Immune Activation, HIV Persistence, and the Cure

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IAS–USA        Topics in Antiviral Medicine

Perspective
Immune Activation, HIV Persistence, and the Cure
HIV infection is characterized by persistent immune activation, even in the                 body is contained in the gut. Cross-
context of suppressive antiretroviral therapy. This persistent activation, which            communication occurs between mi-
appears to be fueled by microbial translocation from the gut resulting from                 crobes and epithelial cells or immune
HIV-related damage, is associated with deficits in immune function that in                  cells as part of a complex system that
turn contribute to persistent activation. The presence of latent HIV reservoirs             protects what is essentially the greatest
in lymphoid tissues also provokes immune activation in the context of immune                surface area of tissue in contact with
suppression, resulting in expansion of the viral reservoir and potential                    the outside environment. In HIV infec-
viral replication, even with suppressive antiretroviral therapy. Therapeutic                tion, there is a massive loss of CD4+ T
strategies are being devised to reduce persistent immune activation and limit               cells in the gut during acute infection,
the size of the HIV reservoir. This article summarizes a presentation by Daniel C.          with enteropathy caused by enterocyte
Douek, MD, PhD, at the IAS–USA continuing education program held in San                     apoptosis and a 2- to 10-fold increased
Francisco, California, in March 2013.                                                       permeability (leakiness) of the gut. Gut
                                                                                            permeability allows translocation of
Keywords: HIV, immune activation, persistence, gut, microbial translocation,                microbial products into the systemic
reservoir, raltegravir intensification, lymphoid tissue                                     circulation, causing systemic immune
                                                                                            activation.
Viral infection is accompanied by an          an altered phenotypic profile, and hy-           The emerging picture of the role of
innate immune response during the             perimmunoglobulinemia.                        microbial translocation from the gut in
acute phase of infection. For most               With regard to the causes of chronic       fueling persistent immune activation is
types of viral infection, immune acti-        immune activation in HIV infection, it        of a cyclic process in which more acti-
vation is reduced as the immune re-           does not appear that HIV alone can ac-        vated T cells are produced, providing
sponse acts to reduce viral load. In          count for the persistence of immune ac-       more target cells for HIV, and resulting
HIV infection, however, immune acti-          tivation. In HIV infection, viral load is a   in immune deficiency via increased
vation persists despite the initial de-       poor predictor of disease progression,        infection of the T cells, low thymic
cline in viral load. Persistent activation    whereas measures of immune activa-            output, lymphoid tissue fibrosis, and
is observed in numerous components            tion, including the frequency of acti-        T and B cell dysfunction (Figure 2).
of the innate immune system, includ-          vated T cells, are independent predic-        Increased immune deficiency results
ing cells (eg, activated phenotypes of        tors of progression. Elite controllers—       in persistent microbial translocation
macrophages and dendritic cells), cy-         individuals who, in the absence of ther-      and poor pathogen control, allowing
tokines and chemokines (tumor necro-          apy, spontaneously control viral repli-       other viruses (eg, cytomegalovirus)
sis factor, interleukin [IL]-1, IL-6, IL-8,   cation to undetectable levels—exhibit         and bacteria to replicate and further
IL-15, and IL-10), acute phase proteins       high levels of activated CD38+ CD8+           priming immune activation. Ongoing
(serum amyloid A, C-reactive protein),        T cells on progression.1 Further, when        immune activation results in systemic
elements of the coagulation cascade           viral load is suppressed with anti-           inflammation, tissue damage (includ-
(D-dimers, tissue factor), elements of        retroviral therapy, immune activation         ing fibrosis of lymphoid tissue) in the
fibrosis (matrix metalloproteinase acti-      persists and is predictive of disease         heart, lungs, liver, and kidneys, and
vation, collagen deposition), and mi-         progression. Potential contributors to        coagulopathy, all of which are associ-
crobial sensors (lipopolysaccharide           chronic immune activation include             ated with non–HIV-related morbidity
binding protein, soluble CD14). In the        increased antigen load, bacterial over-       and mortality. By controlling HIV rep-
adaptive immune system, there is in-          growth, the presence of herpes viruses,       lication, antiretroviral therapy subdues
creased turnover and exhaustion of            and translocation of proinflammatory          some of these processes and allows
T cells, low thymic output, and estab-        mediators across the gut mucosa.              recovery of some T cell populations.
lishment of a viral reservoir. Similarly,                                                   However, it does not stop immune ac-
there is increased turnover of B cells,                                                     tivation, resultant inflammation, or tis-
                                              Consequences of HIV Infection
                                                                                            sue damage completely.
                                              in the Gastrointestinal Tract
                                                                                               As shown by Hunt and colleagues,1,2
Dr Douek is Chief of the Human Immunol-       A healthy gut is characterized by             T cell activation does decline during
ogy Section at the National Institutes of     tight epithelial junctions and a layer        antiretroviral therapy but remains at
Health in Bethesda, Maryland. Dr Douek’s
                                              of mucus (Figure 1). Antimicrobial            higher than normal levels even after
presentation for the IAS–USA was per-
formed in the capacity of a private citizen   peptides and large quantities of anti-        many years of viral suppression. The
and does not necessarily reflect the views    bodies are secreted into the lumen.           higher the level of immune activa-
of the US government.                         The majority of CD4+ T cells in the           tion (indicated by the percentage of

