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.
Mattapallil
J J
JJ
Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of California, Davis, California, USA.
Smit-McBride
Z
Z
Dailey
P
P
Dandekar
S
S
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