Overview of IL-7 in the Treatment of HIV

Keeping in mind the growing body of evidence from basic immunology, preclinical models and, more recently, from early clinical studies, it is becoming increasingly evident that IL-7 may play a unique role in the functioning of the immune system and especially in providing the right T-cells in sufficient numbers to support and improve specific immune responses against infectious agents and malignant T-cells. In that light, as with EPO for red blood cells and G-CSF for neutrophils, IL-7 plays a pivotal role in supporting T-cell expansion and function.

This broad activity of IL-7 leads to the consideration of its role in the restoration of the immune system and the prevention of opportunistic infections in patients who develop severe lymphopenia, such as in HIV infection, or in the control of chronic viral infections such as HIV and HCV.

Infection by Human Immunodeficiency Virus-1 (HIV-1), transmitted sexually or parenterally, remains a frequent and serious chronic condition with more than 33.2 million adults and children living with HIV worldwide, according to the Joint UN Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO), AIDS Epidemic Update (2007).

In North America, Western and Central Europe, the total number of people living with HIV is increasing. This increase is due mainly to the life prolonging effects of antiretroviral therapy and an increase in the number of new HIV diagnoses in Western Europe since 2002, combined with a relatively stable number of new HIV infections each year in North America. Overall, approximately 2.1 million [1.1 million–3.0 million] people in North America, Western and Central Europe were living with HIV in 2007, including the 78 000 [19 000–86 000] who acquired HIV in the past year. In the context of widespread access to effective antiretroviral treatment, comparatively few people died of AIDS—32 000 [20 000–84 000] in 2007.

The demographics of the HIV infected population is rapidly changing, with the average age of HIV patients increasing, Although there are a larger percentage of older patients acquiring the disease, which partially accounts for this changing demographic, the key reason is the longer life expectancy for HIV/AIDS patients, moving HIV into the chronic disease category.

Before Highly Active Antiretroviral Treatment (HAART), the time between infection and death was estimated to range from eight to 13 years; however, now patients can expect a life expectancy equivalent to that of the general population. The advent of HAART has led to a substantial decrease in the mortality rate from AIDS, estimated to have fallen by 70% between 1995 and 2001 with survival rates now believed to be as high as 91%. (Datamonitor).

IL-7, HIV and CD4 T-Cells

However with longer life expectancy come increasingly complex infections, with resistance development common in patients undergoing long-term HAART therapy. As patients become more treatment-experienced, key factors such as dosing frequency and side effects become increasingly vital to compliance and therefore, prescription decisions.

Of particular importance in warding off infection is the key role of T-cells and of keeping CD4+ counts above 400, a factor clearly associated with longer life-expectancy and opening a key therapeutic role to IL-7 therapy.

HIV chronically infects CD4+ T-cells, macrophages and rare targe T-cell populations that bear CD4+, the main receptor for HIV, as well as a co-receptor belonging to the chemokine receptor family. In the vast majority of the patients, HIV replicates actively, at least in CD4+ T-cells, and numerous HIV RNA copies can be detected in plasma. Most HIV clinical manifestations are closely related to the depletion of CD4+ T-cells, the patho-physiological hallmark of the disease.

In blood and lymph nodes, this depletion, caused by a direct effect of HIV or by indirect mechanisms, appears to worsen gradually. A median time of 10 years after the primo-infection, but sometimes after only a few months, in the absence of HAART therapy, the CD4+cell count decreases below 200 CD4+ cells/mm3. Below this threshold, with the disappearance of many antigen specific CD4+ and CD8+ T-cell responses, the life of the patient is threatened by the occurrence of opportunistic infections or other events, notably specific tumors often driven by latent viral infections, but also by neurologic complications or wasting. These complications define AIDS in the WHO classification.

In most patients, HAART therapy effectively suppresses HIV replication and maintains or restores a CD4+ cell count above 200 to 400 CD4+ cells/mm3, and the prognosis of HIV infection is markedly improved. However this treatment does not solve the major medical issues, even in patients who respond optimally, as discussed below.

Pathogenesis of HIV Infection

Two key aspects of the HIV infection pathogenesis remain widely debated:

The relationship between infection and lympho-depletion;
The immune mechanism that explains the infection’s persistence.

Numerous studies including recent observations conducted in SIV infected macaques and in HIV infected patients allowed for a better understanding of the virological and immunological abnormalities that occur at different phases of the infection.

HAART which usually combines a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor with 2 nucleoside analogs was introduced around 1996. It markedly improved patient prognosis, enabling in the majority of patients both to control HIV replication and to maintain or restore a CD4+ cell count above 200, and in the majority cases, to 350 CD4+ T-cells/mm3. A few months after this restoration, prophylaxis for opportunistic infections can be stopped, a protective immune response against opportunistic pathogens being reconstituted. However, responses against common pathogens and normal CD4+ T-cell counts (≥ 500/ mm3) are not always restored. Furthermore, several major issues are not solved by these treatments as discussed below.

