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PLoS Pathog. 2009 Feb;5(2):e1000295. Epub 2009 Feb 13.
Critical loss of the balance between Th17
and T regulatory cell populations in
pathogenic SIV infection.
Favre D, Lederer S, Kanwar B, Ma ZM, Proll S, Kasakow Z, Mold J, Swainson L, Barbour
JD, Baskin CR, Palermo R, Pandrea I, Miller CJ, Katze MG, McCune JM.
Source
Department of Medicine, Division of Experimental Medicine, University of California, San
Francisco, California, United States of America.
Abstract
Chronic immune activation and progression to AIDS are observed after SIV infection in
macaques but not in natural host primate species. To better understand this dichotomy, we
compared acute pathogenic SIV infection in pigtailed macaques (PTs) to non-pathogenic
infection in African green monkeys (AGMs). SIVagm-infected PTs, but not SIVagm-infected
AGMs, rapidly developed systemic immune activation, marked and selective depletion of IL17-secreting (Th17) cells, and loss of the balance between Th17 and T regulatory (Treg) cells
in blood, lymphoid organs, and mucosal tissue. The loss of Th17 cells was found to be
predictive of systemic and sustained T cell activation. Collectively, these data indicate that
loss of the Th17 to Treg balance is related to SIV disease progression.
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PLoS Pathog. 2010 Aug 19;6(8):e1001052.
Damaged intestinal epithelial integrity
linked to microbial translocation in
pathogenic simian immunodeficiency virus
infections.
Estes JD, Harris LD, Klatt NR, Tabb B, Pittaluga S, Paiardini M, Barclay GR, Smedley J,
Pung R, Oliveira KM, Hirsch VM, Silvestri G, Douek DC, Miller CJ, Haase AT, Lifson J,
Brenchley JM.
Source
AIDS and Cancer Virus Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland,
USA. [email protected]
Abstract
The chronic phase of HIV infection is marked by pathological activation of the immune
system, the extent of which better predicts disease progression than either plasma viral load or
CD4(+) T cell count. Recently, translocation of microbial products from the gastrointestinal
tract has been proposed as an underlying cause of this immune activation, based on indirect
evidence including the detection of microbial products and specific immune responses in the
plasma of chronically HIV-infected humans or SIV-infected Asian macaques. We analyzed
tissues from SIV-infected rhesus macaques (RMs) to provide direct in situ evidence for
translocation of microbial constituents from the lumen of the intestine into the lamina propria
and to draining and peripheral lymph nodes and liver, accompanied by local immune
responses in affected tissues. In chronically SIV-infected RMs this translocation is associated
with breakdown of the integrity of the epithelial barrier of the gastrointestinal (GI) tract and
apparent inability of lamina propria macrophages to effectively phagocytose translocated
microbial constituents. By contrast, in the chronic phase of SIV infection in sooty mangabeys,
we found no evidence of epithelial barrier breakdown, no increased microbial translocation
and no pathological immune activation. Because immune activation is characteristic of the
chronic phase of progressive HIV/SIV infections, these findings suggest that increased
microbial translocation from the GI tract, in excess of capacity to clear the translocated
microbial constituents, helps drive pathological immune activation. Novel therapeutic
approaches to inhibit microbial translocation and/or attenuate chronic immune activation in
HIV-infected individuals may complement treatments aimed at direct suppression of viral
replication.
Supplemental Content
J Immunol. 2008 Nov 15;181(10):6687-91.
Cutting edge: Experimentally induced
immune activation in natural hosts of
simian immunodeficiency virus induces
significant increases in viral replication and
CD4+ T cell depletion.
Pandrea I, Gaufin T, Brenchley JM, Gautam R, Monjure C, Gautam A, Coleman C, Lackner
AA, Ribeiro RM, Douek DC, Apetrei C.
Source
Division of Comparative Pathology, Tulane National Primate Research Center, Covington,
LA 70433, USA. [email protected]
Abstract
Chronically SIVagm-infected African green monkeys (AGMs) have a remarkably stable
nonpathogenic disease course, with levels of immune activation in chronic SIVagm infection
similar to those observed in uninfected monkeys and with stable viral loads for long periods
of time. In vivo administration of LPS or an IL-2/diphtheria toxin fusion protein (Ontak) to
chronically SIVagm-infected AGMs triggered increases in immune activation and
subsequently of viral replication and depletion of intestinal CD4(+) T cells. Our study
indicates that circulating microbial products can increase viral replication by inducing
immune activation and increasing the number of viral target cells, thus demonstrating that
immune activation and T cell proliferation are key factors in AIDS pathogenesis.
