The relationship between viral and immunologic factors in patients with viral relapse on antiretroviral therapy is complex and incompletely understood. In this study, we compared patients who maintained virus suppression with patients experiencing viral relapse yet maintaining stable CD4+ lymphocytes while receiving antiretroviral therapy. We found that patients with viral relapse had significantly increased CD8+ lymphocyte activation, compared with that in suppressed patients (measured by CD38 ABC on CD8+ lymphocytes and the absolute numbers and percentages of cells coexpressing CD38 and HLA‐DR antigens). Plasma HIV RNA level correlated with CD8+ lymphocyte activation, even when controlling for CD4+ lymphocyte count. In addition, we found that plasma HIV RNA level correlated with 1 marker of CD4+ lymphocyte activation, CD38 ABC on CD4+ lymphocytes. These findings suggest that a major sequel to viral relapse on antiretroviral therapy is lymphocyte activation.
We presume that CD8+ lymphocyte activation in persons with viral relapse directly reflects increasing HIV replication in a manner similar to the relationship observed during an acute HIV infection. Prior research has shown that increases in CD8+ lymphocyte activation do not coincide with immediate reductions in circulating CD4+ lymphocytes or progression to clinical AIDS‐related events. However, over the longer term, increased CD8+ lymphocyte activation is associated with functional immune impairment and clinical disease progression.
We found similar absolute numbers and percentages of naive CD4+ lymphocytes and similar TREC levels in our viral relapse and virus suppression groups. In addition, plasma HIV RNA levels did not correlate with amounts of naive CD4+ lymphocytes or with TREC levels in multiple regression analyses. These results may indicate continued thymopoiesis during viral relapse and suggest that the thymic microenvironment may be partially preserved in patients with viral relapse, perhaps reflecting a delay in its disruption that is relative to recurrent plasma viral replication or that is perhaps due to a protective effect of antiretroviral medications.
This study has several limitations. As a pilot study, the sample size is small. No assessments were made of host factors, such as HIV‐specific cellular immunity, HIV coreceptor mutations, or virus‐specific factors, such as antiretroviral drug resistance mutations or viral fitness. Finally, although these results could have implications for the clinical management of individual patients, the optimal strategy must be determined in prospective controlled studies. In summary, CD8+ and CD4+ lymphocyte activation occurs with increasing plasma HIV RNA levels on antiretroviral therapy. Further studies are needed to confirm these observations and to clarify their implications for clinical management.