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Immune Activation, HIV Persistence, Cure Volume 21 Issue 4 September/October 2013

                                                                                                                                                                                                                                                                                   CD4+ T cell
                                                                                                                        Epithelial layer
                                                                                                             |||
                                                                                                             O OO
                                                                                                                                                                                                                                                                                   CD8+ T cell

                                                                                               O

                                                                                                                    O
                                                                                                                   ||
                                                                                                         |
                                                                        | | | |O| | | | |O| |O| |O| | O|O
                                                                                                                                                                                       Loss of tight epithelial junctions

                                                                                                                     O| |
                                                                                                                                                                                                                                                                                   B cell

                                                                                                                       O
                                                                                        O

                                                                                                                         O O
                                                                                                                        | | | | |
                                                                                                                                                                                                                                                                                   Infected CD4+ T cell

                                                                                       O

                                                                                                                             O O O
                                                                                                                                                                                                                                                                                   Macrophage
                 | |O|O| | | | O| O

                                                                                      O
                        OOO

         |O |O
                 O

                                                                                                                                   O O
    O|
     O                             | |
 |O |
                                    O

                                                                                                                                  | | | |
                                                                                                                                                                                                                                                                                   Dendritic cell

                                                                                     O O O O
                                                       Mucus layer
                                         O

                                                                                                                                       O O
                                         | | O

                                                                                                                                                                                                                                                                                   Secretory immunoglobulin A
                                                 O

                                                                                                                                           O
                                             |O |

                                                                                                                                          |O | |
                                                 O|

                                                                                                                                                                                                                                                                                   Commensal bacterium

                                                                                                                                               O
                                                                                    O
                                                   O|

                                                                                                                                                   | |O

                                                                                                                                               O
                                                                    | |O O O
                                                                                                                                                        |
                                                                                                                                                   O
                                                     OO

                                                                                                                                                                                                                                                                                   Microfold cell
                                                     | |
                                                      O  | |

                                                                                                                                                            Loss of CD4+ T cells
                                                          O

                                                                             O

                                                              | | |O
                                                              O
                                                                  O O                                                                                                                                                                                    Microbial translocation   High endothelial venules
                                                                                                                                                                                   Enterocyte apoptosis
                                                                                                                                                                                                                                                                                   Defensin

Figure 1. The effects of HIV infection in the gastrointestinal tract. Adapted from Mowat,12 and Brenchley and Douek.13

