Mucosal Immunol. 2008 Jan;1(1):23-30.
HIV infection and the gastrointestinal
immune system.
Brenchley JM, Douek DC.
Source
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and
infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Abstract
There has recently been a resurgence of interest in the gastrointestinal pathology observed in
patients infected with HIV. The gastrointestinal tract is a major site of HIV replication, which
results in massive depletion of lamina propria CD4 T cells during acute infection. Highly
active antiretroviral therapy leads to incomplete suppression of viral replication and
substantially delayed and only partial restoration of gastrointestinal CD4 T cells. The
gastrointestinal pathology associated with HIV infection comprises significant enteropathy
with increased levels of inflammation and decreased levels of mucosal repair and
regeneration. Assessment of gut mucosal immune system has provided novel directions for
therapeutic interventions that modify the consequences of acute HIV infection.
Comment on

Mucosal Immunol. 2008 Jan;1(1):49-58.
Supplemental Content
PLoS One. 2011 Apr 11;6(4):e18580.
Evidence for polymicrobic flora
translocating in peripheral blood of HIVinfected patients with poor immune
response to antiretroviral therapy.
Merlini E, Bai F, Bellistrì GM, Tincati C, d'Arminio Monforte A, Marchetti G.
Source
Department of Medicine, Surgery and Dentistry, Clinic of Infectious Diseases, San Paolo
Hospital, University of Milan, Milan, Italy.
Abstract
In advanced HIV infection, the homeostatic balance between gastrointestinal indigenous
bacteria and gut immunity fails and microbes are able to overcome the intestinal barrier and
gain the systemic circulation. Because microbial translocation is not fully controlled by
antiviral therapy and is associated with inefficient CD4+ reconstitution, we investigated the
profile of translocating bacteria in peripheral blood of 44 HIV-infected patients starting
therapy with advanced CD4+ T-lymphopenia and displaying poor CD4+ recovery on
virologically suppressive HAART. According to CD4+ reconstitution at 12-months HAART,
patients were considered Partial Immunological Responders, PIRs (CD4+≥250/µl, n = 29) and
Immunological non Responders, INRs (CD4+<200/µl, n = 15)). We show that PIRs and INRs
present similarly elevated plasma levels of lipopolysaccharide (LPS) and its ligand sCD14
that were not lowered by virologically suppressive therapy. Bacterial 16S rRNA gene
amplification and sequencing resulted in a highly polymicrobic peripheral blood microbiota
both prior and after 12-month HAART. Several differences in bacterial composition were
shown between patients' groups, mainly the lack of probiotic Lactobacillaceae both prior and
after therapy in INRs. Failure to control microbial translocation on HAART is associated with
a polymicrobic flora circulating in peripheral blood that is not substantially modified by
Supplemental Content
BMC Infect Dis. 2010 Nov 2;10:318.
Long-term mortality in HIV patients virally
suppressed for more than three years with
incomplete CD4 recovery: a cohort study.
Engsig FN, Gerstoft J, Kronborg G, Larsen CS, Pedersen G, Røge B, Jensen J, Nielsen LN,
Obel N.
Source
Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet,
Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. fren74@gmail.com
Abstract
BACKGROUND:
The mortality in patients with persistent low CD4 count despite several years of HAART with
sustained viral suppression is poorly documented. We aimed to identify predictors for
inadequate CD4 cell recovery and estimate mortality in patients with low CD4 count but
otherwise successful HAART.
METHOD:
In a nationwide cohort of HIV patients we identified all individuals who started HAART
before 1 January 2005 with CD4 cell count ≤ 200 cells/μL and experienced three years with
sustained viral suppression. Patients were categorized according to CD4 cell count after the
three years suppressed period (≤ 200 cells/μL; immunological non-responders (INRs), >200
cells/μL; immunological responders (IRs)). We used logistic regression and Kaplan-Meier
analysis to estimated risk factors and mortality for INRs compared to IRs.
RESULTS:
We identified 55 INRs and 236 IRs. In adjusted analysis age > 40 years and > one year from
first CD4 cell count ≤ 200 cells/μL to start of the virologically suppressed period were
associated with increased risk of INR. INRs had substantially higher mortality compared to
IRs. The excess mortality was mainly seen in the INR group with > one year of
immunological suppression prior to viral suppression and injection drug users (IDUs).
