Pion 2006). In addition, the enzymatic function of intracellular APOBEC3G in
lymphocytes may depend on the cellular activation status (Chiu 2005). Meanwhile, the epitopes by
which vif and APOBEC3G interact with each other have been characterized and the pathway of
intracellular degradation of the APOBEC3G-vif complex explored. Of note, specific inhibitors that
block the interaction of vif and APOBEC3G or that interfere with the intracellular degradation of
APOBEC3G could represent promising future treatments. In principle, blockade of cellular structures
will likely be associated with a minimal risk that the development of resistance might compromise
the efficacy of an antiviral agent. Therefore, targeting vif and APOBEC3G represents an interesting
2. The HIV replication cycle
2.1. HIV entry
CD4 as a primary receptor for HIV
CD4 is a 58 kDa monomeric glycoprotein that can be detected on the cell surface of about 60 % of
T-lymphocytes, on T-cell precursors within the bone marrow and thymus, and on monocytes and
macrophages, eosinophils, dendritic cells and microglial cells of the central nervous system. The
extracellular domain of the CD4 on T-cells is composed of 370 amino acids; the hydrophobic
transmembrane domain and the cytoplasmic part of CD4 on T-cells consist of 25 and 38 amino acids,
respectively. Within the extracellular part of CD4, four regions D1-D4 have been characterized that
represent immunoglobulin-like domains. Residues within the V2 region of CD4 (amino acids 40-55) are
important for the bonding of gp120 to CD4 and this region overlaps the part of the CD4 where its
natural ligands, HLA class II molecules, bind.
CD4, as a primary and necessary receptor for HIV-1, HIV-2 and SIV, was already characterized in 1984
(Dalgleish 1984, Klatzmann 1984). The identification of the gp120 binding site on the CD4 of CD4+
T-cells stimulated attempts to use soluble CD4 (sCD4) to neutralize the circulating virus in
patients, the aim being the inhibition of viral spread (Schooley 1990). In the past couple of years,
the idea of blocking CD4 as the primary cellular receptor of HIV has regained interest. PRO542
represents a genetically engineered tetravalent CD4-IgG2 fusion protein that not only inhibited
viral replication in vitro, but also showed an impressive antiviral efficacy in patients with high
viral load that were included in initial clinical trials (Olson 2004).
CD4 attaches to the T cell receptor complex (TCR) on CD4+ T-cells and binds to HLA class II
molecules on antigen-presenting cells. The binding of gp120 to CD4 is not only a crucial step for
viral entry, but also interferes with intracellular signal transduction pathways and promotes
apoptosis in CD4+ T-cells (Banda 1992).
Interestingly, monoclonal antibodies against CD4 induced conformational (CD4i) epitopes to bind to
the gp120 of CD4-independent viruses. This observation suggests that the gp120 of CD4-independent
viruses already exposes the regions that are necessary for coreceptor recognition and binding and
therefore binding to CD4 is not a prerequisite of entry for these viruses. CD4-independent viruses
are easy to neutralize using the serum of HIV-infected patients, suggesting that the immune response
selects against CD4-independent viruses (Edwards 2001).
Chemokine receptors as coreceptors for HIV entry
Experiments, using non-human cell lines transfected with human CD4, showed that expression of human
CD4 on the cell surface of a non-human cell line was not sufficient to allow entry of HIV. Therefore
the existence of additional human coreceptors necessary for viral entry was postulated. On the other
hand, some laboratory HIV-1 isolates, as well as some HIV-2 and SIV isolates are able to infect
human cells independently from CD4. A milestone for the characterization of the early events leading
to HIV-1 entry was an observation by Cocchi and his co-workers in 1995. CD8 T cells from
HIV-infected patients are able to suppress viral replication in co-cultures with HIV-infected
autologous or allogenic CD4+ T-cells, and this is independent from their cytotoxic activity (Levy
1996). Cocchi identified the chemokines MIP-1a, MIP-1ß and Rantes in supernatants from CD8+ T-cells
derived from HIV-infected patients, and was able to show that these chemokines were able to suppress
replication in a dose-dependent manner of some, but not all, viral isolates tested (Cocchi 1995).
MIP-1a, MIP-1ß and Rantes are ligands for the chemokine receptor CCR5, and a few months later
several groups were able to show that CCR5 is a necessary co-receptor for monocytotropic (M-tropic)
HIV-1 isolates (Deng 1996, Doranz 1996, Dragic 1998). A few weeks earlier, the chemokine receptor
CXCR4 (fusin) was described as being the coreceptor used by T-cell-tropic (T-tropic) HIV isolates
(Feng 1996). Monocytotropic (M-tropic) HIV-1 isolates are classically those viruses that are most
easily propagated in macrophage cultures, are unable to infect T-cell lines (i.e., immortalized
T-cells), but are able to easily infect primary T-cells from peripheral blood samples. Conversely,
T-cell-tropic HIV-1 isolates have classically been identified as being those that are easily
propagated in T-cell lines, and grow poorly in macrophages, but are also able to easily infect
primary T-cells from peripheral blood samples. Thus, it should be noted that both M-tropic and
T-tropic HIV-1 variants can easily infect primary human non-immortalized T-cells in vitro.
Chemokines ("Chemotactic cytokines") and their receptors have been previously characterized with
regard to their role in promoting the migration ("chemotaxis") of leukocytes and their
pro-inflammatory activity. They are proteins of 68-120 amino acids which depend on the structure of
their common cysteine motif, and which may be subdivided into C-X-C (a-chemokines), C-C
(ß-chemokines) and C-chemokines. Chemokines typically show a high degree of structural homology to
each other and may share the receptors they bind to. Chemokine receptors belong to the group of
receptors with seven transmembranic regions ("7-transmembrane receptors"), which are intracellularly
linked to G-proteins.