activated CD38+ CD8+ T cells persist-                                                                                                               in a substantially greater reduction in        gut tissues than in peripheral blood
ing during antiretroviral therapy), the                                                                                                             immune activation (higher percent-             and reduced viral persistence (mea-
lower the recovery of CD4+ T cell lev-                                                                                                              age of CD38+ memory CD8+ T cells)              sured as HIV RNA level) in the terminal
els. Overall, these investigators have                                                                                                              than standard antiretroviral therapy.4         ileum.8
shown that numerous markers of in-                                                                                                                  Another study showed that raltegravir
flammation and gut barrier dysfunc-                                                                                                                 intensification resulted in a substantial      Ongoing HIV Replication During
tion are associated with an increased                                                                                                               reduction in the viral reservoir of la-
                                                                                                                                                                                                   Antiretroviral Therapy?
risk of mortality among HIV-infected                                                                                                                tently infected memory CD4+ T cells
patients, independent of CD4+ cell                                                                                                                  (reduction in infectious units per mil-        Although complete inhibition of viral
count and viral load (Figure 3).3 For ex-                                                                                                           lion cells, or IUPM) and in CD8+ T cell        replication is an unlikely curative strat-
ample, elevated blood levels of intesti-                                                                                                            activation in patients with viral sup-         egy for HIV infection, all functional
                                                                                                                                                               5                                   cure strategies are based on first hav-
nal fatty acid binding protein (iFABP),                                                                                                             pression. However, yet another study
a marker of damage in the gut epithe-                                                                                                               showed that the addition of raltegravir        ing achieved complete suppression of
lial lining, are associated with an 8-fold                                                                                                          to an antiretroviral regimen did not fur-      virus. There are substantial data that
increased risk of mortality among HIV-                                                                                                              ther reduce low-level plasma viremia           indicate HIV replication is not ongoing
infected patients.                                                                                                                                  and found no association between per-          during suppressive antiretroviral thera-
                                                                                                                                                    sistence of plasma HIV RNA levels and T        py, but there are also data that suggest
                                                                                                                                                                    6
Immune Activation and HIV                                                                                                                           cell activation.
Persistence                                                                                                                                             One explanation
                                                                                                                                                                                                            Immune deficiency
                                                                                                                                                    for the seemingly
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In addition to the other deleterious
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                                                                                                                                                    divergent findings

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                                                                                                                                                                                                                   Gut

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effects noted, persistent inflamma-                                                                                                                 with raltegravir in-
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tion appears to be associated with                                                                                                                  tensification may
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                                                                                                                                                                                           I TEM                                         Other
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the persistence of HIV. Ongoing HIV                                                                                                                 be that its effects
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                                                                                                                                                                                                                   HIV
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                                                                                                                                                                                              and                                        viruses
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replication in host reservoirs also ap-                                                                                                             are more promi-
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                                                                                                                                                                                              TCM                                      (eg, CMV)
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pears to contribute to persistent in-                                                                                                               nent in gut tissue
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flammation. Research is under way
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                                                                                                                                                    than in peripheral
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                                                                                                                                                                                                            Immune activation
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to determine whether novel investi-                                                                                                                 blood. A number of
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gational approaches can reduce HIV
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                                                                                                                                                    studies have shown
reservoir size, through, for example,                                                                                                               a strong association                     Low thymic output           Systemic inflammation
the use of antiinflammatory drugs or                                                                                                                between cell-based                    Lymphoid tissue fibrosis
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                                                                                                                                                                                                                             Tissue damage
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by enhancement of HIV-specific im-                                                                                                                                                        T and B cell dysfunction           Coagulopathy
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                                                                                                                                                    measures of viral
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munity.                                                                                                                                             persistence and T
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   An association between HIV per-                                                                                                                  cell activation in
sistence and persistent immune acti-                                                                                                                gastrointestinal tis-                                Non–HIV-related morbidity and mortality
vation in patients with undetectable                                                                                                                     7
                                                                                                                                                    sue. As shown in
plasma HIV RNA levels has been shown                                                                                                                Figure 4, raltegra- Figure 2. The role of microbial translocation from the gut in fuel-
in studies of raltegravir intensification.                                                                                                          vir intensification ing immune activation. CMV indicates cytomegalovirus; TCM, cen-
In one study, antiretroviral therapy                                                                                                                reduced immune tral memory T cells; TEM, effector memory T cells. Adapted from
with raltegravir intensification resulted                                                                                                           activation more in Klatt et al.14

