Antiretroviral Suppression of HIV in the Context of Persistently Low CD4 Counts: New Insights

January 1, 2007

Shortly after the introduction of combination antiretroviral therapy, it was noted that a significant fraction of patients, from 8% to 17%, had poor CD4+ T-cell recovery despite suppression of HIV RNA to undetectable levels for at least 6 to 12 months.1

Shortly after the introduction of combination antiretroviral therapy, it was noted that a significant fraction of patients, from 8% to 17%, had poor CD4+ T-cell recovery despite suppression of HIV RNA to undetectable levels for at least 6 to 12 months.1 These immunologic nonresponders (InRs) have been recognized among all types of patients–treated with myriad combination regimens–although nonresponse is a more frequent occurrence in those who have nadir CD4+ cell counts below 100/µL.2 The degree to which this viremia/immune cell disconnect predisposes a patient to heightened sensitivity to opportunistic infections is a matter of debate.2,3 However, the clinical importance of the problem will only increase if HIV disease continues to be diagnosed late in its course.

It is generally accepted that an increase of up to 20% in the CD4+ T-cell count from baseline during the first 6 months of antiretroviral therapy defines a good immunologic response; the goal is maintaining such counts at greater than 250/µL or greater than 17%.4 There have been many explanations proposed as to why such immunologic reconstitution–at least by the numbers–might fail. Individual studies have implicated a TH1:TH2 cytokine imbalance, favoring the latter; abnormalities of interleukin (IL)-7 secretion and IL-7 receptor expression; chronic immune activation; suppression of CD4+ regulatory T cells (Tregs); and bone marrow or thymus gland impairment (reviewed3-5). A recent study from the University of Rome "La Sapienza" provides an extensive analysis of all of these factors within a single, if small, cohort of patients.4

Two groups of chronically HIV-infected patients who were treated with antiretroviral therapy for at least 1 year and who maintained undetectable plasma HIV RNA levels (less than 50 copies/mL) were studied. The first group of 15 persons–the InRs–had CD4+ cellÐcount elevations of less than 20% from baseline or less than 200/µL. They represented 8.1% of the initial cohort of 186 patients and had received a mean of 26.1 ± 14 months of antiretroviral therapy. Two of the 15 had AIDS at baseline, and all received protease inhibitor (PI)-based therapies.

The second group consisted of 20 immunologic responders (IRs) selected from the original cohort for baseline CD4 counts comparable to those of the InRs (187 ± 94 vs 150 ± 120). Two of the 20 had AIDS at baseline, and 16 received PI-based therapy. Fifteen HIV-negative, healthy controls were also monitored.

At baseline, there were no significant differences in demographics, disease duration, or immunologic or virologic parameters between InRs and IRs. After at least 1 year of antiretroviral therapy, mean CD4+ cell counts were significantly lower in the InR group (163 ± 79/µL vs 574 ± 230/µL). This was largely a result of the reduction in absolute number of naive CD45RA+CD62L+ cells, resulting in a higher relative percentage of memory CD45RA2CD62L2 cells in the InR group. A significant inverse correlation was also seen between CD4+ T-cell counts and the number of CD4+ cells expressing the activation marker HLA-DR or the apoptosis-associated Fas marker CD95.

Other phenotypic abnormalities included reduction in CD4+CD25hi Tregs in the InR group (0.58 ± 0.35% vs 1.26 ± 0.47%), decreased expression of the IL-7 receptor CD127, and altered patterns in T-cell receptor repertoires. All of these abnormalities were restricted to CD4 subsets; no significant differences were seen for the CD8+ T cells.

In terms of cytokines, serum IL-7 levels were significantly increased in the InR group. IL-7 is a key cytokine in the regulation of T-cell homeostasis, a survival factor for all types of T lymphocytes, and a costimulatory molecule for T-cell activation.4 Serum interferon-gamma levels were significantly lower in the InR group, while levels of other TH1 and TH2 cytokines, including IL-2, IL-4, and IL-12, were not altered.

Finally, a depressed clonogenic potential of cells from InRs, accompanied by an increase in expression of Fas and its ligand, was described as part of yet unpublished observations implicating bone marrow impairment. Of interest is a recent study relating low total CD4 counts and CD4+ cells expressing the activation marker HLA-DR to those with small (less than 2 cm3) or undetectable thymus glands.3

The University of Rome "La Sapienza" group concluded that patients experiencing a viremia/immune cell disconnect while receiving antiretroviral therapy have a profound compromise in the naive CD4+ T-cell subset. The phenomenon appears to be multifactorial, with chronic depletion of Tregs permitting persistent immune activation independent of detectable viremia in the setting of poor IL-7R expression contributing to a defect in CD4+ cell survival. The increase in expression of apoptotic molecules was consistent with an earlier study showing an increase in spontaneous apoptotic cell death among InRs.5

Whether the InR group experienced more viral "blips"–transient viremia over the 50 copies/mL cutoff–than did the IR group, which might contribute to immune activation in the former, was not examined. It is known that ongoing reactivation of latently infected, resting CD4+ T cells and spread of virus by activated CD4+ T cells can occur in patients with long-term suppression of viremia.6

The clinical significance of immunologic nonresponse to antiretroviral therapy remains to be explored. Functionally, InRs have interferon-gamma production3 and lymphoproliferative responses3,5 to Candida and cytomegalovirus antigens indistinguishable from those of IRs. The current CD4 count remains a strong predictor of development of opportunistic infections even in patients with high CD4 counts, but this is complicated because antiretroviral therapy has a beneficial effect on the incidence of opportunistic infection even after controlling for its beneficial effect on the number of CD4+ cells.7

What might one do to prevent or treat the viremia/immune cell disconnect? The fact that this phenomenon has a higher incidence among those with nadir CD4 counts of less than 100/µL argues for an enhanced public health effort to rapidly identify early HIV infections. Mechanistically, the recent identification of the overexpression of a molecule known as programmed death-1 on HIV-specific killer T cells, which are no longer capable of destroying infected cells in their "exhausted' state,8 suggests another means to regulate T-cell activation and activity in the setting of HIV.

References:

References


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