SDF-1 ("stromal cell-derived factor 1") was identified as the natural ligand of CXCR4 and is able to
inhibit the entry of T-tropic HIV-1 isolates into activated CD4+ T-cells. Rantes ("regulated upon
activation T cell expressed and secreted"), MIP-1a ("macrophage inhibitory protein") and MIP-1ß
represent the natural ligands of CCR5 and are able to inhibit the entry of M-tropic HIV-1 isolates
into T cells. A schematic model is depicted in Figure 4: T-tropic HIV-1 isolates mainly infect
activated peripheral blood CD4+ T-cells and cell lines and use CXCR4 for entry into the CD4+ target
cell. M-tropic isolates are able to infect CD4+ T-cells, monocytes and macrophages, and depend on
the use of CCR5 and CD4 for viral entry.
The interaction of gp120 and the cellular receptors is now understood in more detail. Gp120
primarily binds to certain epitopes of CD4. Binding to CD4 induces conformational changes in gp120
that promote a more efficient interaction of the V3 loop of gp120 with its respective coreceptor.
Membrane fusion is dependent on gp120 coreceptor binding. Gp41, as the transmembrane part of the
envelope glycoprotein gp160, is crucial for the fusion of the viral and the host cell membrane.
Similar to influenza hemagglutinin, it was postulated that consequent to the binding of gp120 to
CD4, a conformational change is induced in gp41 that allows gp41 to insert its hydrophobic NH2
terminal into the target cell membrane. Gp41 has been compared to a "mouse trap" and a
crystallographic analysis of the ectodomanic structure of gp41 seems to confirm that hypothesis
(Chan 1997). The identification of crucial amino acid sequences for this process was used to
synthesize peptides that bind to gp41 within the domains, are critical for the induction of
conformational changes, and that may inhibit membrane fusion.
T20 is the first of several peptides that bind to gp41 and has been tested in clinical trials for
suppressing viral replication (see HAART chapter).
Using transfected cell lines, besides CCR5 and CXCR4, other chemokine receptors, such as CCR3, CCR2,
CCR8, CCR9, STRL33 ("Bonzo"), Gpr 15 ("Bob"), Gpr 1, APJ and ChemR23, were identified and shown to
be used for entry by certain HIV isolates (Deng 1997, Liao 1997). APJ may represent a relevant
coreceptor within the central nervous system. Despite this broad spectrum of potentially available
coreceptors, CCR5 and CXCR4 seem to represent the most relevant coreceptors for HIV-1 in vivo.
Figure 4: Inhibition of virus entry of CCR5-utilizing (monocytotropic) and CXCR4-utilizing (T-cell
tropic) HIV isolates by the natural ligands of the chemokine coreceptors CCR5 and CXCR4.
The importance of CCR5 as the predominant coreceptor for M-tropic HIV isolates is underscored by
another observation. The majority of individuals with a genetic defect of CCR5 are resistant to
infection with HIV-1 (Liu 1996). In vitro experiments show that lymphocytes derived from these
individuals are resistant to HIV-1 infection using M-tropic isolates but not to infection with
T-tropic isolates. Lymphocytes from these individuals do not express CCR5 on their cell surface and
genetically have a 32 base pair deletion of the CCR5 gene. Worldwide, a few patients have been
identified that have acquired HIV-1 infection despite a homozygous deletion of the CCR5. As
expected, all of them were infected with CXCR4-using HIV-1 isolates. In epidemiological studies, the
allelic frequency of the CCR5 gene deletion is 10-20 % among Caucasians, particularly amongst those
of Northern European descent. The frequency of a homozygous individual is about 1% in Caucasians
(Dean 1996). Studies conducted on African or Asian populations, however, do not find this 32 base
pair deletion of the CCR5, suggesting that this mutation arose after the separation of these
populations in evolutionary history.
Individuals that are heterozygous for the 32 bp deletion of the CCR5 show a decreased expression of
CCR5 on the cell surface and are more frequently encountered within cohorts of long-term
non-progressors compared to patients who have a rapid progression of disease (Dean 1996). In
addition, HIV-infected individuals who are heterozygous for the 32 bp deletion of the CCR5, have a
slower progression to AIDS, a better treatment response to HAART and lymphoma incidence is
In addition to the 32bp deletion of the CCR5, other genetic polymorphisms, with regard to the
chemokine receptors (CCR2) or their promoters (CCR5), have been described. Based on the occurrence
of these polymorphisms within defined patient cohorts, they were associated with a more rapid or a
more favorable course of disease, depending on the particular polymorphism (Anzala 1998, Winkler
In patients who have a rapid progression of disease (rapid drop in CD4+ T-cell count), virus
isolates that use CXCR4 as a predominant coreceptor tend to be frequently isolated from their cells,
in comparison to patients with a stable CD4+ T-cell count.
The expression of coreceptors on CD4+ T-lymphocytes depends on their activation level. CXCR4 is
mainly expressed on naive T-cells, whereas CCR5 is present on activated and effector/memory T-cells.
During the early course of HIV-1 infection, predominantly M-tropic HIV-1 isolates are detected.
Interestingly, M-tropic HIV-1 isolates are preferentially transmitted regardless of whether or not
the "donor" predominantly harbors T-tropic isolates. At present, it remains unclear whether this "in
vivo" preference of M-tropic HIV-1 isolates is determined by selected transportation of M-tropic
isolates by sub-mucosally located dendritic cells or whether the local cytokine/chemokine milieu
favors the replication of M-tropic viruses. Recent intriguing studies by Cheng Meyer et al. suggest
that M-tropic HIV-1 viruses are able to 'hide' more easily from the immune system by replicating in
macrophages, in comparison to T-tropic viruses, thus giving them a survival advantage in the
The blockade of CCR5, therefore, seems to represent a promising target for therapeutic intervention
(Figure 5). In vitro, monoclonal antibodies to CCR5 (2D7 and others) are able to block the entry of
CCR5-using HIV isolates into CD4+ T cells and macrophages. Synthetic inhibitors of CCR5 have been
designed and demonstrated a significant reduction of plasma viremia in HIV-infected patients in
clinical trials. In vitro studies, as well as experiments using SCID mice, however, suggest that
blockade of CCR5-using isolates may alter their tropism towards increased usage of CXCR4.
Small molecule inhibitors such as T22, ALX40-4C or AMD3100 are able to inhibit CXCR4 and are also
subject to preclinical and clinical trials (see HAART chapter). Other CCR5 inhibitors have been used
as mucosal microbicides in monkey models and could therefore represent a potential future preventive
approach (Veazey 2005).
