The role of immunity in protection from mucosal SIV infection in macaques

La, Bergmeier; Wang, Y; Lehner, Thomas

doi:10.1034/j.1601-0825.2002.00014.x

Cited by 10 publications

(9 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The production of beta-chemokines by CD8+ T cells was reported in naive and vaccinated macaques, the largest number of beta chemokine-secreting cells being in the rectal mucosa 58 . CCL4 is one of the major HIV-suppressive factors produced by non-cytotoxic CD8+ T cells 59 and the increase in the rectal site (following tonsillar challenge) may contribute to the overall innate antiviral response.…”

Section: Discussionmentioning

confidence: 93%

Characterization of Peripheral and Mucosal Immune Responses In Rhesus Macaques on Long-Term Tenofovir and Emtricitabine Combination Antiretroviral Therapy

Jasny

Geer²,

Frank³

et al. 2012

JAIDS Journal of Acquired Immune Deficiency Syndromes

View full text Add to dashboard Cite

Background The goal of antiretroviral therapy (ART) is to suppress virus replication to limit immune system damage. Some have proposed combining ART with immune therapies to boost antiviral immunity. For this to be successful, ART must not impair physiological immune function. Methods We studied the impact of ART (tenofovir and emtricitabine) on systemic and mucosal immunity in uninfected and SIV-infected Chinese rhesus macaques. Subcutaneous ART was initiated 2 weeks after tonsillar inoculation with SIVmac239. Results There was no evidence of immune dysregulation as a result of ART in either infected or uninfected animals. Early virus-induced alterations in circulating immune cell populations (decreased central memory T cells and myeloid dendritic cells) were detected, but normalized shortly after ART initiation. ART-treated animals showed marginal SIV-specific T cell responses during treatment, which increased after ART discontinuation. Elevated expression of CXCL10 in oral, rectal and blood samples and APOBEC3G mRNA in oral and rectal tissues was observed during acute infection and was down-regulated after starting ART. ART did not impact the ability of the animals to respond to tonsillar application of polyICLC with increased CXCL10 expression in oral fluids and CD80 expression on blood myeloid dendritic cells. Conclusion Early initiation of ART prevented virus induced damage and did not impede mucosal or systemic immune functions.

show abstract

Section: Discussionmentioning

confidence: 93%

Characterization of Peripheral and Mucosal Immune Responses In Rhesus Macaques on Long-Term Tenofovir and Emtricitabine Combination Antiretroviral Therapy

Jasny

Geer²,

Frank³

et al. 2012

JAIDS Journal of Acquired Immune Deficiency Syndromes

View full text Add to dashboard Cite

show abstract

“…A growing body of evidence in fact suggests that dual antiviral mechanisms should be required for effective mucosal protection [26], including stimulation of innate antiviral factors such as β-chemokines that down-regulate the HIV CCR5 co-receptor [27], [28]. It was shown that RANTES, MIP-1α and MIP-1β are significantly associated with protection against rectal mucosal SIV infection [29]. RANTES derivatives are currently considered for microbicide formulation.…”

Section: Discussionmentioning

confidence: 99%

“…The fact that ( i ) the CC chemokines RANTES, MIP-1α and MIP-1β act as potent natural inhibitors of HIV-1 [37], [38], ( ii ) such chemokines are indeed protective to SIV challenge in monkeys by acting as virus entry inhibitors [29], [39], ( iii ) ANPs, in particular PMEO-DAPym, may behave as natural chemokine production enhancers in PBMC and M/M in addition to their viral reverse transcriptase/DNA polymerase inhibition, ( iv ) the increased β-chemokine production found in PMEO-DAPym-exposed PBMC cultures coincided with CCR5 co-receptor down-regulation and ( v ) the supernatants of these drug-exposed cell cultures were able to induce an antiviral refractory state when administered to new non-treated cell cultures, point to an additional and important antiviral (i.e. HIV) potential of PMEO-DAPym through its immunomodulatory properties.…”

Section: Discussionmentioning

confidence: 99%

A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity

et al. 2013

View full text Add to dashboard Cite

Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4+ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).

show abstract

“…Although oral delivery has not been attempted, it produced a persistent antibody response in the mucosa that lasted more than two months after the last injection (38). In another experiment, the injection of SIV antigens in alum was reported to prevent infection or significantly decrease viral load when immunized macaques were challenged with SIV by the rectal route (12). These experiments suggest that alum or Freund adjuvant may not be useful as orally delivered adjuvants.…”

Section: Mucosal Adjuvantsmentioning

confidence: 95%

“…We also don't know if a vaccine targeting both arms of immunity will work. As AIDS is a disease of mucosal origin, it is likely that an effective vaccine against HIV needs to be delivered at the mucosal surface in order to produce an appropriate cell-mediated immune response and possibly secretory IgA (12,65). Principles governing the mucosal response and/or tolerance, especially in humans, are still unknown (35,75,102,142).…”

Section: Introductionmentioning

confidence: 98%

Mucosal AIDS Vaccines

Bourinbaiar¹,

Metadilogkul

Jirathitikal³

2003

Viral Immunology

View full text Add to dashboard Cite

Debates are still being waged over what is the best strategy for developing a potent AIDS vaccine. All the obvious approaches to making AIDS vaccines have been tried in the past two decades without much success. It is clear that new thinking and a revision of prevailing dogmas needs to be in place if we really want a vaccine. Conventional envelope-based antibody-inducing vaccines do not appear to hold promise, and broadly-neutralizing antibodies are now being searched as an alternative to the failed approach with subunit vaccines. The current consensus is that cellular immune responses, especially those mediated by CD8 cytotoxic/suppressor (CTL) and CD4 helper T lymphocytes, are needed to control HIV. Vaccines capable of inducing cell-mediated responses are, therefore, considered critical for controlling the spread of HIV. DNA-based vaccines triggering CTL reaction are currently thought to be an answer, but will they fulfill the promise? In the following paragraphs, a critical assessment of the state of the art will be provided in an attempt to analyze what we know and still don't know. The focus of this review is primarily on mucosal vaccines-a relatively new area in AIDS research. The update on V-1 Immunitor, the first mucosal AIDS vaccine available commercially, is provided within this context. Some of the reviewed concepts may be disputable, but without departure from the uninspiring consensus no substantial progress in the AIDS vaccine field can be envisioned.

show abstract

The role of immunity in protection from mucosal SIV infection in macaques

Cited by 10 publications

References 37 publications

Characterization of Peripheral and Mucosal Immune Responses In Rhesus Macaques on Long-Term Tenofovir and Emtricitabine Combination Antiretroviral Therapy

Characterization of Peripheral and Mucosal Immune Responses In Rhesus Macaques on Long-Term Tenofovir and Emtricitabine Combination Antiretroviral Therapy

A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity

Mucosal AIDS Vaccines

Contact Info

Product

Resources

About