JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH 11:747–749 (2002)© Mary Ann Liebert, Inc.

Guest Editorial

Targeting HIV: The Urgency for Novel Therapeutics

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THIS SPECIAL ISSUE of the Journal of Hematotherapy& Stem Cell Research focuses on the advances that

have been made in the cellular and genetic therapy of hu-man immunodeficiency virus type-1 (HIV-1) infectionand acquired immunodeficiency syndrome (AIDS). Weare also honoring the significant contributions that Dr.Robert Gallo has made in advancing our understandingof HIV immune pathogenesis and developing novel ther-apeutic strategies for targeting HIV-1 infection andAIDS. A highly enlightening and interesting correspon-dence from Dr. Gallo is supported by an authoritative anddetailed investigator profile of him. In these articles, Dr.Gallo exquisitely describes his historical and current re-search interests. Dr. Gallo also alludes quite elegantly tothe future directions of his institute as well as authorita-tively discussing the currently available and potentialtherapeutic options for targeting HIV and AIDS.

This special focus issue of the Journal also includesan invited college of internationally renowned contribu-tors. Leaders in their field have written insightful andthought-provoking overviews and cutting-edge articlesthat collectively enhance our understanding of HIV im-mune pathogenesis. Moreover, these contributions placeinto context means by which HIV and AIDS-associateddiseases could be targeted for therapeutic gain.

Dr. Gallo has arguably been one of the most influen-tial and productive scientists in the field of human retro-virology and HIV research in the last 21 years. Indeed,among his seminal contributions to the literature aremany classics in the field of human retrovirology.Throughout his career, he has studied the basic biologyof normal and abnormal (leukemic) human blood cellgrowth and development. However, it was his indepen-dent co-discovery of HTLV-IIIB, now called HIV-1, asthe etiologic agent of AIDS in 1984 that brought him andhis group international recognition for this major break-through (1–4). The identification of HIV-1 followed hisearlier discovery of the first human retrovirus (HTLV-1)that was also shown to cause a subtype of human leuke-mia (5). A year after this seminal discovery, he and hisgroup discovered HTLV-II, the second known humanretrovirus (6).

Since the discovery of HIV-1 by Dr. Gallo and his col-

leagues, the global pandemic of HIV infection and AIDShas reached horrific proportions. The scope of the prob-lem is worse now than it has ever been. In more than the40 years that HIV has plagued the adult and infant hu-man population, well over 16 million deaths have re-sulted. Approximately 16,000 humans are infected withHIV every day. Further, it is estimated that 1 in every100 adults between the ages of 15 and 49 is infected withHIV across the globe. This represents a staggering 45million people worldwide (7). The vast bulk of these newinfections occur in sub-Saharan Africa, where in somecountries, nearly 50% of the adult population is infected.

The hallmark of infection with HIV-1 and the onset ofAIDS is the persistent and aggressive decline in bothnumbers and function of CD41 T helper lymphocytesthat orchestrate the immune response to combat infectionas well as malignant tumors. Because the immune sys-tem loses the ability to mount a significant antiviral re-sponse, viral replication outpaces the ability of the hostimmune system to thwart it and the syndrome known asAIDS ensues. The development of AIDS thus dramati-cally compromises the immune system and exposes theinfected host to a plethora of opportunistic protozoan,bacterial, fungal, and viral infections that are frequentlycomplicated by the development of AIDS-associated malignancies (lymphomas, cervical carcinoma, Kaposi’ssarcoma) and AIDS-associated neuropathies.

Therapeutically combating HIV-1 alone is in itself adaunting task without the added problem of opportunis-tic infections and AIDS-associated diseases. The life cy-cle of the virus is such that antiretroviral drugs can the-oretically be designed to interrupt all pathways thatpermit genomic integration and replication of the virusonce it has infected a susceptible population of cells.However, the most effective antiretroviral drugs are lim-ited to those that interfere with active viral replication.The depressing fact is that despite combination therapywith antiretroviral drugs and the initial excitement thatsurrounded the use of highly active antiretroviral ther-apy (HAART) to eliminate the virus, life expectancy ofthe patient can realistically be extended by only a fewyears. The reason for this is that the dose-limiting tox-icity of antiretroviral drugs and the emergence of drug-

resistant mutations of HIV compromise the benefits oftherapy.