Strategies are currently being developed to modulate expression of chemokine receptors. Intrakines
are chemokines that stay within the cytoplasm and are able to capture and bind to their
corresponding receptor on its way to the cell surface (Chen 1997). "Short interfering RNA" (siRNA)
represents a new molecular tool that is able to selectively inactivate target genes. Double-stranded
RNA is split by the enzyme dicer-1 into short pieces ("21-23mers"). These oligomers may
complementary bind to longer RNA sequences that are subsequently degraded. This strategy is
currently employed in plants and used for its antiviral activity. The use of siRNA against CCR5 can
prevent the expression of CCR5 in vitro.
Figure 5: Strategies to block infection by CCR5-tropic HIV. Blochage of CCR5 on the cell surface by
non-agonistic ligands (A) or monoclonal antibodies (B). Alternatively, CCR5 cell surface expression
can be reduced by siRNA or intrakine. For further details see text.
Although the therapeutic use of chemokine receptor blockers seems promising, a lot of questions
still remain unanswered. Using knockout mice it was demonstrated that the absence of CXCR4 or SDF-1
is associated with severe defects in hematopoiesis and in cerebellar development (Zou 1997).
Currently, it remains unclear whether the blockade of CXCR4 in postnatal or adult individuals may
also affect other organ systems.
2.2. Postfusion events
Following membrane fusion the virus core "uncoats" into the cytoplasm of the target cell. These
"early events" have recently been studied in more detail. HIV can enter into rhesus lymphocytes but
replication is stopped before or during early reverse transcription. This intracellular blockade is
mediated by a cellular factor, TRIM5a, which is a component of cytoplasmic bodies and whose primary
function is yet known. TRIM5a from various species exhibits differential inhibition on various
retroviruses. For example, TRIM5a from rhesus macaques (TRIM5a?rh) more profoundly inhibits HIV
replication than human TRIM5a, whereas SIV (simian immunodeficiency virus) which naturally infects
Old World monkeys, is less susceptible to either form of TRIM5a ,thus explaining in part the species
specificity of HIV for human cells (Stremlau 2004). TRIM5a from human cells or non-human primates is
able to inhibit replication of other lentiviruses and represents a novel cellular resistance factor
whose definitive biological significance has yet to be fully characterized. It is unclear how
exactly TRIM5a blocks reverse transcription and it has been hypothesized that TRIM5a interferes with
the incoming virus capsid protein targeting it for ubiquitination and proteolytic degradation.
HIV-1 entry into quiescent T cells is comparable to HIV-1 entry into activated T cells, but
synthesis of HIV-1 DNA remains incomplete in quiescent cells (Zack 1990). The conversion of viral
RNA into proviral DNA, mediated by the viral enzyme reverse transcriptase (RT), occurs in the
cytoplasm of the target cell and is a crucial step within the viral replication cycle (Figure 6).
Blockade of the RT by the nucleoside inhibitor zidovudine was the first attempt to inhibit viral
replication in HIV-1 infected patients.
Figure 6: Life cycle of HIV.
Reverse transcription occurs in multiple steps. After binding of the tRNA primers, synthesis of
proviral DNA occurs as a minus-strand polymerization starting at the PBS ("primer binding site") and
extending up to the 5' repeat region as a short R/U5 DNA. The next step includes degradation of RNA
above the PBS by the viral enzyme RNAase H and a "template switch" of the R/U5 DNA with
hybridization of the R sequence at the 3' RNA end. Now the full length polymerization of proviral
DNA with degradation of the tRNA is completed. Reverse transcription results in double-stranded HIV
DNA with LTR regions ("long terminal repeats") at each end.
HIV-1 enters into quiescent T cells and reverse transcription may result in the accumulation of
proviral, non-integrating HIV-DNA. However, cellular activation is necessary for integration of the
proviral HIV DNA into the host cell genome after transportation of the pre-integration complex into
the nucleus. Cellular activation may occur in vitro after stimulation with antigens or mitogens, in
vivo activation of the immune system is observed after antigen contact or vaccination or during an
opportunistic infection. In addition, evidence is emerging that HIV-1 gp120 itself may activate the
infecting cell to enhance integration. Besides monocytes, macrophages and microglial cells, latently
infected quiescent CD4+ T-cells that contain non-integrated proviral HIV DNA represent important
long-living cellular reservoirs of HIV (Chun 1997). For integration of proviral DNA the viral enzyme
integrase is essential. The integrase is highly conserved among different clinical HIV-1 isolates,
and integrase inhibition has now been successfully explored in clinical trials (MK-0518, GS-9137)
and approved for HIV-therapy (Lataillade 2006).
Since natural HIV-1 infection is characterized by continuing cycles of viral replication in
activated CD4+ T-cells, viral latency in these resting CD4+ T-cells likely represents an accidental
phenomenon and is not likely to be important in the pathogenesis of this disease. This small
reservoir of latent provirus in quiescent CD4+ T-cells gains importance, however, in individuals who
are treated with HAART, since the antivirals are unable to affect non-replicating proviruses and
thus the virus will persist in those cells and be replication competent to supply new rounds of
infection, if the drugs are stopped. Thus, the existence of this latent reservoir has prevented
HAART from entirely eradicating the virus from infected individuals.
