Activated memory CD4(+) T helper cells repopulate the intestine early following antiretroviral therapy of simian immunodeficiency virus-infected rhesus macaques but exhibit a decreased potential to produce interleukin-2.
Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model, we performed a longitudinal study to determine the effect of antiretroviral therapy on the phenotype and functional potential of CD4(+) T cells repopulating intestinal mucosa in human immunodeficiency virus infection. Severe depletion of CD4(+) and CD4(+) CD8(+) T cells occurred in the intestinal mucosa during primary SIV infection. The majority of these cells were of activated memory phenotype. Phosphonate 9-[2-(phosphomethoxypropyl]adenine (PMPA) treatment led to a moderate suppression of intestinal viral loads and repopulation of intestinal mucosa by predominantly activated memory CD4(+) T-helper cells. This repopulation was independent of the level of viral suppression. Compared to preinfection values, the frequency of naive CD4(+) T cells increased following PMPA therapy, suggesting that new CD4(+) T cells were repopulating the intestinal mucosa. Repopulation by CD4(+) CD8(+) T cells was not observed in either jejunum or colon lamina propria. The majority of CD4(+) T cells repopulating the intestinal mucosa following PMPA therapy were CD29(hi) and CD11ahi. A subset of repopulating intestinal CD4(+) T cells expressed Ki-67 antigen, indicating that local proliferation may play a role in the repopulation process. Although the majority of repopulating CD4(+) T cells in the intestinal mucosa were functionally capable of providing B- and T-cell help, as evidenced by their expression of CD28, these CD4(+) T cells were found to have a reduced capacity to produce interleukin-2 (IL-2) compared to the potential of CD4(+) T cells prior to SIV infection. Persistent viral infection may play a role in suppressing the potential of repopulating CD4(+) T cells to produce IL-2. Hence, successful antiretroviral therapy should aim at complete suppression of viral loads in mucosal lymphoid tissues, such as intestinal mucosa.
Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of California, Davis, California, USA.
J J
JJ
Mattapallil
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Z
Smit-McBride
P
P
Dailey
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S
Dandekar
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D018845:CD11 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002455:Cell Division; D007156:Immunologic Memory / Q000276:immunology*; D016130:Immunophenotyping; D019012:Integrin beta1 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology*; D007421:Intestine, Small / Q000821:virology; D008137:Longitudinal Studies; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D000068698:Tenofovir; D019562:Viral Load
D000998:Antiviral Agents; D018845:CD11 Antigens; D019012:Integrin beta1; D007376:Interleukin-2; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D000068698:Tenofovir; D000225:Adenine