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Why HAART Doesn't Increase CD4s
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"T Cell Activation Is Associated with Lower CD4+ T Cell Gains in Human
Immunodeficiency Virus-Infected Patients with Sustained Viral
Suppression during Antiretroviral Therapy"
The Journal of Infectious Diseases 2003;187:1534-1543
Peter W. Hunt,1,3 Jeffrey N. Martin,1,4,5 Elizabeth Sinclair,2 Barry Bredt,2 Elilta Hagos,1 Harry Lampiris,3 and Steven G. Deeks1. Positive Health Program and 2General Clinical Research Center, Department of Medicine, San Francisco General Hospital, 3San Francisco Veterans Affairs Medical Center, 4Department of Epidemiology and Biostatistics, and 5Center for AIDS Prevention Studies, University of California, San Francisco
Although T cell activation is associated with disease progression in untreated
human immunodeficiency virus type 1 (HIV-1) infection, its significance in
antiretroviral-treated patients is unknown. Activated (CD38+HLA-DR+) T cell
counts were measured in 99 HIV-infected adults who had maintained a plasma
HIV RNA level 1000 copies/mL for a median of 21 months while receiving
antiretroviral therapy. Patients with sustained viral suppression had lower levels of T cell activation than untreated patients but higher levels than HIV-uninfected control subjects. Persistent T cell activation was associated with decreased CD4+ T cell gains during therapy. For every 5% increase in the proportion of activated CD8+ T cells, 35 fewer CD4+ T cells/mm3 were gained. Increased T cell activation was associated with shorter duration of viral suppression, hepatitis C virus coinfection, frequent low-level viremia, and lower nadir CD4+ T cell counts. Interventions that directly target T cell activation or the determinants of activation may prove to be useful adjuvants to antiretroviral therapy.
DISCUSSION by Authors
Although most HIV-infected patients experience sustained CD4+ T cell gains while receiving virologically suppressive HAART, some patients never experience robust CD4+ T cell gains, and others fail to achieve a normal CD4+ T cell count even after several years of therapy. Because T cell activation is predictive of disease progression in the untreated patients, even independent of virus load, we hypothesized that abnormal T cell activation might
persist in patients experiencing long-term viral suppression and might be associated with the immunologic response to therapy. Among HIV-infected participants with a median of almost 2 years of HAART-mediated viral suppression, we found substantial levels of both CD4+ and CD8+ T cell activation, well above the levels observed in HIV-uninfected persons. Furthermore, higher levels of CD4+ T cell activation were independently associated with lower CD4+ T cell gains experienced in the first 3 months of therapy, and higher levels of CD8+ T cell activation were independently associated with lower CD4+ T cell gains after month 3. Our results provide further support for the hypothesis that T cell activation plays a critical role in HIV pathogenesis.
It has long been proposed that T cell activation may be a mechanism by which HIV infection leads to CD4+ T cell depletion. Given the small proportion of T cells that are actually infected by HIV, it has been inferred that mechanisms
other than direct loss of infected CD4+ T cells must play a role in CD4+ T cell depletion. Indeed, HIV infection activates uninfected, resting T cells either indirectly, via inflammatory cytokines, or directly, via contact with antigen-presenting cells presenting HIV antigens or exposure to gp120 and other viral factors. These activated T cells undergo rapid proliferation and are prone to spontaneous apoptosis. Normally, some progeny of T cells activated by an antigenic stimulus revert back to long-lived resting phenotypes after
withdrawal of the activating stimulus. However, in the presence of ongoing antigen and inflammatory stimulation by HIV, the resting pool of naive and memory CD4+ T cells may be continually drained, resulting in an inability to restore the CD4+ T cells lost as a consequence of HIV infection. This hypothesis is supported by the observation that sooty mangabeys, which fail to develop increased levels of T cell activation and apoptosis in response to simian immunodeficiency virus infection, rarely develop CD4+ T cell depletion, despite ongoing CD4+ T cell infection and destruction by simian immunodeficiency virus.
Our finding that increased CD8+ T cell activation is associated with lower CD4+ T cell gains after 3 months of HAART-mediated viral suppression is consistent with other work relating CD8+ T cell activation to disease progression in
untreated patients. Interestingly, these studies have generally concluded that markers of CD8+ activation, but not CD4+ activation, predict clinical progression, although there is some controversy on this point. One possible
explanation for the predictive superiority of CD8+ T cell activation markers is related to differential rates of HIV infection observed in activated T cells. Because activated CD4+ T cells are preferentially infected by HIV, their
half-lives are determined not only by the rate of activation-induced apoptosis but also by the rate of HIV infection and direct virus-mediated cell death. Higher levels of HIV replication might reduce the percentage of activated CD4+ T cells by accelerating their removal, and therefore CD8+ T cell activation markers can be expected to be more closely associated with the ability of HIV to cause generalized T cell activation and, by extension, the rate at which CD4+ T cells are gained or lost.
It is also interesting that HIV-infected patients maintaining viral suppression in this study had substantially higher levels of T cell activation than did HIV-uninfected control subjects. This difference was observed even when HIV-infected participants with persistent detectable viremia or hepatitis C virus coinfection were excluded. Because the half-life of activated CD4+ and CD8+ T cells is short, the presence of heightened T cell activation after years of suppressive HAART suggests the presence of ongoing antigenic stimulation. This might reflect ongoing low-level HIV replication in lymphoid tissues; the presence of other chronic infections, as a result of continued immunodeficiency (e.g., herpesvirus infections); or persistent immunologic dysregulation that is not reversed by HAART-mediated viral suppression. The
former possibility is consistent with a recent study in which treatment intensification among patients with very low-level viremia (HIV RNA level, 2.550 copies/mL) resulted in decreased levels of plasma HIV RNA and decreased levels of T cell activation.