The emergence of HIV resistance is not assisted by thehighly variable practices that exist in administering anti-retroviral therapy. One school of thought may advocateaggressive and early treatment while another would ad-vocate longer-term approaches. The objective with earlytherapy is the suppression of AIDS-related viremia as ag-gressively as possible. This approach suffers from theside effects that it imparts as well as promoting the emer-gence of resistance. Thus, it is apparent that the require-ment for novel therapeutic strategies to combat HIV in-fection and AIDS-associated diseases has never been sourgent. With this factor in mind, there are alternatives orcomplementary approaches that are currently being con-sidered and adopted. These include delayed initiation oftherapy, structured-treatment interruption (STI) and itscousin pulsed-therapy, protease-sparing therapy, classsparing, and frequent switching of antiretroviral drugtherapy.

It should be noted that despite over 15 years of effort,there is still no cross-protective vaccine in use today, al-though promising candidates are on the horizon. The abil-ity of HIV to evade, subvert, and consequently annihi-late the immune system has collectively thwartedattempts to stimulate an effective anti-HIV immune re-sponse. Clearly, much remains to be understood con-cerning the immune pathogenesis of HIV infection andthe mechanisms of HIV-mediated subversion of host im-munity and drug resistance. Although antiretroviral ther-apy-mediated suppression of HIV-1 is in part effectiveand results in some immune reconstitution, the compli-cations associated with such therapy warrant the urgentrequirement for alternative strategies.

I believe that there is scope for optimism. Novel im-muno-, hemato-, and gene-therapeutic approaches are be-ing considered in the elusive quest for a curative thera-peutic protocol to target drug-resistant HIV or diseasesassociated with AIDS. It is plausible that such novel ap-proaches may be applied as complementary strategies tostructured treatment interruption in an attempt to provokeimmunological rebound and reconstitution followingstructured or pulsed cessation of antiretroviral therapy(8,9). However, as Dr. Gallo points out in his investiga-tor profile, therapeutic approaches that take advantage ofso-called “treatment vacations” should be consideredwith caution.

In this issue of the Journal of Hematotherapy & StemCell Research, Dr. David Scadden, Harvard MedicalSchool, reviews important factors that affect immune re-constitution. He discusses the challenges that lie ahead iffull immunological reconstitution is to be achieved andthe potential hematotherapeutic approaches that could beconsidered to augment the endogenous hematopoieticsystem following HIV infection and intensive use of an-

tiretroviral drugs. Dr. Pierre Cordelier and co-workersfrom Jefferson Medical College describe a gene-thera-peutic approach. This system incorporates a novel SV40-based vector to instruct the synthesis of human interferon-a2 (IFN-a2) by incorporating a virus-transactivatedhuman IFN-a2 gene that is transcribed in response to HIVinfection. The targeted expression of this cytokine maysuppress HIV replication and thus represents a novel ther-apeutic strategy. Continuing the gene therapy theme, Dr.Amrita Krishnan and co-workers from City of Hope Na-tional Medical Center describe their experiences and survey the literature with regard to gene therapeutic ap-proaches in conjunction with myeloablative chemother-apy and autologous peripheral blood progenitor celltransplant for targeting HIV-related non-Hodgkin’s lym-phoma. Similarly, Dr. Elizabeth Kang et al. (NIDDKD,NIH) describe their experience with a nonmyeloablativeconditioning chemotherapy and allogeneic transplanta-tion using gene-modified hematopoietic progenitor cellsto target HIV infected patients with a hematological ma-lignancy.