Until recently it was not clear, why HIV replicates poorly in quiescent CD4+ T-cells. The cellular
protein Murr1 that plays a role in copper metabolism is able to inhibit HIV replication in
unstimulated CD4+ T-cells. Murr1 was detected in primary resting CD4+ T-cells and interferes with
activation of the transcription factor NFkB by inhibiting the degradation of IkBa. IkBa prevents
NFkB from migrating to the nucleus, especially after cytokine stimulation (e.g., TNFa). Because the
HIV LTR region has multiple sites for NFkB, preventing NFkB migration to the nucleus should inhibit
HIV replication. Inhibition of murr-1 by siRNA is associated with HIV replication in quiescent CD4+
T-cells (Ganesh 2003). Persistence of HIV in quiescent CD4+ T-cells and other cellular reservoirs
seems one of the main reasons why eradication of HIV is not feasible. If it is ever possible to
achieve, a more detailed knowledge of how and when cellular reservoirs of HIV are established and
how they may be targeted is of crucial importance for the development of strategies aiming at HIV
Cellular transcription factors such as NFkB may also bind to the LTR regions. After stimulation with
mitogens or cytokines, NFkB is translocated into the nucleus where it binds to the HIV-LTR region,
thereby initiating transcription of HIV genes. Transcription initially results in the early
synthesis of regulatory HIV-1 proteins such as tat or rev. Tat binds to the TAR site
("transactivation response element") at the beginning of the HIV-1 RNA in the nucleus and stimulates
transcription and the formation of longer RNA transcripts. Rev activates the expression of
structural and enzymatic genes and inhibits the production of regulatory proteins, therefore
promoting the formation of mature viral particles. The proteins coded for by pol and gag form the
nucleus of the maturing HIV particle; the gene products coded for by env form the gp120 "spikes" of
the viral envelope. The gp120 spikes of the envelope are synthesized as large gp160 precursor
molecules and are cleaved by the HIV-1 protease into gp120 and gp41. The gag proteins are also
derived from a large 53 kD precursor molecule, from which the HIV protease cleaves the p24, p17, p9
and p7 gag proteins. Cleavage of the precursor molecules by the HIV-1 protease is necessary for the
generation of infectious viral particles, and therefore the viral protease represents another
interesting target for therapeutic blockade. The formation of new viral particles is a stepwise
process: a new virus core is formed by HIV-1 RNA, gag proteins and various pol enzymes and moves
towards the cell surface. The large precursor molecules are cleaved by the HIV-1 protease, which
results in the infectious viral particles budding through the host cell membrane. During the budding
process, the virus lipid membranes may incorporate various host cell proteins and become enriched
with certain phospholipids and cholesterol. In contrast to T cells, where budding occurs at the cell
surface and virions are released into the extracellular space, the budding process in monocytes and
macrophages results in the accumulation of virions within cellular vacuoles.
The replication of retroviruses is prone to error and is characterized by a high spontaneous
mutation rate. On average, reverse transcription results in 1-10 errors per genome and per round of
replication. Mutations can lead to the formation of replication-incompetent viral species. But,
mutations causing drug resistance may also accumulate, which, provided that there is selection
pressure under certain antiretroviral drugs and incomplete suppression of viral replication, may
In addition, viral replication is dynamic and turns over quickly in infected individuals at an
average rate of 109 new virus particles being produced and subsequently cleared per day. Thus,
within any individual, because of the extensive virus replication and mutation rates, there exists
an accumulation of many closely related virus variants within the 'population' of viruses, referred
to as a viral "quasispecies". The selection pressure on mostly the pre-existing mutations may not
only be exerted by certain drugs, but also by components of the immune system, such as neutralizing
antibodies or cytotoxic T cells (CTL).
3. HIV and the immune system
3.1. The role of antigen-presenting cells
Dendritic cells as prototypes of antigen-presenting cells
Dendritic cells, macrophages and B cells represent the main antigen-presenting cells of the immune
system. Dendritic cells (DC) are the most potent inducers of specific immune responses and are
considered essential for the initiation of primary antigen-specific immune reactions. DC precursors
migrate from the bone marrow towards the primary lymphatic organs and into the submucosal tissue of
the gut, the genitourinary system and the respiratory tracts. They are able to pick up and process
soluble antigens and migrate to the secondary lymphatic organs, where they activate antigen-specific
T cells. Because DC have a crucial role in adaptive immunity, there is an increasing interest in
using dendritic cell to induce or expand HIV-specific T-cells. DC from HIV-infected patients have
been purified, incubated with inactivated, non-infectious HIV particles and subsequently used for
vaccination (Lu 2004).
DC represent a heterogeneous family of cells with different functional capacities and expression of
phenotypic markers, depending on the local microenvironment and the stage of maturation. Immature DC
have the capacity to pick up and process foreign antigens, but do not have great T cell stimulatory
capacities. However, mature DC show a predominant immunostimulatory ability. DC in tissues and
Langerhans' cells, which are specialized DC in the skin and mucosal areas, represent a more immature
phenotype and may take up antigen. Once these DC have taken up the antigen, they migrate to the
lymphoid tissues where they develop a mature phenotype. Viruses may induce plasmacytoid DC to
produce substantial amounts of IFN alpha with antiviral activity by stimulating Toll-like receptors
(TLR) (Beignon 2005) therefore linking the innate to the adaptive immune system.
The stimulation of CD8 T-lymphocytes and the formation of antigen-specific cytotoxic T cells (CTL)
depend on the presentation of a peptide together with MHC class I antigens. DC may become infected
with viruses, for instance influenza. Viral proteins are then produced within the cytoplasm of the
cell, similar to cellular proteins, then degraded to viral peptides and translocated from the
cytosol into the endoplasmic reticulum, where they are bound to MHC class I antigens. These
peptide-MHC class I complexes migrate to the DC surface. Interestingly, efficacy of pre-sentation of
viral antigens is comparable regardless whether DC themselves or productively infected or not. An
alternative way, where DC acquire exogenous antigens for MHC class I presentation from e.g. infected
cells is termed cross-presentation and may be relevant for both classical and plamacytoid DC in HIV
immunity (Rawson 2007, Hoeffel 2007).
The number of specific antigen-MHC class I complexes is usually limited and must eventually be
recognized by rare T-cell clones, up to a ratio of 1:100.000 or less. The T-cell receptor (TCR) may
display only a low binding affinity (1mM or less). The high density of co-stimulatory molecules on
the DC surface, however, enhances the TCR-MHC: peptide interaction allowing efficient signaling to
occur through the T-cell and resulting in proliferation (clonal expansion) of the T-cell.
Virus-infected cells or tumor cells often do not express co-stimulatory molecules, and thus may not
be able to induce a clonal expansion of effector cells. This underscores the importance of having a
highly specialized system of antigen-presenting cells, i.e., DC, in operation to prime T-cells to
expand and proliferate initially.
