Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

Kristoff, Jan; Haret-Richter, George S.; Ma, Dongzhu; Ribeiro, Ruy M.; Xu, Cuiling; Cornell, Elaine; Stock, Jennifer; He, Tianyu; Mobley, Adam D.; Ross, Samantha; Trichel, Anita; Wilson, Cara C.; Tracy, Russell P.; Landay, Alan; Apetrei, Cristian; Pandrea, Ivona

doi:10.1172/jci75090

Cited by 83 publications

(102 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[43][44][45] Because the integrity of the mucosal barrier is compromised, bacterial products such as lipopolysaccharide (LPS) can translocate into the periphery and fuel the chronic immune activation that contributes to AIDS progression. 46,47 An effective vaccination strategy against HIV should provide protection to the intestinal Th17 population as these cells predominate in the intestinal mucosa, play a critical role FIG. 1.…”

Section: Selective Depletion Of Cd4 T Cell Subsetsmentioning

confidence: 99%

Induction of Intestinal Immunity by Mucosal Vaccines As a Means of Controlling HIV Infection

Poles

Alvarez²,

Hioe³

2014

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

CD4+ T cells in the mucosa of the gastrointestinal (GI) tract are preferentially targeted and depleted by HIV. As such, the induction of an effective anti-HIV immune response in the mucosa of the GI tract-through vaccination-could protect this vulnerable population of cells. Mucosal vaccination provides a promising means of inducing robust humoral and cellular responses in the GI tract. Here we review data from the literature about the effectiveness of various mucosal vaccination routes-oral (intraintestinal/tonsilar/sublingual), intranasal, and intrarectal-with regard to the induction of immune responses mediated by cytotoxic T cells and antibodies in the GI mucosa, as well as protective efficacy in challenge models. We present data from the literature indicating that mucosal routes have the potential to effectively elicit GI mucosal immunity and protect against challenge. Given their capacity for the induction of anti-HIV immune responses in the GI mucosa, we propose that mucosal routes, including the nonconventional sublingual, tonsilar, and intrarectal routes, be considered for the delivery of the next generation HIV vaccines. However, further studies are necessary to determine the ideal vectors and vaccination regimens for these routes of immunization and to validate their efficacy in controlling HIV infection. HIV Epidemics and Treatment HIV infection has resulted in the death of millions since the early 1980s, and has been responsible for significant morbidity and decline in quality of life for millions more. Each year, an estimated 50,000 people are newly infected with the virus in the United States alone, adding to the 34 million currently living with the virus worldwide.

show abstract

Section: Selective Depletion Of Cd4 T Cell Subsetsmentioning

confidence: 99%

Induction of Intestinal Immunity by Mucosal Vaccines As a Means of Controlling HIV Infection

Poles

Alvarez²,

Hioe³

2014

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

show abstract

“…Among these, the most important contributors appear to be virus replication (19), microbial translocation from the intestinal lumen to the broader circulation as a consequence of mucosal damages inflicted by localized virus replication (3,(20)(21)(22)(23)(24), and dysregulation of T cell homeostasis (25).…”

mentioning

confidence: 99%

“…We assessed CD39 and CD73 expression on CD4 ϩ and CD8 ϩ Tregs isolated from blood, lymph node (LN), and intestine from progressor pigtailed macaques (PTMs) (10,24,49) and nonprogressor AGMs (17,52,53) infected with the same SIVsab strain. We report that CD39 and CD73 are coexpressed predominantly at mucosal sites and that the coexpression levels of these two molecules on CD4 ϩ and CD8 ϩ Tregs are higher in AGMs than in PTMs.…”

mentioning

confidence: 99%

Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

Brocca-Cofano

Gillespie

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

The role of the adenosine (ADO) pathway in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/ SIV) infection remains unclear. We compared SIVsab-induced changes of markers related to ADO production (CD39 and CD73) and breakdown (CD26 and adenosine deaminase) on T cells from blood, lymph nodes, and intestine collected from pigtailed macaques (PTMs) and African green monkeys (AGMs) that experience different SIVsab infection outcomes. We also measured ADO and inosine (INO) levels in tissues by mass spectrometry. Finally, we assessed the suppressive effect of ADO on proinflammatory cytokine production after T cell receptor stimulation. The baseline level of both CD39 and CD73 coexpression on regulatory T cells and ADO levels were higher in AGMs than in PTMs. Conversely, high INO levels associated with dramatic increases in CD26 expression and adenosine deaminase activity were observed in PTMs during chronic SIV infection. Immune activation and inflammation markers in the gut and periphery inversely correlated with ADO and directly correlated with INO. Ex vivo administration of ADO significantly suppressed proinflammatory cytokine production by T cells in both species. In conclusion, the opposite dynamics of ADO pathway-related markers and contrasting ADO/INO levels in species with divergent proinflammatory responses to SIV infection support a key role of ADO in controlling immune activation/inflammation in nonprogressive SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing natural hosts of SIVs from developing SIV-related gut dysfunction. Focusing studies of the ADO pathway on mucosal sites of viral replication is warranted. IMPORTANCEThe mechanisms responsible for the severe gut dysfunction characteristic of progressive HIV and SIV infection in humans and macaques are not completely elucidated. We report that ADO may play a key role in controlling immune activation/inflammation in nonprogressive SIV infections by limiting SIV-related gut inflammation. Conversely, in progressive SIV infection, significant degradation of ADO occurs, possibly due to an early increase of ADO deaminase complexing protein 2 (CD26) and adenosine deaminase. Our study supports therapeutic interventions to offset alterations of this pathway during progressive HIV/SIV infections. These potential approaches to control chronic immune activation and inflammation during pathogenic SIV infection may prevent HIV disease progression.