CONCLUSION:
Age and prolonged periods of immune deficiency prior to successful HAART are risk factors
for incomplete CD4 cell recovery. INRs have substantially increased long-term mortality
mainly associated with prolonged immunological suppression prior to viral suppression and
IDU.
Supplemental Content
Mucosal Immunol. 2011 Sep;4(5):554-63. doi: 10.1038/mi.2011.15. Epub 2011 Apr 27.
Specific prebiotics modulate gut microbiota
and immune activation in HAART-naive
HIV-infected adults: results of the
"COPA" pilot randomized trial.
Gori A, Rizzardini G, Van't Land B, Amor KB, van Schaik J, Torti C, Quirino T, Tincati C,
Bandera A, Knol J, Benlhassan-Chahour K, Trabattoni D, Bray D, Vriesema A, Welling G,
Garssen J, Clerici M.
Source
Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital,
University of Milano-Bicocca, Monza, Italy. andrea.gori@unimib.it
Abstract
Intestinal mucosal immune system is an early target for human immunodeficiency virus type
1 (HIV-1) infection, resulting in CD4(+) T-cell depletion, deterioration of gut lining, and fecal
microbiota composition. We evaluated the effects of a prebiotic oligosaccharide mixture in
highly active antiretroviral therapy (HAART)-naive HIV-1-infected adults. In a pilot doubleblind, randomized, placebo-controlled study, 57 HAART-naive HIV-1-infected patients
received a unique oligosaccharide mixture (15 or 30 g short chain
galactooligosaccharides/long chain fructooligosaccharides/pectin hydrolysate-derived acidic
oligosaccharides (scGOS/lcFOS/pAOS) daily) or a placebo for 12 weeks. Microbiota
composition improved significantly with increased bifidobacteria, decreased Clostridium
coccoides/Eubacterium rectale cluster, and decreased pathogenic Clostridium
lituseburense/Clostridium histolyticum group levels upon prebiotic supplementation. In
addition, a reduction of soluble CD14 (sCD14), activated CD4(+)/CD25(+) T cells, and
significantly increased natural killer (NK) cell activity when compared with control group
were seen in the treatment group. The results of this pilot trial highly significantly show that
dietary supplementation with a prebiotic oligosaccharide mixture results in improvement of
the gut microbiota composition, reduction of sCD14, CD4(+) T-cell activation (CD25), and
improved NK cell activity in HAART-naive HIV-infected individuals.
Supplemental Content
PLoS One. 2010 Nov 29;5(11):e14119.
Qualitative immune modulation by
interleukin-2 (IL-2) adjuvant therapy in
immunological non responder HIVinfected patients.
Sabbatini F, Bandera A, Ferrario G, Trabattoni D, Marchetti G, Franzetti F, Clerici M, Gori
A.
Source
Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital,
University of Milan-Bicocca, Monza, Italy. f.sabbatini@hsgerardo.org
Abstract
BACKGROUND:
Treatment of HIV-infected patients with interleukin-2 (IL-2) produces significant increases in
CD4 T cell counts; however an associated qualitative improvement in cells function has yet to
be conclusively demonstrated. By measuring mycobacterial killing activity, we evaluated IL-
2-mediated functional immune enhancement ex vivo in immunological non-responders
(INRs).
METHODS AND FINDINGS:
PBMC from 12 immunological non-responders (INRs) (CD4+<200/µl, HIV-RNA<50 cp/ml)
on combination antiretroviral treatment (cART) were collected at baseline, and after 3 IL-2
cycles. Eight INRs receiving only cART were studied as controls. After 21 days of PBMC
incubation with a virulent M. avium suspension, counts of residual colony forming units
(CFUs) and concentrations of TNF-α, IL-10 and IFN-γ were determined. In IL-2 treated
patients, a significant reduction in mean residual CFUs of PBMC cultures was observed
(p<0.01). Moreover, following IL-2 treatment, significant increases in PBMC's IFNγ
production (p = 0.02) and substantial reductions in IL-10 levels were observed.
