The immune response to HIV
Nina Bhardwaj, Florian Hladik and Susan Moir
Breaching the mucosal barrier
The main drivers of HIV infection in the genital mucosa are CD4+
memory T cells, but CC-chemokine receptor 5 (CCR5)+ macrophages
have been implicated as well. How HIV reaches these cells is less clear,
but dendritic cells (DCs) probably have an important role. HIV can
enter DCs not only using CD4 and CCR5, but also using C-type
lectin receptors, such as DC-specific ICAM3-grabbing non-integrin
(DC-SIGN) and langerin. DCs form a network within squamous
epithelia, such as those covering the vagina, ectocervix and foreskin,
extending their dendrites higher towards the epithelial surface than do
T cells. In columnar epithelia, such as those covering the endocervix
and rectum, DCs can stretch their dendrites through epithelial tight
junctions towards the luminal surface. It is thus plausible to assume
that DCs are frequently the first leukocyte type encountered by HIV
in the mucosa. HIV might also cross columnar epithelial cells by
transcytosis, a process whereby virions are taken up on the luminal
side of the epithelial cell into a coated vesicle. The vesicle is then
transported to the basal side of the cell, where its contents are released
into the extracellular space of the stroma.
CD1a + DCs residing within squamous epithelia are called
Langerhans cells. Langerhans cells have been shown to endocytose
HIV-1 virions very efficiently, and pass HIV-1 to susceptible CD4+
T cells and to stromal DCs without being themselves productively
infected. To reach Langerhans cells, HIV seems to be able to breach
the mucus layer and then move through the interstitial spaces
between differentiated squamous epithelial cells to depths of 40 μm.
In the ectocervix and vagina, the outer epithelial layers do not contain
classical cell–cell tight junctions, and this might facilitate HIV
entry. By contrast, endocervical columnar epithelial cells are joined
by impermeable tight junctions. This indicates that the vagina and
ectocervix might in fact be quite vulnerable to HIV penetration
and infection, even without microabrasions and tears.
Amplification in draining lymph nodes
In most cases, mucosal HIV infection occurs with a single founder
virus, indicating that the infection probably arises from a single
focus of infected CD4+ T cells. At the end of the initial phase of
localized viral replication, after approximately 10 days, HIV virions
and/or virus-bearing cells reach local lymph nodes, where the infection
strongly amplifies and systemic spread takes off. At this time, DCs in
lymph nodes begin to present processed HIV antigens to naive B cells
and T cells, thereby initiating the adaptive response to the infection.
Subcapsular sinus macrophages might contribute to the establishment
of HIV-specific humoral immunity by displaying captured virions to
follicular B cells.
The DC response to HIV
Conventional DCs are responsible for initiating antiviral adaptive
immunity in the draining lymph node. Furthermore, they activate
natural killer (NK) cells through the secretion of interleukin-12
(IL‑12), IL-15 and IL-18. Conventional DCs have not been shown to
be directly activated by HIV, possibly owing to the blockade of effective
HIV-1 replication in conventional DCs by the nucleoside hydrolase
SAM domain- and HD domain-containing protein 1 (SAMHD1) and
potentially other restriction factors, such as apolipoprotein B mRNA
editing enzyme, catalytic polypeptide-like 3G (APOBEC3G). However,
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some HIV strains circumvent SAMHD1-mediated restriction and in
these cases, interaction of the HIV capsid with cyclophilin A (CYPA) in
conventional DCs has been shown to induce antiviral type I interferons
(IFNs) through a cryptic cytoplasmic sensor. Tripartite motif-
containing protein 5 (TRIM5) also recognizes the HIV capsid lattice
to induce innate immune signalling. The function of conventional
DCs is also impaired during HIV-1 infection. Dysfunction can be a
consequence of direct viral interactions with conventional DCs (for
example, through the interaction with DC-SIGN) or a result of indirect
mechanisms, such as the production of IL-10 by monocytes during
infection. This DC dysfunction could contribute to a lack of effective
antiviral adaptive immunity and a lack of adequate NK cell activation.
Plasmacytoid DCs (pDCs) are mediators of innate immunity.
pDCs activated by HIV-1 produce type I IFNs, which, in addition to
inhibiting viral replication, may contribute to nonspecific CD8+ T cell
proliferation. Furthermore, evidence shows that pDCs produce T cell-
attracting chemokines, which may facilitate viral spread by providing
a source of new CD4+ T cells for HIV to infect. However, HIV-
exposed pDCs also upregulate TNF-related apoptosis-inducing ligand
(TRAIL), which can lead to T cell apoptosis. Finally, HIV-exposed
pDCs prime regulatory T (TReg) cells, which could impair the function
of conventional DCs through secreted IL-10 or cell-bound cytotoxic
T lymphocyte antigen 4 (CTLA4), further blunting adaptive immunity
by promoting ‘immunoregulatory’ conventional DCs. Thus, pDCs can
promote deleterious immunopathology during HIV-1 infection.