show abstract

“…Eleven RMs were inoculated intravenously with plasma samples equivalent to 300 tissue culture infectious doses at 50% (TCID 50 ) of SIVsab92018. The same virus strain induces a persistent nonprogressive infection in the natural African green monkey (AGM) host (13,15) and a pathogenic progressive infection in pigtailed macaques (16)(17)(18). The remaining two RMs were inoculated with plasma samples collected from SIVsab92018 controllers collected at 4 years postinfection (p.i.…”

mentioning

confidence: 99%

Simian Immunodeficiency Virus SIVsab Infection of Rhesus Macaques as a Model of Complete Immunological Suppression with Persistent Reservoirs of Replication-Competent Virus: Implications for Cure Research

Cillo

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

Simian immunodeficiency virus SIVsab infection is completely controlled in rhesus macaques (RMs) through functional immune responses. We report that in SIVsab-infected RMs, (i) viral replication is controlled to <0 to 3 copies/ml, (ii) about onethird of the virus strains in reservoirs are replication incompetent, and (iii) rebounding virus after CD8؉ cell depletion is replication competent and genetically similar to the original virus stock, suggesting early reservoir seeding. This model permits assessment of strategies aimed at depleting the reservoir without multidrug antiretroviral therapy. The report of one patient that was cured of human immunodeficiency virus (HIV) infection (1) renewed enthusiasm for cure research aimed at understanding the mechanisms of HIV persistence and developing therapeutic strategies to reduce/eliminate viral reservoirs (2). However, virus rebound in the Mississippi baby (3) and the Boston patients (4) pointed to the difficulty of achieving a cure/functional cure of HIV infection and the need to develop new strategies to reach this goal. Multiple limitations to the cure have been identified, including (i) rapid establishment of latently infected cells, (ii) residual viral replication in patients receiving combination antiretroviral therapy (cART), which prevents proper reservoir characterization, and (iii) the existence of anatomic reservoirs (privileged sites of latency insufficiently penetrated by drugs) (5, 6). Due to these limitations, it is generally agreed that a more feasible alternative to an HIV infection cure (i.e., complete eradication of HIV and HIV-infected cells from the body) may be a functional cure (i.e., control of HIV infection without complete HIV eradication: undetectable viremia without ART, no disease progression, no CD4 ϩ T-cell loss, and lack of HIV transmission) (6). This concept is supported by the observation that functional cure has been achieved in a fraction of patients that received long-term ART initiated during acute HIV infection (7).Aside from the general barriers to a cure, there are specific limitations to cure research: (i) ethical problems (therapy cannot be stopped in patients without the risks of virus rebound and the development of viral resistance and increased virus transmission), (ii) technical problems (there is no acceptable biomarker for latently infected cells), and (iii) limited availability of invasive samples from the multiple potential reservoir sites (8). These limitations make it imperative that cure research be performed in analogous and tractable animal models. Currently available models need to be improved for such studies. For example, SIVmac infection of rhesus macaques (RMs) (the most widely used animal model for AIDS research) is more difficult to control with ART than HIV-1 infection in humans, requiring complex combination therapies (9, 10). Furthermore, infection with molecular clones (e.g., simian-human immunodeficiency viruses carrying the reverse transcriptase gene [RT-SHIVs]) does not permit tracking of viral spr...

show abstract

Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication

Cited by 83 publications

References 32 publications

Induction of Intestinal Immunity by Mucosal Vaccines As a Means of Controlling HIV Infection

Induction of Intestinal Immunity by Mucosal Vaccines As a Means of Controlling HIV Infection

Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

Simian Immunodeficiency Virus SIVsab Infection of Rhesus Macaques as a Model of Complete Immunological Suppression with Persistent Reservoirs of Replication-Competent Virus: Implications for Cure Research

Contact Info

Product

Resources

About