CONCLUSIONS:
IL-2 therapy restores the ability of the lympho-monocyte system in eliciting an effective
response against mycobacterial infections. Our data indicate the possibility of a clinical role
held by IL-2 in enhancing the immune function of subjects unable to achieve immune
competence through cART alone.
Supplemental Content
Enferm Infecc Microbiol Clin. 2008 Jan;26(1):27-31.
Efficacy of recombinant interleukin-2 (rIL2) in patients with advanced HIV-1
infection and blunted immune response to
HAART.
Crespo M, Caragol I, Falcó V, Ribera E, Urban S, Pahissa A.
Source
Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma
de Barcelona, Spain. mcrespo@vhebron.net
Abstract
OBJECTIVE:
The efficacy of recombinant interleukin-2 (rIL-2) was assessed in HIV-infected patients with
advanced immune suppression and a discordant immune response to highly active
antiretroviral therapy (HAART). The primary endpoint was median change in CD4+ T-cell
counts at the end of treatment as compared to baseline. Secondary endpoints were safety and
changes in the various T-cell subpopulations.
MATERIAL AND METHODS:
In a prospective cohort study, 19 patients with HIV-RNA < 50 copies/mL and < 200 CD4+ T
cells/mm3 without a significant increase in the previous 12 months were scheduled to receive
6 cycles of 4.5 x 10(6) IU subcutaneous rIL-2 daily for 5 consecutive days, every 4 weeks.
RESULTS:
Median age was 43 years, and 64% had a previous AIDS-defining event. Median nadir and
baseline CD4+ cell counts were 36 and 99 cells/mm3, respectively. Three patients
discontinued treatment and one experienced grade 4 side effects. CD4+ T-cell counts
increased to 147 cells/mm3 (range, 24-285) at 1 month following completion of treatment (P
= 0.002), and 180 cells/mm3 (range, 38-280) at 18 months (P < 0.001). This improvement
was associated with a significant decrease in expression rates of the activation markers, HLADR and CD38.
CONCLUSION:
Our results suggest that in patients with advanced HIV-infection showing a blunted immune
response to HAART, rIL-2 might increase the pool of CD4+ T-cells by down-regulating the
status of immune activation.
Comment in

Enferm Infecc Microbiol Clin. 2008 Jan;26(1):1-3.
PMID:
18208763
[PubMed - indexed for MEDLINE]
Supplemental Content
J Med Virol. 2009 Jan;81(1):16-26.
Immunotherapy of HIV-infected patients
with Gc protein-derived macrophage
activating factor (GcMAF).
Yamamoto N, Ushijima N, Koga Y.
Source
Division of Molecular Immunology and Immunotherapy, Socrates Institute for Therapeutic
Immunology, Philadelphia, Pennsylvania 19126-3305, USA. nobutoyama@verizon.net
Abstract
Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal
macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of
HIV-infected patients was lost or reduced because Gc protein is deglycosylated by alpha-Nacetylgalactosaminidase (Nagalase) secreted from HIV-infected cells. Therefore,
macrophages of HIV-infected patients having deglycosylated Gc protein cannot be activated,
leading to immunosuppression. Since Nagalase is the intrinsic component of the envelope
protein gp120, serum Nagalase activity is the sum of enzyme activities carried by both HIV
virions and envelope proteins. These Nagalase carriers were already complexed with anti-HIV
immunoglobulin G (IgG) but retained Nagalase activity that is required for infectivity.
Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase
generated the most potent macrophage activating factor (termed GcMAF), which produces no
side effects in humans. Macrophages activated by administration of 100 ng GcMAF develop a
large amount of Fc-receptors as well as an enormous variation of receptors that recognize
IgG-bound and unbound HIV virions. Since latently HIV-infected cells are unstable and
constantly release HIV virions, the activated macrophages rapidly intercept the released HIV
virions to prevent reinfection resulting in exhaustion of infected cells. After less than 18
weekly administrations of 100 ng GcMAF for nonanemic patients, they exhibited low serum
Nagalase activities equivalent to healthy controls, indicating eradication of HIV-infection,
which was also confirmed by no infectious center formation by provirus inducing agenttreated patient PBMCs. No recurrence occurred and their healthy CD + cell counts were
maintained for 7 years.
