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H I G H L I G H T S
The more the merrier
A U TO I M M U N I T Y
In a surprising new study published inCell, Nora Sarvetnick and colleagueshave shown that autoimmunity canbe caused by insufficient numbers ofT cells. This indicates that having acrowded immune system can actu-ally be good for you and provides apossible explanation for the benefi-cial effects of a ‘less-than-hygienic’environment.
They showed that female auto-immune-prone non-obese diabetic(NOD) mice have fewer peripheralCD4+ T cells than control strains thatdo not develop autoimmunity. Thislymphopaenia was associated withdisease development, as increasing thenumber of T cells in NOD mice byinjection of complete Freund’s adju-vant (CFA; which contains T-cellstimulatory mycobacterial cell-wallcomponents) protected the mice fromdeveloping diabetes. Furthermore, theeffect was due to T-cell number ratherthan phenotype as the transfer ofT cells from NOD littermates alsoprevented diabetes.
The artificial induction of lym-phopaenia — for example, by irra-diation — results in proliferation ofthe remaining T cells to fill the‘space’ that is left. To see if thishomeostatic expansion occurs inNOD mice, the authors monitoredlabelled NOD T cells expressing aT-cell receptor (TCR) specific forpancreatic β-cells after transfer tovarious hosts. These TCR-transgenicT cells only proliferated in lym-phopenic NOD mice and not inNOD mice treated with CFA.Analysis of cell-surface markerssuch as CD62L to distinguishbetween classically activated andhomeostatically expanding T cellswas also used to show that a fargreater percentage of the natural T-cell populations of NOD mice isundergoing homeostatic expansioncompared with non-lymphopenic,non-autoimmune-prone mice.Importantly, NOD mice with themost proliferating T cells had themost severe pancreatic insulitis,
which indicates that there is a directlink between homeostatic expansionand disease.
Part of the explanation for thelymphopenia of NOD mice might liein the observation that they haveincreased levels of interleukin-21(IL-21) production, leading to upreg-ulation of IL-21 receptor (IL-21R)expression by T cells, and clear
Gene therapy for HIVA new therapy that has beendescribed as “probably themost exciting of the anti-HIVstrategies around at themoment” (Alan Kingsman,Oxford Biomedica; BBCNews) is producingencouraging results in Phase Isafety trials, according to areport in New Scientist(15 May 2004).
VRX496 uses anti-sensetechnology to prevent HIVreplication. T cells are isolatedfrom patients and infectedwith a modified form of HIVcontaining an anti-sensegene. T cells containing theintegrated viral genome arere-infused into patients sothat when HIV tries to infectthe modified T cells in vivo,the anti-sense mRNA isproduced and binds to thesense viral mRNA, therebypreventing translation of viralproteins.
So far, three patients whohad failed two regimens ofanti-retroviral drug therapyhave been treated withVRX496. Boro Dropulic,Founder and Chief ScientificOfficer of VIRxSYSCorporation, which isdeveloping VRX496, saysthat no adverse events havebeen observed in thesepatients and they areencouraged by the findingthat “viral load results are notabove pre-dose levels andCD4 counts have remainedstable” (VIRxSYS). On thebasis of these results, theData Safety MonitoringBoard, USA, recommendedin April that a further twopatients should be enrolledin the trial without delay.
Assuming that no safetyconcerns arise, the therapycould soon enter Phase IItrials to determine efficacy.However, not everyone isconvinced. This is the firsttime that a lentiviral vectorhas been used in a clinicaltrial in humans, and concernsabout recombination andother safety issues have led many researchers toabandon research into genetherapy, according to RichardSutton of Baylor College ofMedicine (New Scientist).
Kirsty Minton
IN THE NEWS
In the absence of an effectivevaccine, blocking infection andtransmission of HIV at mucosalsurfaces might be our best chanceof stemming the spread of HIVinfection. Reporting in TheJournal of ExperimentalMedicine, Qinxue Hu et al.explore the potential ofHIV-1-specific antibodies andcompounds that target HIV-1-binding cell-surface receptors toinhibit HIV-1 infection of anddissemination from humancervical tissue.
To infect cells, HIV-1 mustinteract with two receptors,CD4 and a co-receptor — CC-chemokine receptor 5 (CCR5) forR5 viruses and CXC-chemokine
receptor 4 (CXCR4) for X4viruses. Using a CD4-specificantibody or small moleculeinhibitors of CCR5 and CXCR4,the authors could inhibit localizedinfection of mucosal tissue by R5and X4 viruses, respectively.Although in vitro studies haveidentified viruses that can useother co-receptors, here, theyshow that infection of humancervical tissue using co-receptorsother than CXCR4 or CCR5 isunlikely.
In addition to direct infection of mucosal tissue, HIV-1 canbecome attached to migratorycells, facilitating viraltransmission and infection inlymphoid organs. Dendritic cells
(DCs) that express the mannose-binding C-type lectin DC-SIGNare thought to be involved in thisprocess. So, the authors collectedmigratory cells (which includedboth DC-SIGN– and DC-SIGN+
DCs) emigrating from cervicalexplants after HIV-1 inoculationin the presence or absence ofinhibitors, and assayed forinfection of indicator cells in co-cultures. In contrast to infectionof cervical tissue, uptake of HIV-1by migratory cells was notinhibited by a combination ofCXCR4 and CCR5 inhibitors, butwas inhibited when CD4-specificantibodies and mannan werepresent. Presence of DC-SIGN-specific antibody also inhibitedthe capture of infectious virus bymigratory cells, albeit to a lesserextent, indicating an importantbut not exclusive role for thisreceptor in virus capture andtransmission.
Pulling out the stops
H I V
400 | JUNE 2004 | VOLUME 4 www.nature.com/reviews/immunol