Background:  Although effective antiretroviral treatment has considerably reduced the risk of CMV disease in AIDS, CMV continues to be an important opportunistic pathogen in HIV-infected individuals.  CMV disease is also frequently seen in SIV-infected rhesus macaques, the leading animal model for AIDS.  There are many similarities between human and simian CMV infection, making this a suitable animal model for the study of CMV pathogenesis in AIDS.  We investigated the relationship between CMV-specific CD4+ T lymphocytes and CMV reactivation in SIV-infected rhesus macaques.

Methods:  In a cross-sectional analysis, the frequency and phenotype of CMV-specific CD4+ T lymphocytes was determined by flow cytometry in 23 CMV-seropositive rhesus macaques without SIV infection and in 15 CMV-seropositive macaques with SIV infection.  CMV reactivation was assessed by quantitation of plasma CMV DNA by real time PCR.

Results:  The median frequency of interferon-g secreting CMV-specific CD4+ T lymphocytes in the peripheral blood of SIV negative rhesus macaques was 0.63% (range 0.16%-5.8%).  CMV-specific CD4+ T lymphocytes were predominantly Fas^pos, CD27^lo and had variable levels of CD45RA expression.  The frequency of CMV-specific CD4+ T cells was significantly reduced (p <0.05; Mann-Whitney U test) in 9 macaques inoculated with pathogenic SIV (median frequency 0.05%; range 0.0%-1.2%), but not in 6 macaques inoculated with live attenuated SIV (median frequency 1.2%; range 0.22%-2.4%).  CMV-specific CD4+ T cells were not detected in 6/9 pathogenic SIV-infected rhesus macaques.  Plasma CMV DNA was detected in 4/6 of these macaques but in no animal with detectable CMV-specific CD4+ T lymphocytes.  3/4 macaques with detectable plasma CMV DNA progressed to CMV disease.  In SIV-infected macaques, loss of CMV-specific CD4+ T lymphocytes was not predicted by the extent of CD4+ T lymphocytopenia.  Neither was it predicted by the pre-SIV infection frequency of CCR5^pos CMV-specific CD4+ T lymphocytes.  Instead, it was associated with increased CMV and SIV viral loads.

Conclusions:  Loss of CMV-specific CD4+ T lymphocytes during the course of pathogenic lentivirus infection appears to play an important role in CMV reactivation.  Study of factors predisposing to loss of antigen-specific CD4+ T cells is likely to facilitate insight in to the pathogenesis of CMV infection in AIDS.