                                                                                                                                                                                   129
IAS–USA          Topics in Antiviral Medicine

  iFABP                                 8.3                              controllers, who may ex-          mucosal damage at the gut surface.
                       0.24
                                                                         hibit immune activation           These problems can result in immune
Zonulin
                                                                         and disease progression,          suppression, with subsequent poor
                                  4.6
KT ratio                                                                 patients in the VISCONTI          control of pathogens (eg, Streptococ-
 sCD14                                        16                         study had very low levels of      cus, Staphylococcus, herpes viruses),
                                                        70               T cell activation. A potential    even in patients with low or undetect-
    IL-6
                                                   30
                                                                         implication of these findings     able HIV RNA levels.
D-dimer
                                                                         is that very early treatment         Immune activation affects the reser-
                                         9
 TNF R1                                                                  limits the size of the latent     voir of HIV, even in patients taking an-
 hsCRP                                   11                              viral reservoir, which thus       tiretroviral therapy. It causes the gen-
                                                                         limits the magnitude of im-       eration of activated T cells, the tar-
       0.01      0.1          1          10              100   1000
                                                                         mune activation from the          get cells for the virus. Cells that are
           Probability of Mortality in 4th vs 1st Quartile
                                                                         outset, potentially providing     already infected with HIV will prolif-
                                                                         a lower set point for ongoing     erate, producing more HIV-infected
Figure 3. Markers of inflammation and gastrointes-                       inflammation.                     cells and expanding the viral reser-
tinal dysfunction that predict mortality in HIV in-                                                        voir. Viral transcription may begin,
fection. hsCRP indicates high-sensitivity C-reactive
                                                                         Relationship Between              and some viral replication may occur.
protein; iFABP, intestinal fatty acid binding protein;
                                                                                                           There is increasing evidence of the
IL, interleukin; KT, kynurenine-to-tryptophan; sCD14,                    HIV-Specific Immunity
soluble CD14; TNF R1, tumor necrosis factor receptor 1.                                                    risk of new infection events, even in
                                                                         and HIV Persistence
Adapted with permission from Hunt et al.3                                                                  patients taking fully suppressive anti-
                                                                         Ongoing immune activation         retroviral therapy. This increase in HIV
ongoing replication occurs and is as-                          adversely affects the HIV-specific T cell   replication results in further immune
sociated with immune activation. In                            response, as well as overall CD4+ T         activation and, because the patient
determining whether ongoing HIV rep-                           cell reconstitution. Thus, ongoing im-      remains in an immune-suppressed
lication takes place, the source of the                        mune activation may interfere with          state, poor immune control of newly
sample and the assay used to measure                           reconstitution of the HIV-specific T cell   produced virus. Antiretroviral therapy
viral reservoir are crucial. Blood tests                       response. An example of the potential       can profoundly reduce viral replica-
may indicate the absence of ongoing                            relationship between HIV-specific im-       tion but does not eliminate residual
viral replication, whereas gut or other                        munity in the gut and viral persistence     immune activation nor stop the rep-
lymphoid tissue assays that are sensi-                         is provided in a study by Hatano and        lication of virus-containing cells or
tive enough to detect to 1 viral copy per                      colleagues.10 The study showed that in      the expansion of the viral reservoir
million cells may demonstrate ongoing                          patients taking antiretroviral therapy,
replication. Lymphoid tissue is likely                         a stronger HIV-specific T cell response                                        5
the major HIV reservoir in patients on                         in the gut mucosa was associated with
                                                                                                           CD38+ HLA-DR+ Level
                                                                                                            (% of CD8+ T Cells)

                                                                                                                                              0
antiretroviral therapy. The gut is actually                    lower levels of proviral DNA in periph-
the largest lymphoid tissue in the body,                       eral blood mononuclear cells (PBMCs).                                          -5
but widespread destruction of CD4+ T
cells in the gut make the lymph nodes                                                                                                        -10
                                                               Model for Immune Activation
or spleen the more likely primary viral
                                                               and HIV Persistence
                                                                                                                                                    C

                                                                                                                                                                 um

                                                                                                                                                                            um

                                                                                                                                                                                       n

                                                                                                                                                                                            um
                                                                                                                                             -15
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reservoir during chronic infection. It is                                                                                                                                          Co
                                                                                                                                                             en

                                                                                                                                                                         Ile

                                                                                                                                                                                           ct
                                                                                                                                                   PB

                                                                                                                                                                                           Re
                                                                                                                                                            od
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in these tissues that evidence of viral                        If the mechanisms for the associa-                                                                       Location
reservoir expansion and resultant ongo-                        tion between immune activation and
ing immune activation can be found.                            HIV persistence can be identified, it                                       2000
                                                                                                           (copies/million CD4+ T cells)

    Results of the recently reported                           may be possible to direct therapeu-
                                                                                                                                              0
                                                                                                                  HIV RNA Level

VISCONTI (Viro-Immunological Sus-                              tic strategies at these mechanisms.
tained Control after Treatment Inter-                          Figure 5 shows a potential model for                                        -2000
ruption) study9 indicate an association                        more fully explaining HIV pathogen-
                                                                                                                                           -4000
between ongoing viral replication and                          esis in a way that incorporates persis-
                                                                                                                                                        C