The interaction of dendritic cells and B/T-cells
B and T-lymphocytes may be regarded as the principle effector cells of antigen-specific immune
responses. However, their function is under the control of dendritic cells. DC are able to pick up
antigens in the periphery. These antigens are processed and expressed on the cell surface, together
with co-stimulatory molecules that initiate T-cell activation. B-cells may recognize antigen after
binding to the B-cell receptor. Recognition of antigen by T-cells requires previous processing and
presentation of antigenic peptides by DC. T-cells express different T-cell receptors (TCR) that may
bind to the peptide: MHC class I on the surface of dendritic cells to allow activation of CD8
T-cells, or to the peptide: MHC class II molecules, to activate CD4+ T-cells. The ability of DC to
activate T-cells also depends on the secretion of stimulatory cytokines such as IL-12, which is a
key cytokine for the generation and activation of TH1 and natural killer (NK) cells.
Only a few DC and small amounts of antigen are sufficient to induce a potent antigen-specific T-cell
response, thus demonstrating the immunostimulatory potency of DC. The expression of adhesion
molecules and lectins, such as DC-SIGN, support the aggregation of DC and T-cells and promote the
engagement of the T-cell receptor (TCR). DC-SIGN is a type C lectin that has also been shown to bind
to lentiviruses, such as SIV and HIV-1 and -2 by interaction of gp120 with carbohydrates
(Geijtenbeek 2000). Mycobacteria and Dengue virus may also bind to DC-SIGN. In vivo,
immunohistochemical studies show expression of DC-SIGN on submucosal and intradermal DC, suggesting
an implication of DC-SIGN in vertical and mucosal transmission of HIV. The expression of DC-SIGN was
shown to enhance the transmission of HIV to T cells and allows utilization of coreceptors if their
expression is limited. Thus DC-SIGN may be a mechanism whereby HIV-1 is taken up by DC in the
mucosal tissues. It is then transported by the DC to the lymphoid tissues where HIV-1 can then
infect all the residing CD4+ T-cells.
3.2. Lymphatic tissue as the site of viral replication
Viral replication within the lymphatic tissue is already extensive in the early stages of the
disease (Embretson 2003, Pantaleo 1993). During the initial phase of HIV-1 infection, there is a
burst of virus into the plasma, followed by a relative decline in viremia. During this time, a
strong HIV-1 specific cytotoxic T-cell response is generated, which coincides with the early
suppression of plasma viremia in most patients. Virions are trapped by the follicular dendritic
cell (FDC) network within the lymphoid tissue. Macrophages, and activated and quiescent CD4+ T-cells
are the main targets of infection. Permanent viral reservoirs, mainly in macrophages and latently
infected CD4+ T-cells, are established in the early phase of infection and probably represent the
major obstacle so far to successful eradication of HIV. During the whole course of infection with
HIV-1, the lymphoid tissue represents the principle site of HIV-1 replication. The frequency of
cells containing proviral DNA is 5-10x higher in lymphoid tissue than in circulating peripheral
mononuclear cells in the blood, and the difference in viral replication in lymphoid tissue exceeds
that in the peripheral blood by about 10-100x.
After entry of HIV-1 into a quiescent CD4+ T-cell and after completion of reverse transcription, the
viral genome is represented by proviral unintegrated HIV DNA. In vitro experiments have shown that
HIV-1 preferentially integrates into active genes ("hot spots") (Schroder 2002). The activation of
CD4+ T-cells is necessary for the integration of the HIV DNA into the host cell genome and is
therefore a prerequisite for the synthesis of new virions. In this regard, the micromilieu of the
lymphoid tissue represents the optimal environment for viral replication. The close cell-cell
contact between CD4+ T-cells and antigen-presenting cells, the presence of infectious virions on the
surface of the FDC, and an abundant production of pro-inflammatory cytokines such as IL-1, IL-6 or
TNFa promotes the induction of viral replication in infected cells and augments viral replication in
cells already producing the virus. It should be noted that both IL-1 and TNFa induce NFkB, which
binds to the HIV-1 LTR to promote proviral transcription. The importance of an antigen-induced
activation of CD4+ T-cells is underlined by several in vivo and in vitro studies that demonstrate an
increase in HIV-1 replication in association with a tetanus or influenza vaccination or an infection
with Mycobacterium tuberculosis (O'Brian 1995). Even though the clinical benefit of vaccination
against common pathogens (e.g. influenza and tetanus) in HIV-1-infected patients outweighs the
potential risk of a temporary increase in viral load, these studies indicate that in every situation
where the immune system is activated, enhanced viral replication can also occur.
Patients undergoing HAART demonstrate a dramatic decrease in the number of productively infected
CD4+ T cells within the lymphoid tissue (Tenner-Racz 1998). However, in all patients examined so
far, there persists a pool of latently infected quiescent T cells despite successful suppression of
plasma viremia. It is these latently infected cells that may give rise to further rounds of viral
replication, if the antiviral drugs are stopped. In addition, the long-term persistence of HIV-1
structural proteins and glycoproteins in germinal centers of lymph nodes in the absence of
detectable virus replication in patients under HAART has been reported (Popovic 2005)
During the natural course of HIV-1 disease, the number of CD4+ T-cells slowly decreases while plasma
viremia rises in most patients. If sequential analysis of the lymphoid tissue is performed,
progression of the disease is reflected by destruction of the lymphoid tissue architecture and a
decreased viral trapping. Various immunohistological studies indicate that the paracortex of the
lymph nodes represents the primary site where HIV replication is initiated (Embretson 1993, Pantaleo
1993). Infection of the surrounding CD4+ T-cells, as well as the initiation of T-cell activation by
DC, contributes to the spreading of HIV-1 within the lymphoid environment. Similar to SIV infection
in rhesus macaques, HIV infection, at all stages of disease, is associated with preferential
replication and CD4+ T-cell destruction in the gut lamina propria and submucosa than in lymph nodes
(Brenchley 2004, Mehandru 2004). This is likely because the gut is predominantly populated by
CCR5-expressing effector memory CD4+ T-cells, which are ideal targets for HIV replication compared
to the mixed populations of CD4+ T-cells found within the lymph nodes. Several studies have
demonstrated that, during acute infection, depletion of CD4+CCR5+ memory cells within the
mucosa-associated lymphatic tissue is a hallmark of both HIV and SIV infection. In the early phase
of SIV infection, up to 60 % of all CD4+ T-cells within the intestinal lamina propria were shown to
express viral RNA. Most of these cells are destroyed by direct and indirect mechanisms within a few
days. Further disease progression seems to depend largely on the capacity of the host to
reconstitute the pool of memory cells within the mucosa-associated lymphoid tissue. In view of this
data, some researchers argue that initiation of HAART during acute HIV infection is crucial in order
to limit long-term damage to the immune system.
