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
Background
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.
Methodology
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.
Leave a Reply