Although abnormal levels of T cell activation were observed in our participants, it is notable that the levels appeared to decrease as the duration of viral suppression increased. We did not perform repeated measurements over time and therefore cannot exclude the possibility that patients with high levels of persistent T cell activation were preferentially excluded from our sample because of virologic failure; however, the observed association was not confounded by the extent of low-level viremia and suggests that levels of CD8+ T cell activation continue to decrease for years after viral suppression is achieved. This might reflect a continued, albeit gradual, decrease in the level of viral replication that remains below the level of detection of standard plasma HIV RNA assays and/or it might reflect the slow decay of the latent reservoir of infected cells. In either case, a slow decrease of CD8+ T cell activation over time might be one explanation for the slow, but persistent,
CD4+ T cell gains observed in the majority of patients with long-term HAART-mediated viral suppression.
Our finding that persistent CD4+, but not CD8+, T cell activation during suppressive HAART is associated with decreased CD4+ T cell gains in the first 3 months of therapy suggests that redistribution of CD4+ T cells from lymphoid
tissue is more closely associated with a decrease in CD4+ T cell activation than with a decrease in CD8+ T cell activation.
Because most patients with untreated HIV infection have high levels of pre-HAART CD4+ T cell activation, we can assume that those patients with the lowest levels of CD4+ T cell activation during suppressive HAART were likely to have had the largest decrease in T cell activation in the first few months of therapy. Because CD4+ T cell activation is closely associated with cell adhesion molecule and chemokine receptor expression, we can speculate that a
large reduction in CD4+ T cell activation is associated with a large redistribution of CD4+ T cells from lymphoid tissue. The observation of Hejdeman et al, who measured pre- and post-HAART activation levels in a cohort of HIV-infected patients initiating HAART, that patients who experience a reduction in the plasma HIV RNA level of <1 log still experience an early and sustained gain in CD4+ T cell counts that correlates with a reduction in the level of CD4+ T cell activation markers despite unchanged levels of CD8+ T cell activation markers, is consistent with this hypothesis.
Although our primary focus was on T cell activation, our results remain consistent with other research demonstrating an association between thymic function and CD4+ T cell restoration in patients receiving virologically suppressive HAART. In our study, high levels of CD8+ T cell activation, older age, and decreased levels of naive CD4+ T cells were all independently associated with blunted late CD4+ T cell gains. To the extent that age and the percentage of naive CD4+ T cells are surrogates for thymic function when adjusting for levels of T cell activation, our data support a model in which 2
related but largely independent factors determine the CD4+ T cell gains experienced by patients with HAART-mediated viral suppression: T cell activation and thymic function.
A potential limitation of our study is the lack of pre-HAART and repeated during-HAART measurements of T cell activation. Because we only measured markers of T cell activation once and measured HAART-mediated CD4+ T cell
changes retrospectively, we cannot prove that high levels of T cell activation predict lower CD4+ T cell gains. However, existing prospective data on untreated HIV-infected individuals show that our interpretation of a causal relationship is plausible. Another potential limitation is the male predominance and high prevalence of protease inhibitorbased regimens in our cohort, which may limit the generalizability of our findings to other patient populations.
Finally, we found several factors to be associated with persistent T cell activation, which suggest potential approaches to optimizing the immunologic responses to virologically suppressive HAART. First, we observed increased levels of CD8+ T cell activation in participants with lower pre-HAART nadir CD4+ T cell counts. This observation is consistent with a recent report of decreased responses to vaccination in HAART-treated patients with normal current CD4+ T cell counts but low CD4+ T cell nadirs and suggests that initiating therapy earlier in untreated patients might be associated with
improved immunologic function. However, because levels of CD8+ T cell activation may decline even after several years of viral suppression, it is possible that the immunologic perturbations caused by delaying therapy may be reversible. Second, we observed increased CD8+ T cell activation in participants with frequent low-level viremia. This suggests that further
suppression of viral replication resulting from intensification of HAART may provide some marginal immunologic benefits, as has been observed in 2 recent studies. Third, hepatitis C virus coinfection was associated with persistent T cell activation, which confirms the conclusions of work published elsewhere. This observation suggests that treatment of other chronic inflammatory diseases might improve immunologic responses to HAART. Fourth, because almost all of our participants had abnormal levels of CD8+ T cell activation, treatment of T cell activation itself with immunomodulatory medications might be beneficial in HAART-treated patients with sustained viral suppression. In a recent trial, patients with early HIV infection who were treated with HAART plus 8 weeks of cyclosporin achieved and maintained much higher CD4+ T cell counts and levels of HIV-specific immune responses than did patients treated with HAART alone. Although trials of cyclosporin in chronically infected patients with varying degrees of viral suppression have failed to show
benefit, future trials of immunomodulators may hold promise if they are targeted at chronically infected patients maintaining viral suppression.
In summary, we have shown that abnormal levels of T cell activation exist in most patients experiencing long-term HAART-mediated viral suppression and that the extent of activation is associated with treatment-associated CD4+ T cell gains. Improving our understanding of how HIV activates the immune system may lead to the development of more-specific adjuvants to HAART that reverse the immunologic perturbations caused by HIV infection.
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