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Interferon Alfa Therapy: Toward an Improved Treatment for HIV Infection Editorial
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"This finding suggests that Peg-interferon alfa-2a may eliminate latent HIV genomes, a possibility that would shed light on the search for a sterilizing as well as a functional cure for HIV......This unexpected finding suggests that when optimally effective, Peg-interferon alfa-2a may be able not only to suppress viral replication by enhancing the immune response to HIV, but also to assist in clearance of the viral reservoir......this result suggests that interferon alfa administration before and during STIs could provide a safer way to evaluate viral control in the absence of HAART. Thus, further study of interferon alfa therapy in HAART-treated patients will at once enhance our understanding of how viral replication can be limited in the absence of HAART and provide us with a tool to study alternative approaches to a cure."
The Journal of Infectious Diseases Jan 2013
Lucy A. McNamara1,2 and Kathleen L. Collins1,3
1Department of Microbiology and Immunology, 2Department of Epidemiology, and 3Department of Internal Medicine, University of Michigan, Ann Arbor
(See the major article by Azzoni et al)
Highly active antiretroviral therapy (HAART) is an expensive, lifelong treatment for human immunodeficiency virus (HIV) infection that is associated with significant toxicity. Despite advances in treatment, there remains a need for novel therapies for HIV infection. One strategy is to achieve a functional cure, in which treatment can be safely stopped despite the presence of residual virus, by finding approaches that enhance the immune response to HIV. Such a therapy would require boosting a patient's immune system to suppress viral replication below clinically relevant levels, thereby eliminating the need for HAART. A sterilizing cure, by contrast, is one in which all functional HIV genomes within the body are eliminated. Latent HIV genomes represent a major barrier to a sterilizing cure because these genomes do not produce viral proteins and thus cannot be eliminated by the immune system or by current therapies [1].
In this issue, Azzoni and colleagues assessed the potential of pegylated (Peg) interferon alfa-2a to suppress HIV replication [2]. In what could be a first step towards a functional cure, they found that Peg-interferon alfa-2a permitted a subset of subjects to maintain low viral loads for 12-24 weeks in the absence of HAART. Furthermore, they found that in patients with a favorable virologic response to Peg interferon alfa-2a, levels of HIV provirus in peripheral blood mononuclear cells (PBMCs) were reduced. This finding suggests that Peg-interferon alfa-2a may eliminate latent HIV genomes, a possibility that would shed light on the search for a sterilizing as well as a functional cure for HIV.
Interferon alfa is used clinically for the treatment of hepatitis B and C virus infections, and several studies have assessed the capacity of this cytokine to limit HIV replication in vivo [3-9]. Multiple studies confirm that interferon alfa can reduce viral load and delay disease progression in viremic patients [3, 5-11]. However, interferon alfa's potential to suppress viremia in patients with well-controlled viral loads is less clear. Recently, one study subjected HAART-treated patients with a viral load of <400 copies/mL for at least 6 months and a CD4+ T-cell count of >350 cells/μL to a series of three 4-week structured treatment interruptions (STIs), during which they received interferon alfa therapy or no treatment [4]. Treatment was then suspended until the end of the trial. Interferon alfa administration was observed to significantly blunt the viral load rebound during the 4-week STI phase, but it did not prolong the time to treatment resumption after treatment was suspended. This study also noted that interferon alfa was deleterious in patients with a low nadir CD4+ T-cell count [4].
This issue's study by Azzoni et al is the first to show an effect of Peg-interferon alfa-2a treatment on viral load rebound during a multimonth interval of treatment interruption and the first to identify an effect of Peg-interferon alfa-2a on the HIV proviral reservoir [2]. In this study, the authors recruited 23 HAART-treated, HIV-positive patients with HIV plasma RNA levels of <50 copies/mL [2]. All subjects received Peg-interferon alfa-2a therapy in addition to HAART for 5 weeks; then HAART but not Peg-interferon alfa-2a therapy was interrupted for 12-24 weeks [2]. Viral suppression was maintained through week 12 of treatment interruption in 45% of patients and through week 24 in 30% of patients; in both cases, the proportion of patients with suppressed viral loads was significantly greater than expected on the basis of data from historical controls [2]. The authors comment that the higher level of suppression observed in this study compared with other trials may have resulted from coadministering Peg-interferon alfa-2a with ART prior to treatment interruption. Subjects in this study also had complete viral suppression (viral load, <50 copies/mL) and a high degree of immune reconstitution (CD4+ T-cell count, >450 cells/mL) [2].
