Evidence from many studies indicates that persistent immune activation is associated with poor CD4 T cell recovery in individuals on antiretroviral therapy (ART), even when HIV viral load is suppressed to undetectable levels. One potential source of ongoing immune activation could be the replication of other co-infecting viruses, such as cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV).
To evaluate this possibility, a group of researchers at UCSF studied the levels of these viruses in both saliva and peripheral blood mononuclear cells (PBMC) of individuals with high CD8 T cell activation and poor CD4 T cell recovery on ART. These individuals were defined as “cases” and compared to controls with low CD8 T cell activation and good CD4 recovery. High CD8 T cell activation was defined as greater than 10% of CD8 T cells co-expressing the activation markers CD38 and HLA-DR, and poor CD4 recovery was defined as levels persistently below 500 cells/mL. Controls were selected based on the opposite criteria (<10% activated CD8 T cells and CD4 cells always >500 cells/mL). A total of 11 cases and five controls were evaluated.
The results showed no differences between the groups, or any correlations between levels of any or all of the viruses and immune activation: “The proportions of all CMV, EBV or KSHV DNA positive specimens between the cases and controls were essentially the same, as were the proportions of subjects in each group that intermittently or continuously shed CMV, EBV or KSHV DNA in saliva. In addition, the median number of copies of CMV, EBV and KSHV DNA longitudinally in cases was virtually identical to that in controls.” The researchers offer the caveats that their study is very small, and sampling relatively infrequent. They are also exploring the same question in a different way, by investigating whether treatment with the anti-CMV drug valganciclovir can reduce immune activation and/or increase CD4 counts in individuals on ART. Results from this trial are expected later this year.
In discussing their findings, the authors write: “Given the strong association between inflammation/immune activation and disease outcomes in treated HIV disease, defining the mechanisms associated with HIV-associated inflammation is of high importance. Our preliminary data do not provide strong evidence for a role of persistent high level herpesvirus replication.”
PLoS ONE 4(4): e5277. doi:10.1371/journal.pone.0005277
Mark A. Jacobson, Dirk P. Ditmer, Elizabeth Sinclair, Jeffrey N. Martin, Steven G. Deeks, Peter Hunt, Edward S. Mocarski, Caroline Shiboski
Most HIV-infected patients receiving virologically suppressive antiretroviral therapy continue to have abnormal, generalized T cell activation. We explored whether the degree of ongoing cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) replication was associated with higher virus-specific T cell activation and the failure to achieve normal absolute CD4+ T cell counts in the face of long-term suppressive antiretroviral therapy.
Longitudinally collected PBMC and saliva specimens obtained from HIV-infected patients on effective antiretroviral therapy for at least one year (plasma HIV RNA <75 copies/mL) were examined using a multiplex CMV, EBV and KSHV DNA PCR assay. Eleven cases were chosen who had CD8+ T cell CD38+HLA-DR+ expression >10% and plateau absolute CD4+ T cell counts <500 cells/µL. Five controls from the same study had CD8+ T cell CD38 expression <10% and plateau absolute CD4+ T cell counts >500 cells/µL.
Results and Conclusions
Among all subjects combined, 18% of PMBC samples were positive for CMV DNA, and 27%, 73% and 24% of saliva samples were positive for CMV, EBV and KSHV DNA, respectively. No significant differences or trends were observed between cases and controls in proportions of all CMV, EBV or KSHV DNA positive specimens, proportions of subjects in each group that intermittently or continuously shed CMV, EBV or KSHV DNA in saliva, or the median number of genome copies of CMV, EBV and KSHV DNA in saliva. Overall, number of genome copies in saliva were lower for KSHV than for CMV and lower for CMV than for EBV. Although replication of CMV, EBV and KSHV persists in many antiretroviral-suppressed, HIV-infected patients, we observed no evidence in this pilot case-control study that the magnitude of such human herpesvirus replication is associated with abnormally increased CD8+ T cell activation and sub-normal plateau absolute CD4+ T cell counts following virologically suppressive antiretroviral therapy.