Supplemental Content
PLoS Pathog. 2009 Apr;5(4):e1000372. Epub 2009 Apr 10.
Association of progressive CD4(+) T cell
decline in SIV infection with the induction
of autoreactive antibodies.
Kuwata T, Nishimura Y, Whitted S, Ourmanov I, Brown CR, Dang Q, Buckler-White A,
Iyengar R, Brenchley JM, Hirsch VM.
Source
Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto,
Japan.
Abstract
The progressive decline of CD4(+) T cells is a hallmark of disease progression in human
immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. Whereas
the acute phase of the infection is dominated by virus-mediated depletion of memory CD4(+)
T cells, chronic infection is often associated with a progressive decline of total CD4(+) T
cells, including the naïve subset. The mechanism of this second phase of CD4(+) T cell loss is
unclear and may include immune activation-induced cell death, immune-mediated
destruction, and regenerative or homeostatic failure. We studied patterns of CD4(+) T cell
subset depletion in blood and tissues in a group of 20 rhesus macaques inoculated with
derivatives of the pathogenic SIVsmE543-3 or SIVmac239. Phenotypic analysis of CD4(+) T
cells demonstrated two patterns of CD4(+) T cell depletion, primarily affecting either naïve or
memory CD4(+) T cells. Progressive decline of total CD4(+) T cells was observed only in
macaques with naïve CD4(+) T cell depletion (ND), though the depletion of memory CD4(+)
T cells was profound in macaques with memory CD4(+) T cell depletion (MD). ND
macaques exhibited lower viral load and higher SIV-specific antibody responses and greater
B cell activation than MD macaques. Depletion of naïve CD4(+) T cells was associated with
plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated
CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa),
dsDNA, and phospholipid (aPL). Consistent with a biological role of these antibodies, these
latter antibodies were accompanied by clinical features associated with autoimmune disorders,
thrombocytopenia, and catastrophic thrombotic events. More importantly for AIDS
pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of
naïve CD4(+) T cell depletion. These results suggest an important role of autoreactive
antibodies in the CD4(+) T cell decline observed during progression to AIDS.
Supplemental Content
J Clin Invest. 2011 Mar 1;121(3):1102-10. doi: 10.1172/JCI44876. Epub 2011 Feb 7.
Lack of clinical AIDS in SIV-infected sooty
mangabeys with significant CD4+ T cell loss
is associated with double-negative T cells.
Milush JM, Mir KD, Sundaravaradan V, Gordon SN, Engram J, Cano CA, Reeves JD, Anton
E, O'Neill E, Butler E, Hancock K, Cole KS, Brenchley JM, Else JG, Silvestri G, Sodora DL.
Source
Division of Infectious Disease, Department of Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas, USA.
Abstract
SIV infection of natural host species such as sooty mangabeys results in high viral replication
without clinical signs of simian AIDS. Studying such infections is useful for identifying
immunologic parameters that lead to AIDS in HIV-infected patients. Here we have
demonstrated that acute, SIV-induced CD4(+) T cell depletion in sooty mangabeys does not
result in immune dysfunction and progression to simian AIDS and that a population of
CD3(+)CD4(-)CD8(-) T cells (double-negative T cells) partially compensates for CD4(+) T
cell function in these animals. Passaging plasma from an SIV-infected sooty mangabey with
very few CD4(+) T cells to SIV-negative animals resulted in rapid loss of CD4(+) T cells.
Nonetheless, all sooty mangabeys generated SIV-specific antibody and T cell responses and
maintained normal levels of plasma lipopolysaccharide. Moreover, all CD4-low sooty
mangabeys elicited a de novo immune response following influenza vaccination. Such
preserved immune responses as well as the low levels of immune activation observed in these
animals were associated with the presence of double-negative T cells capable of producing
Th1, Th2, and Th17 cytokines. These studies indicate that SIV-infected sooty mangabeys do
not appear to rely entirely on CD4(+) T cells to maintain immunity and identify double-
negative T cells as a potential subset of cells capable of performing CD4(+) T cell-like helper
functions upon SIV-induced CD4(+) T cell depletion in this species.
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