                                                                                                                                                                 um

                                                                                                                                                                            um

                                                                                                                                                                                      on

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                                                                                                                                                    M

immune activation. In this study, 14                           tent immune activation and the role of
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patients started taking antiretroviral                         the viral reservoir in fueling immune
                                                                                                                                                                                 Ri
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                                                                                                                                                                 Te

therapy soon after HIV infection and                           activation. Persistent immune activa-                                                                  Location
continued it for many years. When                              tion causes many problems in the im-
antiretroviral therapy was stopped,                            mune system, including low thymic
                                                                                                           Figure 4. The effects of raltegravir inten-
the patients did not exhibit viral re-                         output, lymphoid tissue fibrosis, poor      sification on immune activation (top) and
bound. Like elite controllers, these pa-                       immune reconstitution and renewal           HIV RNA levels (bottom) in peripheral blood
tients had very low levels of cell-asso-                       of CD4+ T cells, and dysfunction of T       mononuclear cells (PBMCs) and gut tissue
ciated HIV DNA. However, unlike elite                          and B cells. It also continues to cause     sites. Adapted from Yukl et al.8

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Immune Activation, HIV Persistence, Cure Volume 21 Issue 4 September/October 2013

                                               Immune suppression                          enhance T cell re-      therapy intensification. It is also pos-
                                                                                           newal, antifibrotic     sible that gene therapy could be used
                                             Poor control of pathogens                     drugs, anti-aging       to reduce the viral reservoir. It has
                                             Translocation of microbial
                                                     products                              strategies, antiin-     already been shown that stem-cell
                                                                                           flammatory agents,      transplants can lead to a reduction in
  Target cell generation                                           Low thymic output       and anticoagulants      the size of the viral reservoir (ie, in
Infected cell proliferation                                     Lymphoid tissue fibrosis   (Table). Combination    the Berlin patient11), serving as proof
    Virus transcription             Immune activation           Poor CD4+ cell renewal
     Virus production                                           T and B cell dysfunction
                                                                                           approaches will like-   of principle that such genetic ap-
  New infection events                                              Mucosal damage         ly be necessary to      proaches may be viable. Drugs with
                                                                                           reduce persistent       biologic activity against latent virus
                          HIV infection
                                                                                           immune activation       exist and are being assessed, and vac-
                                                                                           and counteract its      cines may be developed to enhance
                                              Effects of HIV infection                     effects in the body,    host clearance mechanisms (ie, by
                                                                                           given the multifac-     boosting the damaged HIV-specific
                                                                                           torial pathogenesis     immune response). As noted, a com-
Figure 5. The central role of persistent immune activation in HIV
infection. Adapted from Klatt et al.14                                                     of HIV infection.       bination of approaches will be neces-
                                                                                                                   sary to address the many aspects of
that can result from persistent im-                                Conclusion: In the Context of                   HIV infection and persistent immune
mune activation.                                                   a Cure                                          activation.
    Although this picture of pathogen-
esis may appear daunting with regard                               Numerous mechanisms contribute to               Presented by Dr Douek in March 2013. First
to achieving a cure for HIV infection,                             HIV persistence, many of which are cur-         draft prepared from transcripts by Matthew
it actually suggests many points in the                            rently being addressed therapeutical-           Stenger. Reviewed and edited by Dr Douek in
processes underlying persistent im-                                ly. The unifying theme in these efforts         October 2013.
mune activation that can serve as ther-                            is to reduce the size of the HIV reser-
                                                                                                                   Financial Affiliations: Dr Douek has no rel-
apeutic targets. Among the therapeutic                             voir. Strategies to achieve this include
                                                                                                                   evant financial affiliations to disclose.
interventions in development are che-                              reducing persistent inflammation and
mokine receptor inhibitors, antiinfec-                             increasing immune function, potential-
tive therapies, drugs that may reduce                              ly including the strategies of early an-        References
microbial translocation, drugs that may                            tiretroviral therapy and antiretroviral
                                                                                                                    1. Hunt PW, Brenchley J, Sinclair E, et al. Re-
                                                                                                                       lationship between T cell activation and
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Microbial translocation                          Sevelamer, colostrum, rifaximin                                       tion, and coagulation predict higher mor-
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IAS–USA          Topics in Antiviral Medicine

 7. Sheth PM, Yi TJ, Kovacs C, et al. Mucosal             HIV-infected patients with a subopti-      Additional Suggested Reading
    correlates of isolated HIV semen shed-                mal CD4+ T cell response. J Infect Dis.
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