Supplemental Content
FREE at:
http://www3.interscience.wiley.com/cgi-bin/fulltext/121531612/PDFSTART
GcMAF and MAF 314
Marco Ruggiero
Dept. Molecular Biology University of Florence
http://www.marcoruggiero.org/pdf/Oct%2022.pdf
Vitamin D-Receptor with differential
responses to macrophage activating factor
in human monocytes.
Marco Ruggiero
Dept. Molecular Biology University of Florence
Seminar at the Center for Cancer Research NIH, Bethesda, Maryland Aug. 2010
http://www.marcoruggiero.org/pdf/GcMAF%20at%20the%20NIH.pdf
J Clin Gastroenterol. 2010 Oct;44(9):e201-5.
Probiotic yogurt consumption is associated
with an increase of CD4 count among
people living with HIV/AIDS.
Irvine SL, Hummelen R, Hekmat S, Looman CW, Habbema JD, Reid G.
Source
Brescia University College, London, Canada.
Abstract
AIM:
To evaluate the long term effect of yogurt supplemented with Lactobacillus rhamnosus Fiti on
the immune function (CD4 count) of people living with HIV/AIDS.
BACKGROUND:
Gastrointestinal infections and the leakage of microbial products from the gut have a profound
impact on the deterioration of the immune system among people living with HIV/AIDS.
Among persons not infected with the virus, probiotics can prevent gastrointestinal infections
and restore an effective gut barrier, suggesting they might have a beneficial effect on the
immune function of people living with HIV/AIDS.
STUDY:
We carried out an observational retrospective study over a period of 3 years, with longitudinal
comparison of the CD4 count within participants (n=68) before and during probiotic yogurt
consumption, and compared with a control group of participants not consuming the yogurt
(n=82).
RESULTS:
Among the yogurt consumers before use and the nonconsumers, an average increase in CD4
count was seen of 0.13 cells/μL/day (95% CI; 0.07-0.20, P=<0.001). After commencing
consumption, yogurt consumers experienced an additional increase of 0.28 cells/μL/day (95%
CI; 0.10-0.46, P=0.003). When adjusting for length of time using antiretroviral medication,
the additional increase explained by yogurt consumption remained 0.17 cells/μL/day (95%
CI; 0.01-0.34, P=0.04). Treatment with antiretroviral medication was associated with an
increase of 0.27 cells/μL/day (95% CI; 0.17-0.38, P=<0.001).
CONCLUSION:
The introduction of probiotic yogurt, made by local women in a low-income community in
Tanzania, was significantly associated with an increase in CD4 count among consumers living
with HIV.
FREE: http://www.marcoruggiero.org/pdf/Irvine%20et%20al..pdfJ Clin Gastroenterol.
Immunology. 2009 Sep;128(1 Suppl):e366-75. Epub 2008 Nov 7.
The decrease of regulatory T cells correlates
with excessive activation and apoptosis of
CD8+ T cells in HIV-1-infected typical
progressors, but not in long-term nonprogressors.
Jiao Y, Fu J, Xing S, Fu B, Zhang Z, Shi M, Wang X, Zhang J, Jin L, Kang F, Wu H, Wang
FS.
Source
Department of Infectious Diseases, Beijing You-an Hospital Affiliated to Capital Medical
University, Beijing, China.
Abstract
Persistent HIV infection results in a decrease in absolute counts of CD4(+) CD25(+)
regulatory T cells (Treg). To investigate the role of decreased Treg counts in the regulation of
excessive activation and apoptosis of CD8(+) T cells in human immunodeficiency virus
(HIV)-1 infection, we characterized Treg in 83 HIV-1-infected individuals, including 19 longterm non-progressors (LTNPs) and 51 typical progressors (TPs) who were treatment-naïve,
and 13 AIDS patients on highly active antiretroviral therapy (HAART), of whom nine were
complete responders (CRs) and the remaining four were non-responders (NRs) to the
treatment. TPs but not LTNPs had a significant decrease in absolute counts of circulating
Treg, which was inversely correlated with the activation and apoptosis of CD8(+) T cells.
