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Research Article

Lack of Mucosal Immune Reconstitution during Prolonged Treatment of Acute and Early HIV-1 Infection

  • Saurabh Mehandru,

    Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America

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  • Michael A Poles,

    Affiliations: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America, Department of Medicine, Division of Gastroenterology, New York University School of Medicine, New York, New York, United States of America

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  • Klara Tenner-Racz,

    Affiliation: Bernhard-Nocht Institut Fur Tropenmedizin, Hamburg, Germany

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  • Patrick Jean-Pierre,

    Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America

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  • Victoria Manuelli,

    Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America

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  • Peter Lopez,

    Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America

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  • Anita Shet,

    Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America

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  • Andrea Low,

    Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America

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  • Hiroshi Mohri,

    Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America

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  • Daniel Boden,

    Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America

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  • Paul Racz,

    Affiliation: Bernhard-Nocht Institut Fur Tropenmedizin, Hamburg, Germany

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  • Martin Markowitz mail

    To whom correspondence should be addressed. E-mail: mmarkowitz@adarc.org

    Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America

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  • Published: December 05, 2006
  • DOI: 10.1371/journal.pmed.0030484

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Gut mucosa in HIV infection and ‘immune milk’

Posted by plosmedicine on 31 Mar 2009 at 00:03 GMT

Author: Shawn J. Green
Position: No occupation was given
Institution: Origo Biosciences
E-mail: shawng@origobiosciences.com
Submitted Date: December 13, 2006
Published Date: December 15, 2006
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

This past week three noteworthy papers, published in PLoS, Journal of Virology and Nature Medicine directs our attention to the gut as a critical target in HIV-1 infection and portal for therapeutic intervention.

In PLoS, Mehandru, Markowitz and colleagues report that over half of the CD4+ T cells in the gut mucosa are lost within the first few weeks after HIV-1 infection and remain consistently low, compared to peripheral blood sources, despite long term anti-retroviral therapy; furthermore, of the few CD4+ T cells that persist in the gut, a significant increase in immune activation is observed [1]. Consistent with earlier observations in SIV models, Veazey reminds us that the battle against HIV-1 should focus on the intestinal mucosa with therapeutic strategies to reduce gut immune activation [2].

The longitudinal study in J. Virology by Guadaplupe, Dandekar and co-workers showed a similar discordance in CD4+ T cells between restoration in peripheral blood and significant delay in the gut mucosa of chronic infected individuals during anti-retroviral therapy. Here, the depletion in CD4+ T cells was associated with an increase in gut immune activation, CD8+ T cells, and associated-inflammation with a corresponding decease in epithelial growth and repair-associated genes in gut mucosal tissue [3]. Consistent with this observation, Brenchley, Douek, and colleagues report in Nature Medicine that HIV infection causes a 'leaky gut' that result in the translocation of gut-derived endotoxin and the subsequent triggering of immune activation.

Collectively, these observations suggest that an orally-active therapeutic, used in conjunction with anti-retroviral therapy, be designed to both block gut-derived microbial translocation and stimulate restitution of the gut epithelium. The hope would be to restore immunological integrity of the intestinal mucosal barrier, thereby, controlling immune activation, both locally, in the gut mucosa, and systemically by suppressing cellular targets distal to the gut that directly contributes to the progression of AIDS [5-8].

The design for such an orally-active therapeutic may be found in the complex formula of bovine colostrum and ‘immune milk,’ which has long been recognized to offer passive protection to a broad number of enteric bacterial and viral pathogens, primarily via the transfer of immunoglobulins and suppression of gut associated-inflammation with promotion of mucosal repair and regeneration.

The gut in chronic HIV-1 infected individuals appears to be reminiscent of new born calves. Calves are born with a highly immature mucosal immune system and ‘leaky gut’ and, if not immediately corrected, results in death due to infection and associated-systemic immune activation. However, the cow’s first-milking rescues her calves from harmful gut microbes with a uniquely complex cocktail enriched with neutralizing polyclonal antibodies and cytokine-tissue repair factors.

Regular consumption of biologically-active bovine colostrum has been known for years to promote the development of infantile gut-associated lymphoid tissue, enhance CD4+ levels, while suppressing CD8+ and inflammatory bowl disease (IBD), including ulcerative colitis and Crohn’s disease [5]. The severity of IBD is often correlated with gut microbial-endotoxin translocation, which now appears in chronic HIV-1 infected individuals [4]. Similar to bovine colostrum, ‘immune milk’ from properly vaccinated cows affords passive immunity against bacterial, viral, and fungal infections in the human GI tract, as well as, tames gut inflammation [8].

Hence, there may be lessons learned from Bessie’s ‘immune milk.’ If viewed as a unique formula that has evolved to complement gut immunity, ‘immune milk’ may also provide relief in chronic HIV infected individuals. Initial studies have already shown that ingestion of colostrum alleviates refractory diarrhea in HIV patients with a corresponding increase in both body weight and peripheral blood CD4+ T cells [9,10]. As we learn more about the gut microenvironment in HIV infected individuals, Bessie may prove to be a worthwhile platform for the consideration of ‘immune milk’ exhibiting HIV neutralizing activity along with its innate anti-inflammatory and tissue regenerative properties.

References

1. Mehandru S. et al. PLoS 3, e484 (2006).
2. Veazey R.S., Lackner A.A. PLoS. 3, e515 (2006).
3. Guadalupe M. et al. J. Virol. 80, 8236 (2006).
4. Brenchley J.M. et al. Nat. Med. advance online publication, 19 Nov 2006.
5. Playford R.J., MacDonald C.E., Johnson W.S. Am. J. Clin. Nutr. 72, 5 (2000).
6. Korhonen, H. et al. Brit. J. Nutr. 84, S135 (2000).
7. Zeitlin L., Cone R.A., Whaley K.J. Emerg. Infect. Dis. 5, 54 (1994). 8. Green SJ, Brendsel J. Gut 55,1681 (2006).
9. Plettenberg A et al. J. Mol. Med. 71, 42 (1993).
10. Claes-Hnrik F. et al. Scandinavian J. Gastroenterology. 41, 682 (2006).

Competing interests declared: This letter is not intended to promote, endorse, or support the use of any currently available commercial sources of colostrum or ‘immune milk;’ Origo Bioscience Institute, a newly formed non-profit, is interested in the development of low-tech, low-cost technology platforms for the production and processing of ‘immune milk’ from cows and goat to prevent and treat diarrheal illness and associated malnutrition in developing nations.