Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection.
BACKGROUND
During acute and early HIV-1 infection (AEI), up to 60% of CD4(+) T cells in the lamina propria of the lower gastrointestinal (GI) tract are lost as early as 2-4 wk after infection. Reconstitution in the peripheral blood during therapy with highly active antiretroviral therapy (HAART) is well established. However, the extent of immune reconstitution in the GI tract is unknown.


RESULTS
Fifty-four AEI patients and 18 uninfected control participants underwent colonic biopsy. Forty of the 54 AEI patients were followed after initiation of antiretroviral therapy (18 were studied longitudinally with sequential biopsies over a 3-y period after beginning HAART, and 22 were studied cross sectionally after 1-7 y of uninterrupted therapy). Lymphocyte subsets, markers of immune activation and memory in the peripheral blood and GI tract were determined by flow cytometry and immunohistochemistry. In situ hybridization was performed in order to identify persistent HIV-1 RNA expression. Of the patients studied, 70% maintained, on average, a 50%-60% depletion of lamina propria lymphocytes despite 1-7 y of HAART. Lymphocytes expressing CCR5 and both CCR5 and CXCR4 were persistently and preferentially depleted. Levels of immune activation in the memory cell population, CD45RO+ HLA-DR+, returned to levels seen in the uninfected control participants in the peripheral blood, but were elevated in the GI tract of patients with persistent CD4+ T cell depletion despite therapy. Rare HIV-1 RNA-expressing cells were detected by in situ hybridization.


CONCLUSIONS
Apparently suppressive treatment with HAART during acute and early infection does not lead to complete immune reconstitution in the GI mucosa in the majority of patients studied, despite immune reconstitution in the peripheral blood. Though the mechanism remains obscure, the data suggest that there is either viral or immune-mediated accelerated T cell destruction or, possibly, alterations in T cell homing to the GI tract. Although clinically silent over the short term, the long-term consequences of the persistence of this lesion may emerge as the HIV-1-infected population survives longer owing to the benefits of HAART.
Mehandru
Saurabh
S
Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
Poles
Michael A
MA
Tenner-Racz
Klara
K
Jean-Pierre
Patrick
P
Manuelli
Victoria
V
Lopez
Peter
P
Shet
Anita
A
Low
Andrea
A
Mohri
Hiroshi
H
Boden
Daniel
D
Racz
Paul
P
Markowitz
Martin
M
D000208:Acute Disease; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D019713:Receptors, CCR5 / Q000032:analysis; D019718:Receptors, CXCR4 / Q000032:analysis
D044966:Anti-Retroviral Agents; D019713:Receptors, CCR5; D019718:Receptors, CXCR4