Virus Load and Cytolitic Responses in Human Immunodeﬁciency Virus Infection: What

In a recent study [1], Sufka et al. describe the immunologic and virologic outcomes of a group of human immunodeficiency virus (HIV)–infected patients experiencing prolonged discordance between the level of CD4 T cells and virus load. There is growing interest in this subset of patients, since understanding the mechanisms that enable the host to maintain or even reconstitute levels of CD4 T cells, in the face of active virus replication, will probably shed light on the pathogenesis of HIV infection. However, some of the conclusions on immunologic outcome that are drawn by the authors may be inappropriate. First, using an ELISPOT assay, they found significantly higher levels of HIVspecific cytolitic (CTL) responses in patients with discordant response to treatment (group D) than in patients with complete suppression of the virus (group S), although these responses were similar to those found in patients experiencing virologic failure (group F). Sufka et al. interpreted their data as proof that an enhanced HIV-directed immune response is responsible for the discordant response. However, the question of what is cause and what is effect, in the virus-load/CTLresponse couple, is unsolved, and we feel that the Sufka et al.’s data, in fact, suggest that virus replication drives CTL response. It has been well demonstrated that CTL responses can be found in virtually every patient with both chronic HIV infection and uncontrolled virus replication [2,3]. A certain level of antigenic stimulus seems to be needed to maintain specific CTL responses [4]. Furthermore, it is not appropriate to rely only on a quantitative measure of CTL response when one is attempting to draw conclusions about its potential effect on control of virus replication [5]. In our opinion, the higher levels of CTL responses in patients in group D, compared with those in patients in group S, could reflect low levels of virus replication; thus, low levels of virus replication might not be the result of higher levels of CTL, as suggested by Sufka et al. Supporting this possibility are the higher levels of CTL that we have recorded in a group of patients treated with a 2-drug regimen who maintained low virus-load levels during a 12-month period, compared with patients in other studies, who were treated with highly active antiretroviral therapy and who had no detectable viremia. However, our patients, unlike those in group D, did not present a discordant response [6]. Second, using the combination of HLADR and CD38 markers, as well as a quantitative assay, Sufka et al. analyzed the levels of immune activation, to measure the levels of expression of CD38 on T cells. They found lower levels of activation on CD4 and CD8 T cells in patients in group D, compared with those in patients in group F. Then, they concluded that diminished levels of activation might be another factor contributing to the discordant response. We too have quantitatively analyzed the expression of CD38 on CD8 T cells, and we have found a significant, direct correlation between the levels of CD38 expression and plasma viremia. Thus, higher levels of virus replication imply more immune activation [7]. The lower levels of CD38 expression in patients in group D, compared with those in patients in group F, most likely reflect lower levels of virus replication in patients in the former group. Since levels of activation and apoptosis are directly correlated with each other [8], the lower levels of activation in patients in group D could result, not unexpectedly, in lower levels of apoptosis. Having used seronegative subjects as control subjects, Sufka et al. [1] did not show whether activation was in the normal range in patients in group D. We think that this comparison is pivotal in any attempt to prove that this mechanism may play a role in the discordant response. Without these data, Sufka et al. cannot justifiably conclude that lower levels of activation in patients in group D, compared with those in patients in group F, may enable the host to maintain or even reconstitute levels of CD4 T cells, in the presence of virus replication. Moreover, to control for this variable, Sufka et al. should have examined patients in both group D and group F who had similar levels of virus replication. We feel that some of the misinterpretation by Sufka et al. may be attributable to different levels of virus replication in the different study groups.