Chronic activation of the immune system is a hallmark of progressive HIV infection and predicts
disease outcome. High-level immune activation and T cell apoptosis is absent from nonpathogenic SIV
infections in natural primate hosts. Recently, it was reported that nef alleles from the great
majority of primate lentiviruses, including HIV-2, downmodulate TCR-CD3 from infected T cells,
thereby blocking their responsiveness to activation (Schindler 2006). In contrast, nef alleles from
HIV-1 and a subset of closely related SIVs fail to downregulate TCR-CD3 and to inhibit cell death.
Thus, Nef-mediated suppression of T cell activation is a fundamental property of primate
lentiviruses that likely evolved to maintain viral persistence in the context of an intact host
immune system. In addition, reaserch has shown that circulating microbial products, probably derived
from the gastrointestinal tract, are a cause of HIV-related systemic immune activation (Brenchley
2006). The authors show that increased lipopolysaccharide is bioactive in vivo and correlates with
measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce
microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys,
microbial translocation did not seem to occur. These data establish a mechanism for chronic immune
activation in the context of a compromised gastrointestinal mucosal surface and provide new
directions for therapeutic interventions that modify the consequences of acute HIV infection.
Recent studies have also examined the effect of HIV infection on the thymus gland and its role in
CD4+ T-cell depletion and homeostasis. Recent work has suggested that thymic output of CD4+ T-cells
is decreased during HIV infection, particularly with older age, and that this defect is due to
abnormalities of intra-thymic proliferation of T-cells, whose mechanism is still undefined, as
thymocytes do not express CCR5 and should not necessarily be targets of HIV (Mehandru 2004, Douek
3.3. The HLA system and the immune response to HIV
CD8 T-cells recognize "their" antigen (peptide) in context with HLA class I molecules on
antigen-presenting cells, whereas CD4+ T-cells require the presentation of antigenic peptides in
context with HLA class II molecules. The generation of an HIV-specific immune response is therefore
dependent on the individual HLA pattern.
Antigen-presenting cells may bind HIV peptides in different ways within "grooves" on the HLA class I
molecules. Therefore, CD8 T-cells can be activated in an optimal or suboptimal way or may not be
activated at all. Using large cohorts of HIV-1 infected patients, in whom the natural course of
disease (fast versus slow progression) is known, HLA patterns were identified that were associated
with a slow versus fast disease progression. These studies suggest that the HLA type could be
responsible for the benign course of disease in about 40 % of patients with a long-term
non-progressive course of disease. Homozygosity for HLA Bw4 is regarded as being protective.
Patients who display heterozygosity at the HLA class I loci characteristically show a slower
progression of immunodeficiency than patients with homozygosity at these loci (Carrington 1999). An
initial study demonstrated that HLA B14, B27, B51, B57 and C8 are associated with a slow disease
progression, however, the presence of HLA A23, B37 and B49 were associated with the rapid
development of immunodeficiency (Kaslow 1996). All patients with HLA B35 had developed symptoms of
AIDS after eight years of infection. More recent studies suggest that discordant couples with a
"mismatch" at the HLA class I have a protective effect towards heterosexual transmission (Lockett
In vitro studies in HLA B57-positive patients demonstrate that these patients display HLA
B57-restricted CTL directed against HIV-1 peptides. However, it is possible that the identification
of protective HLA alleles or HLA-restricted peptides in HIV-1-infected patients with a benign course
of disease does not necessarily indicate that the same alleles or peptides are crucial for the
design of a protective vaccine. Kaul and co-workers were able to show that CD8+ T-cells from
HIV-1-exposed but uninfected African women recognize different epitopes than CD8+ T-cells from
HIV-1-infected African women (Kaul 2001). This suggests that the epitopes, that the immune system is
directed against during a natural infection, might be different from those that are protective
against infection. In addition, the individual HLA pattern may affect the adaptive immune response
and the evolution of viral escape mutations (Friedrich 2004, Leslie 2004). CTL from patients with
HLA B57 and B58 may "force" the virus to develop certain mutations in gag that enable the virus to
escape the CTL response. However, these mutations result in a reduced replicative competence. If
such a virus is transmitted to another individual with a different HLA background, the virus may
"back" mutate to the original genotype and regain its full replicative competence. Similar MHC
alleles as in monocygotic twins leat, at least during the early phase of the infection, to similar
HIV-specific CTL-specificities (Draenert 2006).
HLA class II antigens are crucial for the development of an HIV-1-specific CD4+ T-cell response.
Rosenberg (1997) was the first to show that HIV-1-infected patients with a long-term non-progressive
course of disease had HIV-1-specific CD4+ T-cells that could proliferate against HIV-1 antigens. The
identification of protective or unfavorable HLA class II alleles is less well elaborated than the
knowledge about protective HLA class I alleles. Cohorts of vertically infected children and
HIV-infected adults demonstrate a protective effect of HLA DR13 (Keet 1999).
KIR receptors ("Killer cell immunoglobulin like receptors") represent ligands that bind to HLA class
I antigens and by functioning as either activating or inhibiting receptors they regulate the
activation status of NK cells. Polymorphisms of KIR genes were shown to correlate with slow or rapid
progression of HIV disease, especially when the analysis includes known HLA class I polymorphisms
(Fauci 2005, Martin 2007) thereby indicating a relevant function of N cells in HIV immunity. During
HIV infection, NK cells may not only be decreased, but may also show a diminished cytolytic
activity. Preliminary results suggest that low numbers of NK cells are associated with a more rapid
progression of disease.
