The Challenge of Viral Reservoirs in HIV-1 Infection

Blankson, Joel N.; Persaud, Deborah; Siliciano, Robert F.

doi:10.1146/annurev.med.53.082901.104024

Cited by 547 publications

(449 citation statements)

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“…Moreover, an increasing body of evidence suggests that reservoirs, cell types or anatomical sites ('sanctuaries'), represent a major barrier to virus eradication. 1 HIV-specific CD8 þ T lymphocytes (CTL) are considered crucial in the control of viral replication. 2 Excessive induction of apoptosis has been proposed as one major mechanism of abnormal T-cell response during HIV and Simian Immunodeficiency Virus (SIV) infections.…”

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confidence: 99%

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

et al. 2007

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SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8 þ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8 þ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-b and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8 þ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8 þ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/ memory CD8 þ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1 þ expressing cells. Finally, we provide evidence that abrogation of TGF-b in vitro enhances T-cell proliferation and reduces CD8 þ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS. Cell Death and Differentiation (2007) 14, 1747-1758; doi:10.1038/sj.cdd.4402192; published online 6 July 2007Virus production in Human Immunodeficiency Virus 1 (HIV-1)-infected individuals is largely the result of a dynamic process involving continuous rounds of de novo infection and replication in CD4 þ cells with rapid turnover of both free virus and virus producing cells. Moreover, an increasing body of evidence suggests that reservoirs, cell types or anatomical sites ('sanctuaries'), represent a major barrier to virus eradication. 1 HIV-specific CD8 þ T lymphocytes (CTL) are considered crucial in the control of viral replication. 2 Excessive induction of apoptosis has been proposed as one major mechanism of abnormal T-cell response during HIV and Simian Immunodeficiency Virus (SIV) infections. 3 However, most studies, which investigated the potential relationship between HIV and SIV infections and apoptosis have focused on cells from peripheral blood, rather than on cells from lymphoid organs.Peripheral lymphoid tissues such as the axillary and inguinal (Ing) lymph nodes (LNs), which drain the arms and legs, respectively, and the spleen, are considered major sites of HIV/SIV replication. 4 Accumulating data also indicate that gut-associated lymphoid tissue (GALT), which contains inductive sites, Peyer's patches and mesenteric (Mes) LNs, and effectors sites located within lamina propria and epithelium of the intestinal wall, is also an early and predominant tissue site of viral replication and may be a reservoir for HIV/SIV. 5,6 Because T cells from the GALT are required to maintain a state of immunological tolerance toward a myriad of dietary and resident bacterial antigens, the chronic exposure of HIV/ SIV-specific antigens coul...

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TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

et al. 2007

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“…De nombreux travaux faisaient état de la présence du virus dans les organes lymphoïdes primaires et secondaires, en particulier l'intestin, ainsi que dans les organes non lymphoïdes. Ainsi, cette question du réservoir peut se poser à la fois sur le plan cellulaire mais également sur le plan anatomique [3,4].…”

Section: Persistance Virale Chez Les Patients Vih : L'hypothèse D'un unclassified

Sanctuaire du virus de l’immunodéficience humaine et mécanismes d’échappement

Estaquier

Hurtrel

2008

Med Sci (Paris)

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Persistance virale chez les patients VIH : l'hypothèse d'un réservoir cellulaire viralLes avancées dans le traitement de l'infection par le VIH ont permis au cours de ces dernières années de ralentir la progression de la maladie et d'en prévenir les conséquences pathologiques chez une grande majorité de patients. L'introduction des multi-thérapies, associant en particulier des anti-protéases, a réduit de façon considérable la charge virale plasmatique, jusqu'à un niveau indétectable [1]. En dépit d'une diminution rapide, en quelques jours, de cette réplication virale, il existe une seconde phase caractérisée par une réduction de la réplication virale beaucoup plus lente, cette seconde phase pouvant refléter l'existence d'un réservoir cellulaire. Deux types cellulaires peuvent expliquer cette dynamique, le macrophage et le lymphocyte T CD4 au repos ayant intégré le génome viral. Cette persistance virale explique pourquoi les interruptions de traitement conduisent en quelques jours à une réplication virale intense. La charge virale plasmatique atteint alors un niveau équivalent à celui qui préexistait à l'institution de la thérapie, et ce quelle que soit la durée du traitement. Dans la mesure où la multiplication du VIH est la résultante d'un équilibre entre l'infection de nouvelles cibles -les cellules CD4 -, la production de virions et la réponse immunitaire Inefficacité du contrôle du virus par les lymphocytes T CD8À l'époque où ces observations étaient publiées, de nombreux travaux montraient que les lymphocytes T CD8 cytotoxiques -cellules capables de lyser une cellule infectée via l'expression de granzyme B et de perforinesont une arme indispensable au contrôle des agents > Depuis 25 années, l'identification du réservoir du virus de l'immunodéficience humaine (VIH) est source de questions. Dans un travail récent, nous montrons que les ganglions mésentériques drainant la région intestinale pourraient constituer un réservoir majeur du virus. Ce concept a été établi chez un modèle animal, le macaque Rhésus. De plus, parmi les mécanismes susceptibles de participer à la dissémination du virus dans l'ensemble de l'organisme, certains éléments suggèrent le rôle majeur de la mort par apoptose des lymphocytes T CD8. Cette mort cellulaire programmée est associée à une augmentation de l'expression, dans les ganglions, de facteurs immunosuppresseurs comme le TGF-β (transforming growth factor-b), ainsi que des molécules IDO (indoléamine 2, 3 dioxygénase) et PD-1 (programmed death molecule 1) impliquées dans la régulation du métabolisme des lymphocytes T. Ainsi, ces facteurs immunosuppresseurs offrent au virus les conditions favorables à sa persistance au sein de ce sanctuaire. < À la mémoire de Bruno Hurtrel

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“…HIV infected cells latently harbouring the virus are resistant to highly active antiretroviral therapy (HAART) and to the host immune response [96,97]. The first link between HIV latency and RNAi was provided by Maitra and co-workers [63].…”

Section: Rnai and Hiv-1 Pathogenesismentioning

confidence: 99%

RNA interference and HIV‐1 infection

Kanzaki

Ornelas

Argañaraz

2007

Reviews in Medical Virology

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Life-prolonging antiretroviral therapy remarkably reduces viral load, but it does not eradicate the virus. An important obstacle preventing virus clearance is the presence of latent virion reservoirs in the host. However, new promising antiviral approaches are emerging, and a number of host cell factors involved in the disease progression and control of HIV-1 replication have been recently discovered. For instance, the RNA interference (RNAi) mechanism, besides many functions conserved throughout evolution, works as a defence mechanism against noxious transcripts which may provide a new tool to block viral replication. The recent definition of basic RNAi mechanisms, as well as the discovery of micro RNAs (microRNAs) encoded by the host cell genome and by HIV-1, also suggest that RNAi may be involved in the control of HIV replication.

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The Challenge of Viral Reservoirs in HIV-1 Infection

Cited by 547 publications

References 189 publications

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

Sanctuaire du virus de l’immunodéficience humaine et mécanismes d’échappement

RNA interference and HIV‐1 infection

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