Of particular interest are the reviews of Dr. Terry Fryand Dr. C. Mackall from the National Cancer Institute(NIH), who discuss the role of the thymus and the novelimmune-modulatory cytokine interleukin-7 (IL-7) in im-mune reconstitution and T cell regeneration followingcombinatorial antiretroviral therapy. Similarly Dr. LenaAl-Harthi and Dr. Alan Landay provide a timely reviewof the phenomenon of immune recovery in HIV infec-tion and the role of the thymus and of newly emigratingT cells in strategies aimed at achieving long-term main-tenance of immune reconstitution. Finally, Dr. RichardKornbluth, University of California at San Diego, pro-vides a detailed and unique survey of the importance ofCD40 ligand (CD40L), and he elegantly describes somenovel applications of CD40L constructs. His reviewmakes clear that CD40L is an important molecule foractivating antigen-presenting cells and thereby initiat-ing the immune response. Because CD40L contributesto the antiviral mechanisms of the host by inducing anti-HIV b-chemokines and by activating CD81 T cells, Dr. Kornbluth discusses the hypothesis that reversingthe relative CD40L deficiency that is seen in HIV in-fection could be beneficial.

The studies published in this issue highlight the piv-otal role that the hematopoietic system plays in combat-ing HIV infection. Strategies for promoting and sustain-ing immune reconstitution are certainly needed asantiretroviral therapy alone is clearly insufficient. Thereare numerous alternative strategies being developed thatwill result in more effective treatment outcomes of thedisease in the foreseeable future. The answer, at least inpart, lies in harnessing the potential of the hematopoieticsystem and manipulating cells derived from it for thera-peutic gain. Important questions that have been raised

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and answered during the past two decades are beginningto provide additional clinical advances in the manage-ment of HIV infection and AIDS. The contributed man-uscripts in this special issue of the Journal highlight togood effect some of the encouraging and impressive ad-vances that have been made.

REFERENCES

1. Popovic M, MG Sarngadharan, E Read and RC Gallo.(1984). Detection, isolation, and continuous production ofcytopathic retroviruses (HTLV-III) from patients with AIDSand pre-AIDS. Science 224:497–500.

2. Gallo RC, SZ Salahuddin, M Popovic, GM Shearer, M Kap-lan, BF Haynes, TJ Palker, R Redfield, J Oleske, B Safai,G White, P Foster and PD Markham. (1984). Frequent de-tection and isolation of cytopathic retroviruses (HTLV-III)from patients with AIDS and at risk for AIDS. Science224:500–503.

3. Schupbach J, M Popovic, R Gilden, MA Gonda, MG Sarn-gadharan and RC Gallo. (1984). Serological analysis of asubgroup of human T-lymphotropic retroviruses (HTLV-III)associated with AIDS. Science 224:503–505.

4. Sarngadharan MG, M Popovic, L Bruch, J Schupbach andRC Gallo. (1984). Antibodies reactive with human T-lym-photropic retroviruses (HTLV-III) in the serum of patientswith AIDS. Science 224:506–508.

5. Gallo RC. (1981). Growth of human normal and leukemicT cells: T-cell growth factor (TCGF) and the isolation of anew class of RNA tumor viruses (HTLV). Blood Cells7:313–329.

6. Kalyanaraman VS, MG Sarngadharan, M Robert-Guroff, IMiyoshi, D Golde and RC Gallo. (1982). A new subtype ofhuman T-cell leukemia virus (HTLV-II) associated with aT-cell variant of hairy cell leukemia. Science 218:571–573.

7. Henry K. (2000). The case for more cautious, patient-fo-cused antiretroviral therapy. Ann Intern Med 32:306–11.

8. Zinkernagel, R. (2000). What is missing in immunology tounderstand immunity? Nature Immunol 1:181–185.

9. Montaner LJ. (2001). Structured treatment interruptions tocontrol HIV-1 and limit drug exposure. Trends Immunol.22:92–96.

Address reprint requests to:Dr. Marc Adrian WilliamsDepartment of Neurology

The Neuromuscular Research LaboratoryJohns Hopkins University School of Medicine

600 North Wolfe Street, Meyer 5-119Baltimore, MD 21287

Tel.: (410)-614-4205Fax: (410)-955-1961

E-mail: mawilliams888@aol.com

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