In summary, various genetic polymorphisms have been identified that have an impact on the course of
HIV disease. However, there is currently no rationale to recommend routine testing of individual
patients or to base therapeutic decisions on genetic testing.
3.4. The HIV-specific cellular immune response
Cytotoxic T-cells (CTL) are able to recognize and eliminate virus-infected cells. A number of
studies clearly demonstrate that CTL are crucial for the control of HIV replication and have a
substantial impact on disease progression once infection is established. However, there is little
evidence to assume that CTL play a major role in primary protection.
In comparison to HIV-1-infected patients with a rapid decline in CD4+ T-cell numbers, patients with
a long-term non-progressive course of disease ("LTNP" = long-term non-progressors) have high
quantities of HIV-1-specific CTL precursors with a broad specificity towards various HIV-1 proteins.
The different capacities of certain HLA alleles to present viral particles more or less efficiently
and to induce a generally potent immune response may explain why certain HLA alleles are associated
with a more rapid or a slowly progressive course of disease (see above).
Individuals have been described, who developed CTL "escape" mutants after years of stable disease
and the presence of a strong CTL response. The evolution of CTL escape mutants was associated with a
rapid decline in CD4+ T-cells in these patients, indicating the protective role of CTL (Goulder
HIV-specific CTL responses have been detected in individuals exposed to, but not infected by HIV-1.
Nef-specific CTL have been identified in HIV-1-negative heterosexual partners of HIV-infected
patients and env-specific CTL have been found in seronegative healthcare workers after exposure to
HIV-1-containing material by needle stick injuries (Pinto 1995). Unfortunately patients with a broad
and strong CTL response do not seem to be protected from superinfection by a different, but closely
related HIV isolate (Altfeld 2002).
The presence of a CTL response is not correlated just with the suppression of plasma viremia during
the initial phase of HIV infection. Patients who underwent structured therapy interruptions,
especially when HAART was initiated early following infection, demonstrated the appearance of
HIV-specific CTL during the pauses.
However, it is still unclear in most patients who exhibit a potent temporary CTL response, why this
CTL response diminishes later on. The appearance of viral "escape" mutants might explain why
previously recognized epitopes are no longer immunodominant.
The nef protein may downregulate HLA class I antigens and therefore counteract the recognition of
infected cells by CTL. In addition, the majority of infected individuals show detectable CTL
responses. It is unclear why they are unable to control the virus. Interestingly, CTL from
HIV-infected patients shows a lack of perforin and an immature phenotype in comparison to
anti-CMV-directed effector cells (Harari 2002), even though the ability to secrete chemokines and
cytokines is not impaired. Another recent study provided evidence that the killing capacity of
HIV-specific CTL was associated with the ability to simultaneously produce interferon-? and TNFa
(Lichtenfeld 2004). Finally, it has been shown that HIV-infection is associated with upregulated or
maintained high expression of PD-1 on CD4 and CD8 T cells and CTLA-4 on CD4 T cells specific for
HIV. Both receptors lead to reversible T cell dysfunction with reduced proliferative capacity and
cytokine production (Kaufmann 2007, Trautmann 2006).
CD8+ T-cells may also become infected with HIV (Saha 2001), although this was not demonstrated for
HIV-specific CD8 T-cells. It is unclear, whether CD8 T-cells temporarily express CD4 and which
chemokine coreceptors mediate infection of these CD8+ T-cells.
Proliferation and activation of CTL is dependent on antigen-specific T cell help. Rosenberg and his
group were able to demonstrate that initiation of HAART during primary HIV infection was associated
with persistence of an HIV-specific CD4+ T-cell response that was not detected in patients analyzed
during the chronic stage of disease (Rosenberg 1997). HIV preferentially infects pre-activated CD4+
T-cells and as HIV-specific CD4+ T-cells are among the first cells to be activated during HIV
infection, their preferential infection was demonstrated by Douek and his group (Douek 2002).
Therefore, it is currently unclear whether the loss of HIV-specific CTL activity during the course
of disease reflects an instrinsic defect of CTL or develops secondary to a loss of specific CD4+
Various therapeutic vaccine strategies have been developed during the last few years and mostly
tested in SIV-infected rhesus macaques aiming at inducing an SIV-specific CTL response that may
alter the natural course of disease. Recently, a promising vaccine approach was reported using
autologous dendritic cells in SIV-infected rhesus macaques that were pulsed with inactivated SIV (Lu
2003). In contrast to the unvaccinated control group, monkeys that were vaccinated showed a dramatic
decrease in the viral load, and the development of anti-SIV-directed humoral and cellular immune
responses. Similar strategies in HIV-infected individuals lead to significant reduction of viral
load paralleled by detection of gag-specific CD8+ T-cells and HIV-specific CD4+ T-cells producing
IFN? and/or interleukin-2 (Lu 2004).
In addition to the cytotoxic activities directed against HIV-infected cells, CD8+ T- cells from
HIV-1 infected patients exhibit a remarkable, soluble HIV-1 inhibitory activity that inhibits HIV-1
replication in autologous and allogeneic cell cultures (Walker 1996). Despite multiple efforts, the
identity of this inhibitory activity ("CAF") has not been clarified, although chemokines, such as
MIP-1a, MIP-1ß or RANTES (Cocchi 1995), IL-16 (Baier 1995), the chemokine MDC (Pal 1997), and
defensins (Zhang 2002), may account for at least some of the inhibition.
