CD8+ T Cells Specific for EBV, Cytomegalovirus, and Influenza Virus Are Activated during Primary HIV Infection1

Primary viral infections, including primary HIV infection, trigger intense activation of the immune system, with marked expansion of CD38+CD8+ T cells. Whether this expansion involves only viral-specific cells or includes a degree of bystander activation remains a matter of debate. We therefore examined the activation status of EBV-, CMV-, and influenza virus (FLU)-specific CD8+ T cells during primary HIV infection, in comparison to HIV-specific CD8+ T cells. The activation markers CD38 and HLA-DR were strongly expressed on HIV-specific CD8+ T cells. Surprisingly, CD38 expression was also up-regulated on CD8+ T cells specific for other viruses, albeit to a lesser extent. Activation marker expression returned to normal or near-normal values after 1 year of highly active antiretroviral therapy. HIV viral load correlated with CD38 expression on HIV-specific CD8+ T cells but also on EBV-, CMV-, and FLU-specific CD8+ T cells. In primary HIV infection, EBV-specific CD8+ T cells also showed increased Ki67 expression and decreased Bcl-2 expression, compared with values observed in HIV-seronegative control subjects. These results show that bystander activation occurs during primary HIV infection, even though HIV-specific CD8+ T cells express the highest level of activation. The role of this bystander activation in lymphocyte homeostasis and HIV pathogenesis remains to be determined.