Biotecnologia Aplicada Elfos Scientiae ISSN: 0684-4551 Vol. 14, Num. 4, 1997, pp. 271-274

Is IFN a bad or a good guy in the HIV story?

Pedro Lopez-Saura

Centro de Investigaciones Biologicas, apartado postal 6996, La Habana, Cuba. Tel: 21-9635; Fax: 21-0553. E-mail: clintr@cigbdec.cigb.edu.cu

Code Number:BA97062
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ABSTRACT

The role of interferons (IFN) in human immunodeficiency virus (HIV) infection and disease is not completely clear. Experimental and clinical data point in both directions: as pathogenic and as infection-limiting factors. All types of IFN have anti-retroviral effect in vitro and clinical trials suggest that treatment with IFN alpha can be beneficial to HIV-seropositive individuals at the early stages of infection. Contrarily, HIV induces an acid-labile IFN and its presence in serum as well as IFN- inducible molecules are markers of advanced disease and poor prognosis. IFN gamma can facilitate virus spread but it also participates in the defense against several opportunistic pathogens. The overall result is probably a balance between both kinds of actions. It depends on several factors such as the type or subtype of interferon involved at each stage of disease, other pathogens that can be present, and relations with other cytokines.

Key words: interferon, human immunodeficiency virus, acquired immune deficiency syndrome

RESUMEN

El papel de los interferones (IFN) en la infeccion por el virus de la inmunodeficiencia humana (VIH) no esta completamente aclarado. Las evidencias de trabajos experimentales y clinicos apuntan en ambas direcciones: como factores patogenicos y como limitantes de la infeccion. Todos los tipos de IFN tienen efecto anti-retroviral in vitro y los ensayos clinicos sugieren que el tratamiento con IFN alfa puede ser beneficioso a individuos seropositivos al VIH en los estadios tempranos de la infeccion. Por el contrario, el VIH puede inducir un IFN acido-labil y su presencia en suero y la de moleculas inducibles por IFN son marcadores de enfermedad avanzada y mal pronostico. El IFN gamma puede facilitar la diseminacion viral pero tambien participa en la defensa contra varios patogenos oportunistas. El resultado global es probablemente un balance entre ambos tipos de acciones, en dependencia de los tipos o subtipos de IFN involucrados en cada etapa de la enfermedad, la presencia de otros patogenos y las relaciones con otras citoquinas.

Palabras clave: interferon, virus de la inmunodeficiencia humana, sindrome de inmunodeficiencia adquirida

The bad guy

The review article by Dianzani and Capobianchi (1) suggests a possible pathogenic role of interferons (IFN) in Human Immunodeficiency Virus (HIV) infection and the Acquired Immunodeficiency Syndrome (AIDS). They use mainly three kinds of arguments, mostly derived from their own experimental data.

1. HIV itself, HIV-infected cells and the envelope protein gp120 can induce acid-labile IFN, which consists in a mixture of glycosylated and unglycosylated IFN alpha subtypes and a small amount of IFN gamma. This IFN activity appears in the serum of AIDS patients and its concentration, as well as the levels of several IFN-response markers (neopterin, beta2- microglobulin) correlate with disease activity. Accordingly, other groups consider the IFN responses of HIV-positive patients as markers for monitoring progression of AIDS and therapy (2).

2. IFN alpha, despite and because its antiretroviral activity, can induce the selection of IFN-resistant strains in patients (3).

3. IFN gamma, enhancing adhesion molecules expression, can promote cell fusion and facilitate virus diffusion, even bypassing the CD4 receptor binding step (4).

HIV-seropositive patients, starting at the early stage of viral infection, generally have an increased percentage of lymphocytes potentially able to produce IFN gamma, compared with healthy blood donors. IFN gamma expression in patient lymphocytes increased with the progressive stages of HIV infection (8). IFN gamma synergizes with Tumor Necrosis Factor (TNF) action on HIV-1 expression and on apoptosis of HIV-1-infected promonocytic U937 cells and its persistently HIV-1-infected clone U1 (9).The effect of IFN gamma alone was negligible. This coordinate action of TNF alpha and IFN gamma could represent an important mechanism for disease progression in HIV infection. These findings demonstrate that cytokine effects on viral expression may vary depending on their single or combined application.

The good guy

Several experimental and clinical evidences, some of them referred in the above-mentioned review (1), indicate that IFN can be considered an HIV infection-limiting factor. IFN alpha has anti-retroviral activity in vitro (10). It inhibits both, virion production in persistently HIV- infected cell lines (11-17) and de novo infection (15). These effects have been demonstrated in lymphoid and monocytic cell lines (16, 18). Several steps of the virus replication cycle can be inhibited (19). When used for the treatment of AIDS-related Kaposi's sarcoma, IFN alpha shows antiviral effect, given by a decrease in serum viral p24 levels and reversal of positive HIV cultures (20, 21).

