Abstract & Commentary: Gut punch: Persistence of HIV despite suppression
Gut punch: Persistence of HIV despite suppression
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine. Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for Boehringer-Ingelheim and GSK.
Summary: CD4+ T-cell depletion occurs in gut-associated lymphoid tissue (GALT) despite long term suppression of viremia by HAART. Higher levels of proviral DNA exist in GALT than in peripheral blood lymphocytes (PBMCs) of aviremic patients. Cross-infection between these two compartments appears to occur.
Source: Chun T-W, et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008;197:714-720.
Eight hiv-infected patients (mean CD4+ t cell count 622 cells/uL) who had been receiving effective HAART for an average of 8.4 years were included in this study. PBMCs were obtained by leukapheresis and endoscopic terminal ileum biopsies were performed to obtain samples of Gut-Associated Lymphoid Tissue (GALT). Standard techniques, including fluorescence-activated cell sorting (FACS), were used to separate various subpopulations of lymphocytes. Quantitative real-time PCR was used to measure HIV DNA.
While the percent age of CD4+ T cells in GALT was slightly lower than that in peripheral blood in HIV-negative individuals (40% vs 65%), the mean %age of CD4+ T cells in these eight study participants was only 11.3%, suggesting incomplete recovery of CD4+ T cells in this compartment despite years of effective viral suppression in these patients.
FACS-enriched resting (CD25-/CD69-/HLA-DR-) and activated (CD25+/CD69+/HLA-DR+) CD4+ T cells in blood and CD8-depleted cells obtained from GALT were subjected to quantitative PCR for detection of HIV DNA. The frequency of cells carrying proviral DNA was highest in GALT (mean 4887 cells per million CD4+ T cells) vs resting T cells (mean 1083 cells per million CD4+ T cells) and activated T cells (mean 1796 cells per million CD4+ T cells).
Phylogenetic analysis of HIV env sequences from GALT and the two peripheral blood compartments showed a high degree of relatedness, suggesting trafficking/cross-infection between the three compartments.
Commentary
I remember vividly a comment made by Hans Wigzell (Karolinska Institute) in a lecture he gave at the DuPont Company around 1986, "Remember — the final battle of HIV infection is fought in the lymph nodes!" GALT is the largest component of the human lymphoid system.
This important study from Tony Fauci's own Laboratory of Immunoregulation at NIAID highlights the excellent work for which this group has been known over the years. This carefully-performed study provides insight into the pathogenesis of HIV infection and conclusively confirms findings from small earlier studies in which profound CD4+ T cell depletion in GALT in HIV-infected patients was observed despite effective antiretroviral therapy.1 Similar degrees of CD4+ T cell depletion have been seen with SIV infection in macaques.2 Due to the relatively free trafficking of lymphocytes between the peripheral blood and GALT compartments, this GALT CD4+ lymphopenia has implications for systemic immunodeficiency, as well as local immunodeficiency, nonspecific gastrointestinal symptoms, and opportunistic infections commonly seen in HIV infection. The surprisingly high levels of proviral DNA in GALT, despite relative gastrointestinal CD4+ lymphopenia in these aviremic patients, likely also provide an explanation for some of the viral dynamics of long-term persistence of low-level viremia in patients on antiretroviral therapy (as demonstrated in the previously reviewed paper by Sarah Palmer).3
[This article originally appeared in the May 2008 issue of Infectious Disease Alert.]
References
- Guadalupe M, et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol. 2003;77:11708-11717.
- Veazey RS, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998;280:427-431.
- Palmer S, et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. PNAS. 2008;105:3879-3884.
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