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Comprehensive Assessment of HIV Target Cells in the Distal Human Gut Suggests Increasing HIV Susceptibility Toward the Anus

McElrath, M. J. MD, PhD*,†,‡; Smythe, K. BS*; Randolph-Habecker, J. PhD§; Melton, K. R. BA§; Goodpaster, T. A. BA§; Hughes, S. M. MA, BS, BA; Mack, M. MD; Sato, A. MS*; Diaz, G. BS*; Steinbach, G. MD, PhD#,**; Novak, R. M. MD††; Curlin, M. MD*; Lord, J. D. MD, PhD‡‡; Maenza, J. MD*,†; Duerr, A. MD, PhD, MPH*,§§; Frahm, N. PhD*,‡; Hladik, Florian MD, PhD*,†,‖the NIAID HIV Vaccine Trials Network

JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1st, 2013 - Volume 63 - Issue 3 - p 263–271
doi: 10.1097/QAI.0b013e3182898392
Basic and Translational Science

Background: Prevention of rectal HIV transmission is a high-priority goal for vaccines and topical microbicides because a large fraction of HIV transmissions occurs rectally. Yet, little is known about the specific target-cell milieu in the human rectum other than inferences made from the colon.

Methods: We conducted a comprehensive comparative in situ fluorescence study of HIV target cells (CCR5-expressing T cells, macrophages, and putative dendritic cells) at 4 and 30 cm proximal of the anal canal in 29 healthy individuals, using computerized analysis of digitized combination stains.

Results: Most strikingly, we find that more than 3 times as many CD68+ macrophages express the HIV coreceptor CCR5 in the rectum than in the colon (P = 0.0001), and as such rectal macrophages seem biologically closer to the HIV-susceptible CCR5high phenotype in the vagina than the mostly HIV-resistant CCR5low phenotype in the colon. Putative CD209+ dendritic cells are generally enriched in the colon compared with the rectum (P = 0.0004), though their CCR5 expression levels are similar in both compartments. CD3+ T-cell densities and CCR5 expression levels are comparable in the colon and rectum.

Conclusions: Our study establishes the target-cell environment for HIV infection in the human distal gut and demonstrates in general terms that the colon and rectum are immunologically distinct anatomical compartments. Greater expression of CCR5 on rectal macrophages suggests that the most distal sections of the gut may be especially vulnerable to HIV infection. Our findings also emphasize that caution should be exercised when extrapolating data obtained from colon tissues to the rectum.

*Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA;

Departments of Medicine;

Global Health, University of Washington, Seattle, WA;

§Experimental Histopathology Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA;

Department of Obstetrics and Gynecology, University of Washington, Seattle, WA;

Department of Internal Medicine II, University Hospital, Regensburg, Germany;

#Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;

**Department of Gastroenterology, University of Washington, Seattle, WA;

††Department of Medicine, University of Illinois, Chicago, IL;

‡‡Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA; and

§§Department of Epidemiology, University of Washington, Seattle, WA.

Correspondence to: Florian Hladik, MD, PhD, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Eastlake Avenue East, E5-147, Seattle, WA 98109-1024 (e-mail:

The authors declare no conflicts of interest.

Supported by NIH grants U01AI068618 (to M. J. McElrath) and R01HD51455 (to F. Hladik).

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Received October 11, 2012

Accepted January 23, 2013

© 2013 Lippincott Williams & Wilkins, Inc.