The T cell response to HIV
It takes up to 30 days before HIV-specific CD8 + T cells begin to
measurably curtail viral replication, through the direct cytolytic effects
of perforin and granzymes on infected CD4+ T cells and through the
indirect effects of cytokines and other soluble factors.
At the same time, HIV starts to mutate epitopes recognized by CD8+
T cells, in particular those present in the founder virus. The earliest
T cell responses are often specific for Env and Nef, whereas Gag-specific
and Pol-specific responses tend to arise later. Epitope changes are
rapidly optimized for the fittest variants and occur through three main
mechanisms: mutations that affect HLA allele binding; mutations that
affect TCR recognition; and mutations that affect epitope processing,
which can also occur in sequences flanking the actual T cell epitope.
During the initial months of HIV infection, CD8+ T cells are
the strongest contributors to viral control. Once a balance has been
reached between the adaptive T cell response and the ability of HIV
to escape, the initial viral set point is reached. Immunodominant
responses to more conserved virus epitopes probably result in a lower
set point viraemia. The HLA type of the infected individual seems
to be important in determining which CD8+ T cell epitopes become
immunodominant; patients with HLA types associated with CD8+
T cell recognition of more conserved HIV regions (such as HLA-B27+
patients and HLA-B57+ patients) have a better clinical outcome.
The earliest and strongest immune dysfunction in HIV disease
is that of CD4+ T cells. Owing to the massive killing of these cells
by HIV-1, T helper cell functions are increasingly compromised
during the course of infection. The relative inefficiency of CD8 +
T cell responses against escape mutants, compared with the initially
strong responses against founder virus sequences, might be a direct
consequence of waning T helper cell function. Over time, CD8 +
T cells also become exhausted owing to persistent antigen exposure
and repeated activation. Whereas recently activated T cells give rise
to central memory T cells with high proliferative capacity and effector
memory T cells with potent cytotoxic and cytokine-producing abilities,
exhausted T cells lose proliferative capacity and effector functions.
Negative regulatory molecules of immune activation, in particular
T cell immunoglobulin domain- and mucin domain-containing
protein 3 (TIM3), programmed cell death protein 1 (PD1) and
CTLA4, are upregulated on T cells during HIV infection. TReg cells
express the TIM3 ligand galectin 9, through which they exert an
immunosuppressive effect on CD8+ T cells. CD8+ T cells restricted by
the protective HLA alleles HLA-B27 and HLA-B57 express less TIM3
following activation and are therefore less prone to TReg cell-mediated
inhibition and exhaustion, probably contributing to the improved viral
control and clinical outcomes in patients with these haplotypes.
The B cell response to HIV
HIV does not replicate in B cells, although infectious virions on
the surface of B cells may facilitate the early events of infection by
mediating the more efficient passage of the virus to target cells, as
has been proposed for DCs and follicular DCs. Early after infection, a
high viral burden and the presence of high levels of pro-inflammatory
factors lead to rapid dysregulation of B cells in various tissues, starting
with intestinal mucosal tissues and followed by other secondary
lymphoid tissues as the virus disseminates. These alterations in B cells
probably contribute to the inadequacy of the HIV-specific B cell and
antibody responses. Although most of our understanding of B cell
immunopathogenesis in HIV infection is derived from the analysis
of B cells and antibodies that circulate in the blood, there have been
important insights gained from direct analyses of lymphoid tissues,
sites where most of the body’s B cells reside. In early HIV infection, the
intestinal mucosa undergoes numerous changes that cause polyclonal
B cell activation but also a loss of germinal centres, which is associated
with increased follicular lysis and B cell apoptosis. In the chronic
phase of HIV infection, when patients are clinically asymptomatic,
follicular hyperplasia is observed in secondary lymph nodes, and these
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changes reflect increased activation and differentiation of germinal
centre B cells. In late-stage HIV infection, when patients become
symptomatic, secondary lymphoid tissues become involuted and fibrotic
with increased deposition of collagen. These changes are associated with
the loss of homeostasis and the reversal of immune-activating effects on
B cells, culminating in a generalized loss of immune function.
Further reading
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The immune response during acute HIV-1 infection: clues for vaccine development.
Nature Rev. Immunol. 10, 11–23 (2010).
3. Freel, S. A., Saunders, K. O. & Tomaras, G. D. CD8+ T‑cell‑mediated control of HIV-1
and SIV infection. Immunol. Res. 49, 135–146 (2011).
4. Khaitan, A. & Unutmaz, D. Revisiting immune exhaustion during HIV infection.
Curr. HIV/AIDS Rep. 8, 4–11 (2011).
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interventions. Annu. Rev. Med. 62, 127–139 (2011).
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the immune response to HIV-1. Nature Rev. Immunol. 11, 176–186 (2011).
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