Efficient HAART was found to increase Treg counts in CR patients and temper the excessive
activation and apoptosis of CD8(+) T cells. Moreover, isolated Treg significantly inhibited the
spontaneous and anti-CD3-induced apoptosis of CD8(+) T cells in a dose-dependent manner
in vitro. Thus, our findings indicate that the decrease in Treg closely correlates with the
increase in apoptotic CD8(+) T cells and disease progression in chronic HIV-1 infection, and
that Treg may play a key role in maintaining the balance between the amount and quality of
CD8(+) T cells in HIV-1 infection. Manipulation of Treg function may be a promising
strategy for immune therapy of this disease.
Supplemental Content
AIDS. 2011 Oct 23;25(16):1981-6.
T-cell signalling in antiretroviral-treated,
aviraemic HIV-1-positive individuals is
present in a raised state of basal
activation that contributes to T-cell
hyporesponsiveness.
Downey JS, Attaf M, Moyle G, Gazzard B, Gotch F, Imami N.
Source
Section of Immunology, Department of Medicine, Imperial College London, UK.
j.downey@imperial.ac.uk
Abstract
OBJECTIVE:
Successful antiretroviral therapy (ART) suppresses plasma HIV-1 RNA below detection
limits, reducing the chronic insult to the immune systems of infected individuals and
supporting a degree of immunological recovery. However, the surface phenotypic profile of T
cells in ART-treated patients does not resemble that of healthy, uninfected individuals, but
rather shows upregulation of proteins associated with an exhausted immune system. We
sought to address whether aviraemic HIV-1 infection, therefore, contributed to long-term
alterations in intracellular signalling events within the T cells of infected individuals that
contributed to the exhausted phenotype.
DESIGN:
A flow cytometric approach was employed to assess levels of phosphorylation within T-cell
signalling proteins in ART-treated HIV-1-positive patients and HIV-negative individuals.
METHODS:
The relative phosphorylation levels of extracellular signal-regulated kinases (ERK), c-Jun Nterminal kinases (JNK), p38, zeta-chain-associated protein kinase 70 (ZAP70), linker of
activated T cells, SLP76, nuclear factor kappaB were measured within resting and stimulated
CD4(+) and CD8(+) T cells from aviraemic HIV-1-positive and healthy individuals by
intracellular staining and flow cytometric analysis.
RESULTS:
Basal levels of phospho-ZAP70, phospho-ERK and phospho-JNK were two-fold to three-fold
higher in HIV-1-positive individuals compared with healthy controls, with phospho-p38 also
showing a tendency to increase in HIV-1-positive individuals. Interestingly, in contrast to
healthy controls, peripheral blood mononuclear cells from aviraemic, infected individuals
were refractory to stimulation with IL-2 and CD3/CD28 showing no enhancement of
phosphorylation.
CONCLUSION:
CD4(+) and CD8(+) T cells from HIV-1-positive individuals are poorly responsive to direct
stimulation through the T-cell receptor due to chronically raised basal activation levels of
intracellular signalling molecules.
J Infect Dis. 2003 Jul 15;188(2):232-8. Epub 2003 Jun 9.
Disturbed glutathione metabolism and
decreased antioxidant levels in human
immunodeficiency virus-infected patients
during highly active antiretroviral
therapy--potential immunomodulatory
effects of antioxidants.
Aukrust P, Müller F, Svardal AM, Ueland T, Berge RK, Frøland SS.
Source
Section of Clinical Immunology and Infectious Diseases, Medical Department,
Rikshospitalet, N-0027 Oslo, Norway. pal.aukrust@rikshospitalet.no
Abstract
Oxidative stress has been implicated in the pathogenesis of human immunodeficiency virus
(HIV) infection. We examined the effect of highly active antiretroviral therapy (HAART) on
plasma levels of several antioxidants and intracellular glutathione-redox status in CD4+ T
cells, in 20 HIV-infected patients. HAART was accompanied by both an improvement of
glutathione-redox status and an increase in levels of antioxidant vitamins, without full
normalization. Glutathione supplementation in vitro increases T cell proliferation and
suppresses the spontaneous release of tumor necrosis factor-alpha from peripheral blood
mononuclear cells, in HIV-infected patients receiving HAART. Our findings suggest that
therapeutic intervention aimed at normalization of oxidative disturbances in HIV infection
could be of interest, in addition to HAART.
Supplemental Content