3.5. The TH1/TH2 immune response
Depending on the secretion pattern of cytokines, CD4+ T-cells may be differentiated into TH1 and TH2
cells. TH1 CD4+ T-cells primarily produce interleukin-2 (IL-2) and IFN?, which represent the
cytokines that support the effector functions of the immune system (CTL, NK-cells, macrophages). TH2
cells predominantly produce IL-4, IL-10, IL-5 and IL-6, which represent the cytokines that favor the
development of a humoral immune response. Since TH1 cytokines are critical for the generation of
CTLs, an HIV-1-specific TH1 response is regarded as being a protective immune response. Studies on
HIV-exposed but non-infected individuals have shown, that following in vitro stimulation with HIV-1
env antigens (gp120/gp160) and peptides, T-cells from these individuals secrete IL-2 in contrast to
non-exposed control persons (Clerici 1991). Similar studies were undertaken in healthcare workers
after needle-stick injuries and in newborns from HIV-infected mothers. Although these observations
may indicate that a TH1-type immune response is potentially protective, it should be considered,
that similar immune responses might also have been generated after contact with non-infectious viral
particles and therefore do not necessarily imply a means of protection against a
3.6. HIV-1 specific humoral immune responses
The association between an HIV-1-specific humoral immune response and the course of disease is less
In a SIV model, injection of an antibody cocktail consisting of various neutralizing antibodies is
able to prevent SIV infection after a mucosal virus challenge (Ferrantelli 2004), indicating that
primary protection is mainly dependent on a broad humoral immune response. This data suggests that
HIV-specific antibodies are necessary for a preventive vaccine strategy. In contrast, B-cell
depletion by a monoclonal antibody directed against B-cells in monkeys with already established SIV
infection, does not affect the course of plasma viremia (Schmitz 2003).
A slow progression of immunodeficiency was observed in patients with high titers of anti-p24
antibodies (Hogervorst 1995), persistence of neutralizing antibodies against primary and autologous
viruses (Montefiori 1996), and lack of antibodies against certain gp120 epitopes (Wong 1993).
Long-term non-progressors with HIV tend to have a broad neutralizing activity towards a range of
primary isolates and show persistence of neutralizing antibodies against autologous virus. At
present, it is unclear whether the presence of neutralizing antibodies in LTNP represents part of
the protection or whether it merely reflects the integrity of a relatively intact immune system.
Individuals that have a substantial risk for HIV-1 infection, but are considered "exposed,
non-infected", by definition represent individuals with a lack of a detectable antibody response to
HIV-1. This definition implies that a systemic humoral immune response may not represent a crucial
protective mechanism. It has been shown that these individuals may demonstrate a local (mucosal) IgA
response against HIV-1 proteins that are not detected by the usual antibody testing methods (Saha
2001). Thus, local IgA, rather than systemic IgG, may be associated with protection against HIV-1
infection. There is also some evidence that some anti-HIV-1 antibodies can enhance the infection of
A number of old and recent studies have shown that neutralizing antibodies do exist in
HIV-1-infected individuals, however, there is a time lag in their appearance. That is, individuals
will develop neutralizing antibodies to their own viruses with time, however, by the time these
antibodies develop, the new viruses circulating in the individual's plasma will become resistant to
neutralization, even though the older ones are now sensitive to the current antibodies in the
patient's serum. Thus, the antibody response appears to be hitting a 'moving' target, allowing
viruses to escape continuously. Further knowledge gained on understanding the mechanisms of humoral
escape will likely lead to potential new therapies.
A few years ago, selected patients with advanced HIV infection were treated with plasma from
HIV-infected patients at an earlier stage of the disease. No significant effect on the course of
disease was notable (Jacobson 1998). The therapeutic application of neutralizing antibodies with
defined specificity looked more promising, since a few acute and chronically infected patients were
able to control their viral load at least temporarily after stopping antiretroviral therapy (Trkola
3.7. A vaccine against HIV ?
Improved knowledge and understanding of the pathophysiological mechanisms during the course of HIV-1
infection have not only contributed to the development of antiretroviral treatment strategies, but
have given rise to new therapeutic approaches, such as cytokine therapies, e.g., IL-2 and
therapeutic vaccination. However, the most important challenge and thus, the demand for a better
understanding of the immunopathogenesis of HIV-1 infection, remains the development of a protective
vaccine, which is urgently needed to interrupt the epidemic especially in countries of the
Sub-Sahara and Southeast Asia.
The documentation of exposed but uninfected individuals and findings in LTNP suggests that, besides
a genetic predisposition, HIV-specific protective immune mechanisms could potentially confer
protective and possibly even preventive immunity. Results from animal studies suggest that immune
protection might be generated when the immune system is stimulated in the appropriate way. The
induction of an HIV-specific CD8 response in non-human primates is able to ameliorate the course of
disease. On the other hand, in vivo depletion of CD8+ T-cells in non-human primates by monoclonal
antibodies will lead to an increase in viral load. Immunogens that induce neutralizing antibodies in
non-human primates will prevent infection with the homologous viral strain. Transfer of neutralizing
antibodies to uninfected primates or human SCID mice is able to prevent infection with the
homologous HIV strain.
The spectrum of vaccine strategies against HIV includes HIV-derived peptides or proteins, the use of
viral or bacterial vectors, naked DNA, pseudovirions or the use of live attenuated HIV strains. The
discussion about whether a vaccine should primarily aim at inducing a humoral or a cellular based
protective immune response has now resulted in the belief that both humoral and cellular mechanisms
contribute to protection.
Many neutralizing antibodies either do not or only poorly show inhibition of primary viral isolates.
A major problem lies in the high variability of the gp120 glycoprotein itself. Furthermore, gp120
epitopes may be highly glycosylated and certain structural domains are hidden, at least temporarily,
so that immunodominant epitopes may not be recognized (Chen 2005, Derdeyn 2005). In addition, there
is no evidence that a cytotoxic T-cell response can prevent an uninfected individual from exogenous
HIV infection. A report from Altfeld (2002) is interesting in this regard. It concerns an
HIV-infected patient who was started on HAART during primary infection. The patient developed a
robust anti-HIV CD8+ T-cell response that was closely monitored and documented by in vitro
experiments. In spite of the strong CTL response, superinfection with a second HIV strain occurred,
despite cross-reactive CTL epitopes.
The discussion about how to best monitor the induction of protective immune responses remains
controversial. Does a CTL response as measured by its cytolytic activity or by cytokine production
the in vitro correlate of protection? How are in vitro tests linked to in vivo protection? Despite
all efforts undertaken so far, the way to an effective and universally applicable preventive vaccine
still seems to be a long one.
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