Gonna Wash That Virus Right Out of My Cells: IL-2, HAART, and HIV Eradication
Gonna Wash That Virus Right Out of My Cells: IL-2, HAART, and HIV Eradication
abstract & commentary
Synopsis: Replication competent HIV was undectable in peripheral blood mononuclear and lymph node cells in a small number of patients who had received both highly active antiretroviral therapy and recombinant IL-2.
Source: Chun TW, et al. Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1 infected patients receiving highly active anti-retroviral therapy. Nat Med 1999;5:651-655.
A major barrier to virological cure in hiv infection is the persistence of virus in cellular reservoirs. The size of the pool of resting CD4+ T cells latently infected with HIV was analyzed in 26 patients who had received highly active antiretroviral therapy (HAART) for a mean of 20-21 months and whose plasma HIV RNA was less than 50 copies/mL. Fourteen of the patients also received IL-2 intravenously or subcutaneously in doses of 3-18 million units daily for five days with intervals between treatment of at least eight weeks. These 14 patients had received a mean of 10 such cycles over 39 months. Although the study was not randomized, the two groups appeared similar at baseline.
Using a quantitative micro-co-culture method whose limit of detection was 0.032 infectious units per million cells (IUPM), the median IUPM in patients receiving HAART + IL-2 was 0.032, while it was 0.440 in those receiving HAART alone (P = 0.01). In assays examining as many as 20 million resting CD4+ T cells, infectious virus was detectable in all the patients receiving HAART alone, but was undetectable (IUPM < 0.032) in six (42%) of the 14 IL-2 recipients.
When cells from the six IL-2 recipients with undetectable replication competent virus in this assay were examined in an assay of up to 330 million resting CD4+ T cells, the median IUPM was 0.0069 and no infectious virus could be detected in three of the six. A repeat of this high-input assay 4-5.5 months later also failed to detect infectious virus in these three, despite the fact that a small fraction continued to contain proviral DNA (10-98 copies per million cells).
Excisional lymph node biopsy was performed on two of the patients in whom replication competent virus could not be detected in peripheral blood cells in the high-input assays. Despite culture of 40-50 million cells highly enriched for CD4+ T cells and macrophages, replication competent virus was not detected. Once again, however, a small proportion of cells contained proviral DNA.
Comment by Stan Deresinski, MD, FACP
Several recent studies have demonstrated the persistence of latently infected CD4+ cells in patients receiving HAART for prolonged periods and in whom virus was not detectable in plasma. These findings have led to a discounting of the notion that HAART could lead to viral eradication. In fact, recent analyses have suggested that the decay half-life of these latently infected cells is such that 10-40 years of HAART would be required before viral eradication could be anticipated.
IL-2 administration to patients not receiving antiretroviral therapy commonly induces a transient burst of viral replication, probably as a consequence of the release of pro-inflammatory cytokines, such as TNF-a. The latter interacts with NFkB, which in turn is transported to the cell nucleus and upregulates HIV replication after interaction with the viral LTR. Thus, it is theorized that IL-2 may be capable of contributing to the elimination of latently infected cells as a result of their activation.
Increased viral replication may lead directly to cell death or may increase the cell’s vulnerability to the immune system by increasing viral antigen display to immune cells whose competence may have been enhanced by IL-2 administration. GM-CSF may play a similar role in macrophages. The use of therapeutic vaccination in this setting has been recommended as another means to achieve this end. The recent observation of lack of viral resurgence after treatment discontinuation in a few patients whose effective HAART was repeatedly interrupted has been interpreted to suggest that viral control was the consequence of "self-immunization."
Chun and colleagues acknowledge a number of drawbacks in their study, chief of which is the lack of randomization. Nonetheless, their observation is intriguing. However, to know what it means will require a simple maneuver—stopping HAART with careful subsequent observation. It may be desirable, however, to assay for virus in other cellular reservoirs in the patients in whom replication competent virus could not be detected prior to discontinuation of therapy. v
Necrotizing Fasciitis After Varicella: An Association with Ibuprofen Use?
abstract & commentary
Synopsis: A case-control study found an association between ibuprofen use and the development of necrotizing fasciitis in children with varicella.
Source: Zer DM, et al. A case-control study of necrotizing fasciitis during primary varicella. Pediatrics 1999;103: 783-790.
Zer and associates at the children’s hospital in Seattle were impressed with what appeared to be an increase in the number of invasive Group A streptococcal (GAS) infections, including cases of necrotizing fasciitis (NF) complicating varicella that were seen in their institution in 1993-1995. Previous reports had shown an eight times increased frequency of the use of ibuprofen in children who developed invasive GAS infections compared to controls; however, this increase was not statistically significant.1
Nineteen children were admitted to their hospital with NF complicating primary varicella. Demographic data, clinical parameters, and possible risk factors in these 19 children were compared to a control group of 29 children hospitalized with soft tissue infections other than NF within three weeks of varicella. There was no difference between the groups in clinical manifestations such as fever, pain, swelling, and erythema; use of acetaminophen and antibiotics was also similar. However, 9/19 cases with NF had used ibuprofen prior to hospitalization compared to 4/29 controls. The association was even stronger in only those NF cases with documented GAS infections, where 8/16 cases used ibuprofen compared with 0/8 controls (P = 0.02).
Several reasons for this apparent association have been suggested. These include a masking of local symptoms that might delay diagnosis as well as effects of ibuprofen on suppressing neutrophil function and augmentation of inflammatory cytokine production.
Although proof of an association of ibuprofen use and invasive GAS infections including NF would require a large-scale study—similar to the ones that showed a causal link with aspirin use and Reye’s syndrome2—pediatricians should discourage the use of ibuprofen in children with varicella until more information is available. Acetaminophen is the best alternative. This serious syndrome is also further ammunition for advocating routine varicella immunization. (Dr. Louis M. Bell is Associate Professor of Pediatrics [Infectious Diseases], University of Pennsylvania School of Medicine, Philadelphia, PA.) v
References
1. Peterson CL, et al. Risk factors for invasive group A streptococcal infections in children with varicella: A case control study. Pediatr Infect Dis J 1996;15:151-156.
2. Surgeon General’s advisory on the use of salicylates and Reye syndrome. MMWR Morb Mortal Wkly Rep 1982;31:289-290.
In children with primary varicella, all of the following are correct except:
a. There may be a causal relationship between the use of ibuprofen and invasive GAS including NF.
b. Acetaminophen is the preferred analgesic/antipyretic.
c. Ibuprofen’s anti-inflammatory actions may delay diagnosis.
d. Children who have NF have more severe local manifestations than children with other soft tissue infections.
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