Immunological or Viral Failures:

Some patients, often called Immunological Non Responders (INR), despite complete control of HIV replication, do not achieve sufficient restoration of their CD4+ T-cell count, which remains below 200 CD4+ cells/mm3 6 months or more after the initiation of the triple therapy. INR represents at least 5% of the treated population, the prevalence of which depends on the definition criteria which are used to characterize them. As shown in large cohorts, the risk of disease progression or death is significantly higher when compared to patients who achieve better T-cell restoration.
Other patients representing 5% of the population or less fail globally to respond to HAART, both virologically and immunologically. The HIV RNA load in circulation remains high and thus the CD4+ T-cell pool continues to decline. Such failure usually corresponds to the selection over time of HIV mutants that are resistant to anti-retroviral drugs.
Patients who are diagnosed late and develop an AIDS classifying event remain at risk for immunodeficiency complications several months after initiation of the HAART treatment, despite rapid control of HIV replication, the tempo of the immune-reconstitution being relatively slow

Co-Infection by Other Viruses

Chronic co-infection by other viruses is still a source of additional complications which may or may not qualify as AIDS:

Nearly 25% and 5% of HIV patients are co-infected by Hepatitis C Virus (HCV) and Hepatitis B virus (HBV), respectively. Most of them develop chronic hepatitis which is often more aggressive than in non-HIV patients. Furthermore, the reference therapies are often poorly tolerated and less effective, inducing, for instance, in HCV co-infected patients, a sustained viral response in less than 40% of the cases. After a few years, these patients may develop cirrhosis and its complications.
Virtually all the adult HIV patients are co-infected with Epstein Barr Virus (EBV). The latter is involved in the pathogenesis of Hodgkin’s disease, which is more frequent in HIV patients and can occur in the setting of moderate lymphocytopenia. Furthermore, in patients with severe depletion of CD4+ T-cells, EBV onco-proteins expressed by B cells which escape T-cell check can drive the development of many lympho-proliferative disorders regarded as AIDS defining complications.
Other viruses are also involved in the development of AIDS-qualifying tumors and diseases. For instance, Human Herpes Virus 8 (HHV-8) is pivotal in the development of Kaposi’s sarcoma and some latent papillomaviruses drive the development of cervical cancers. Furthermore, these papillomaviruses also foster the occurrence of anal cancers and, possibly other malignancies, which are not considered AIDS classifying events.

Chronicity of HAART Treatment

The vast majority of the HAART treated patients never develop effective HIV specific CD4+ and CD8+ T-cell responses, despite optimal control of HIV replication and the recovery of a nearly normal CD4+ T-cell count. HIV infection cannot be eradicated by these treatments and remains a chronic infection. Importantly, HIV infects “latent reservoirs” such as quiescent memory T-cells and macrophages, representing a source for renewed viral replication following cessation of therapy. HAART should be administered throughout a patient’s life time and immune and viral status monitored closely, an obviously costly and constraining activity. Furthermore, some patients remain poorly compliant on these treatments resulting, due to their intermittent observance, in the development of HIV resistant mutants.

Toxicity of anti retroviral drugs is also not negligible, with their long term administration leading notably and frequently to the development of lipo-dystrophic syndrome, hyperlipidemia, hyperglycemia or metabolic syndrome, and bone disorders, mainly osteoporosis and osteonecrosis. An increased risk of cardio-vascular complications may also be fostered by HAART-induced metabolic disorders.

Potential Indications of IL-7 in HIV Infected Patients

IL-7 is a physiological immuno-enhancer which fosters restoration of T-cells in lymphopenic patients and improves T-cell responses against chronically expressed antigens.

IL-7 quantitative and functional effects make it a promising drug which could potentially address, in HIV infected patients, several of the unmet medical needs mentioned above. Furthermore, numerous recent studies highlight the importance of IL-7 pathway impairment in the pathogenesis of Simian immunodeficiency virus (SIV) infected monkeys or HIV infected patients.

At least 2 potential indications of IL-7 should be explored, both corresponding to unmet medical needs:

To rescue patients who experience immunological failure on HAART. IL-7 will likely improve recovery of CD4+ T-cells in patients who remain lymphopenic under HAART, while HIV replication is at least partly suppressed. Despite recent progress, morbidity and mortality of these patients remain higher than in patients who better restore their cell immunity. IL-7 deserves to be investigated as a drug to treat the true INR patients, but also patients with sub-optimal CD4+ T-cell recovery and slight residual viral load.
To overcome the usual limitations of HAART, observed in nearly all treated patients, including the persistent insufficiency of the anti HIV T-cell response, leading to life-long, relatively toxic, constraining and costly anti-retroviral treatments; IL-7, as a stand-alone therapy or combined with anti-HIV therapeutic vaccines, may be developed to delay or spare HAART. Furthermore, the improvement of the anti HIV T-cell response by IL-7 may decrease the viral load and slow down CD4+ T-cell decline after structured anti-retroviral therapy interruption.