Furthermore, the authors assessed the level of integrated HIV-1 DNA in PBMCs in 13 patients, 6 of whom exhibited virological failure and 7 of whom maintained virological suppression at week 12 of the treatment interruption [2]. No change in the number of copies of HIV-1 DNA per CD4+ T cell was observed in the patients experiencing virological failure [2], a useful finding because it demonstrates that in the presence of Peg-interferon alfa-2a, an STI can be undertaken without detectably increasing the size of the latent viral reservoir in the peripheral blood. Moreover, a significant decrease in the HIV-1 DNA load per CD4+ T cell was detected in the 7 subjects who maintained viral suppression at week 12 [2]. This unexpected finding suggests that when optimally effective, Peg-interferon alfa-2a may be able not only to suppress viral replication by enhancing the immune response to HIV, but also to assist in clearance of the viral reservoir.
Given the small size of this study and the necessity of using historical controls, these results must be interpreted cautiously. However, they raise several interesting questions for future studies. One question is how interferon alfa activates the immune response to both suppress viral replication and reduce the reservoir of HIV proviral DNA. Interferon alfa promotes an antiviral response to HIV that inhibits viral replication at multiple stages of the replication cycle [12]. Specifically, interferon alfa upregulates APOBEC3G, TRIM5α, and tetherin in vitro; upregulation of both APOBEC3G and tetherin in response to interferon alfa therapy has been confirmed in vivo [8]. The upregulation of these factors in response to interferon alfa therapy might inhibit viral replication directly by causing mutations in viral genomes (in the case of APOBEC3G) or by preventing viral uncoating (for TRIM5α) or budding (for tetherin). Alternatively, APOBEC3G upregulation could suppress viral replication by activating other immune cells. Recent work has shown that APOBEC3G activity can enhance recognition of HIV-infected cells by CD8+ cytotoxic T cells [13] and natural killer (NK) cells [14]. A study showing that interferon alfa treatment in vivo enhances NK cell function provides further support for the relevance of this mechanism [15].
It is less clear how interferon alfa could contribute to a reduction in HIV proviral DNA in PBMCs. If the proviral genomes detected in this study represent latent virus, neither APOBEC3G, TRIM5α, nor tetherin should have any impact on the amount of HIV-1 DNA detected. Instead, the finding that there is a decrease in the number of HIV-1 genomes detected may suggest that interferon alfa reactivates latent HIV-1, leading to the loss of the infected cells through the virus's cytotoxic effects or the action of the immune system. Alternatively, the decrease in proviral genomes in a subset of interferon alfa-treated individuals might indicate that a fraction of these genomes derive from ongoing replication during HAART therapy, rather than from latent viruses. In this case, the mechanism through which interferon alfa could reduce the number of proviral genomes detected is more obvious. However, although there is some evidence that ongoing replication can occur in a subset of HAART-treated patients with suppressed viral loads [16-19], the majority of the evidence suggests that residual replication is not a major source of viral persistence in these patients [20-25]. Further study is required to confirm that interferon alfa reduces the amount of HIV-1 DNA detected in the PBMCs of at least a subset of patients and to help us better understand this interesting finding.
Another question is why Peg-interferon alfa-2a therapy was effective in suppressing viral replication only for some individuals in this study. Analogous to a recent study on the control of hepatitis C virus infection, in which Ge et al found that the response to interferon alfa treatment is associated with a polymorphism in the IL28B gene [26], the authors examined multiple polymorphisms associated with improved or reduced hepatitis C virus or HIV control. No association between any genotype and response to Peg-interferon alfa-2a was found; however, this study was too small for any but the strongest association between genotype and treatment outcome to be detected. Alternative biomarkers for response to interferon alfa should also be investigated, such as variation in levels of APOBEC3G [14, 27], TRIM5α, or tetherin. Finally, HIV characteristics may determine which individuals can respond to interferon alfa. This possibility would again be analogous to hepatitis C virus infection, in which patients infected with viral genotype 1 are less likely to respond to interferon alfa treatment than are patients infected with viral genotype 2 or 3 [28].
Although the results of the present study need to be confirmed in a larger cohort, the clinical implications of this research are promising. Since the SMART study, which demonstrated that STIs were associated with a significantly increased risk of opportunistic disease or death [29], it has been difficult to assess the efficacy of therapies designed to limit viral rebound without concerns about endangering the health of study participants. In the current study, however, Azzoni et al have demonstrated that it is possible to subject participants to an STI without increasing the reservoir of HIV DNA in the peripheral blood. Although HIV DNA and adverse health outcomes are very different outcome measurements, this result suggests that interferon alfa administration before and during STIs could provide a safer way to evaluate viral control in the absence of HAART. Thus, further study of interferon alfa therapy in HAART-treated patients will at once enhance our understanding of how viral replication can be limited in the absence of HAART and provide us with a tool to study alternative approaches to a cure.
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