T cell activation is associated with decreased CD4+ T cell gains during ARV therapy

Graham McKerrow, HIV i-Base

Persistent T cell activation is associated with decreased CD4+ T cell gains during therapy, according to researchers in San Francisco. They found that increased T cell activation was associated with shorter duration of viral suppression, hepatitis C coinfection, frequent low-level viremia, and lower nadir CD4+ T cell counts.

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. For this study 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 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, say the authors.

Participants were selected from the Study of the Consequences of the Protease Inhibitor Era (SCOPE), a clinic-based cohort of 450 chronically HIV-infected patients who receive primary care in HIV/AIDS clinics. The cohort was assembled to represent distinct groups of HIV-infected persons: 25% of participants were untreated at enrolment; 50% were receiving HAART but were in a state of virologic failure at enrolment, with plasma HIV RNA levels consistently >1000 copies/mL for at least 24 weeks; and 25% were receiving HAART at enrolment and had been experiencing virologic suppression with plasma HIV RNA levels consistently <50 copies/mL for at least 24 weeks, with allowance for occasional transient detectable viremia 1000 copies/mL. Participants were seen at four-month intervals, at which times a detailed questionnaire that collected information about antiretroviral use and risk behaviour was administered and blood and saliva specimens were obtained. The first 175 consecutive SCOPE participants had immunophenotyping of T cells performed at the second study visit. Participants were included in the present analysis if they were receiving HAART, had a plasma HIV RNA level 1000 copies/mL on the day of immunophenotyping and for at least three months before immunophenotyping, and had a documented CD4+ T cell count determination within six months before the initiation of HAART.

Among HIV-infected participants with a median of almost two years of HAART-mediated viral suppression, the researchers 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 three months of therapy, and higher levels of CD8+ T cell activation were independently associated with lower CD4+ T cell gains after month three. These results provide further support for the hypothesis that T cell activation plays a critical role in HIV pathogenesis, the authors write.

Their finding that increased CD8+ T cell activation was associated with lower CD4+ T cell gains after three months of HAART-mediated viral suppression is consistent with other work relating CD8+ T cell activation to disease progression in untreated patients.

They write that 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.

In their discussion, the authors write: “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 (eg herpesvirus infections); or persistent immunologic dysregulation that is not reversed by HAART-mediated viral suppression.

“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 three 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.

“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.”

Reference:

Hunt PW, Martin JN, Sinclair E et al. T Cell Activation Is Associated with Lower CD4+ T Cell Gains in Human Immunodeficiency Virus-Infected Patients with Sustained Viral Suppression during Antiretroviral Therapy. J Infect Dis. 2003 May 15;187(10):1534-43. Epub 2003 Apr 23.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12721933&dopt=Abstract