Constitutive, autocrine, low level IFN beta synthesis increased resistance to HIV-1 in transfected lymphocytes from healthy and HIV-infected individuals in a gene-therapy experimental model (22). The newly identified type I IFN tau has also shown anti-retroviral action on cultures of primary peripheral lymphocytes or monocyte-derived macrophages infected with HIV-1 isolates (23).

Recombinant IFN alpha-2b has been used in HIV seropositive, asymptomatic carriers in a long-lasting randomized trial (24). The IFN alpha-2b treated group had a significantly longer median time to disease progression: 147 (95 % confidence interval: 116 - 180) vs. 75 (67 - 83) months since infection. CD4 cell count decrease was prevented or at least significantly slowed down and serum p24 detection tests suggested that viral burden was reduced. Further follow-up of these patients (25) showed that IFN treatment prolonged survival since infection from 110 (101 - 120) to 140 (127 - 152) months. The IFN treated group had significantly more long-term survivors (23.4 vs. 3.6 %). Similar results were obtained in a parallel group of patients treated with natural leukocyte IFN alpha (26). Other groups have obtained comparable results with IFN alpha in smaller trials (27, 28) and even with oral IFN (29).

In some clinical trials, IFN alpha treatment had no beneficial effect (30- 32). They were probably too short-lasting. But there are no trials where IFN administration at any of the stages of HIV infection has been deleterious to the patients, which could be expected if IFN played a pathogenic role. Moreover, removal of the "abnormal" IFN present in HIV- infected patients did not improve their clinical or biological status (33).

There is little, if any, experience with IFN gamma in HIV-infection clinics. Some experimental data suggest that it can also have a protective effect during HIV infection and AIDS. IFN gamma has anti-HIV activity in monocytes (34). Both systemic (35) and aerosolized (36) IFN gamma are effective for the prophylaxis and treatment of Pneumocystis carinii pneumonia. Besides the well-known effect on alveolar macrophage activation, this action can be mediated by a decrease of the expression of lung cell surface alpha1beta5 integrins (37), necessary for the parasite's attachment. IFN gamma production in response to antigen challenge is impaired during advanced HIV infection as expected from the reduction in CD4 lymphocytes, which are its major producing cells (38), which contrasts with the increased production per cell mentioned before (8). HIV-infected patients with toxoplasmosis have significantly lower IFN gamma levels than non-HIV infected subjects even with more severe infection (39). A result in the same sense has been reported for Tuberculosis-bearing HIV-infected patients. Steady state mRNA for IFN gamma was decreased in HIV-positive when compared with HIV-negative patients with Tuberculosis, as part of their limited CD4 alveolitis which impairs an effective immune response (40). Additionally, IFN-gamma can restore the cell-mediated immunity of asymptomatic HIV positive individuals in vitro, while anti-IFN gamma antibodies present in the sera of patients with AIDS interfere with the activity of the lymphokine (41).

What to interfere with? That is the question

Interferons were named so for their property to interfere with viral replication and infection (42). This property has been generalized to almost all kinds of virus, including retrovirus (10). On the other hand, arguments by Dianzani and Capobianchi (1) and others (5-9) suggest that IFN, both type I and II, interfere with host defense mechanisms against HIV. Both points of view may be correct.

The IFN that appears in the serum of AIDS patients, despite its antiviral activity against the RNA viruses used for its quantification, has no anti- HIV activity in vitro (43) or in vivo (33). Its induction could be a way to avoid the regulatory action of "good" IFN alpha (probably alpha-2 and other major natural subtypes) upon virus replication. Coincidentally, IFN alpha induction by HIV seems to follow a different mechanism from induction by double-stranded RNA virus, at least in monocytes and macrophages (44).

Another factor that has to be considered to explain the apparent experimental duality is the cytokine environment. Cytokine effects on viral expression may vary depending on their single or combined application, as was mentioned above (9). In the clinics, the cytokine environment will vary with the stage of the disease, CD4 cell count, presence of other pathogens, and other factors. The balance of positive and negative effects will determine the overall effect: whether IFN treatment is beneficial or not for HIV-infected subjects.

In the successful clinical trials the more highly significant difference between IFN-treated and control subjects was obtained in the proportion who developed mild complications (minor opportunistic infections or reversible general or neurological symptoms) (24), which can indicate that IFN alpha is more beneficial at the early stages of infection. This is also supported by evidence such as that NK effector cells from earlier HIV-infected homosexual men were better stimulated by IFN alpha than cells from longer- term infected subjects (45). The use of IFN alpha in more advanced disease, mainly in combination with anti-retroviral chemotherapy, has reported little (46) or no success at all (47, 48).

The answers to the questions posed here need further basic research to elucidate the molecules and mechanisms involved. Finally, controlled clinical trials will say the last word.

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