Acquired Immunodeficiency Syndrome (AIDS) Key Discoveries

The National Cancer Institute has assumed a leading role in Acquired Immunodeficiency Syndrome (AIDS) research since the disease was first recognized in 1981. Because of the research programs and administrative mechanisms already in place, investigators were able to rapidly apply existing methods in drug screening and advances in cancer virus research technology to the study of AIDS. The large scale preparation of HIV-1 in permanent cell lines led to the development of a serological test for AIDS which enabled the detection of AIDS in our nation's blood supply. Detection of the virus in latent form has been established through the in situ hybridization method which allowed scientists to detect the virus in brain and blood cells, T lymphocytes and macrophages. Recent key discoveries, by NCI investigators include:

• Development, testing and successful clinical trials of the drugs azidothymidine (AZT), dideoxyinosine (ddI) and dideoxycytidine (ddC), confirming their effectiveness as anti-retroviral agents against AIDS.

• Progress in treating children with AIDS has occurred through the rapid introduction of antiretroviral agents into clinical trials. The studies performed by the Pediatric Branch contributed to the licensure of AZT for children in May of 1990 and dideoxyinosine (ddI) in October 1991. The latter, based solely on Pediatric Branch Studies, occurred simultaneously with licensure for adults, a historical event. The Pediatric Branch is currently completing studies of combination regimens to optimize activity (e.g., AZT plus ddI) as well as to offset toxicity (e.g., AZT plus G-CSF and erythropoietin).

• Viral particles are detectable in plasma throughout the early stages of primary infection. The number of viral particles in plasma decrease by up to 200-fold following the initial viremia of primary infection. NCI scientists have documented that changes in the titer of viral particles seem to monitor disease progression, with increasing viral particles detected as the infection moves from the asymptomatic phase in AIDS-related complex (ARC) or full blown AIDS. The increase in viral particles bears an inverse relationship to CD4 count. Scientists at NCI and elsewhere have adapted Polymerase Chain Reaction (PCR) technology to detect and quantitate the amount of HIV-1 RNA present in plasma. Thus, the RNA-PCR assay may provide a sensitive marker of response to therapy.

• There is evidence that HIV from patients on long-term AZT therapy which has become resistant to AZT remains sensitive to ddI and ddC. NCI investigators have studied the phenotypic and genotypic changes of HIV-1 strains isolated from 9 patients before and after prolonged therapy with either an alternating regimen of AZT and ddC or ddI alone. From these studies, it appears that HIV-1 develops reduced susceptibility of AZT more readily than to ddC and ddI. Moreover, an alternating regimen of AZT and ddC does not block the emergence of AZT-resistant HIV-1 variants. NCI scientists will initiate a study examining a new combination of AZT and a new purine analog, PMEA, by early 1994. PMEA possesses activity against both RNA and DNA viruses, inhibiting both HIV reverse transcriptase and DNA polymerase-alpha from CMV and other herpesviruses, and may exert its inhibitory effects on latent as well as replicating HIV, with perhaps a special activity against the HIV reservoir in monocytes/macrophages.

• Identification through the high-capacity AIDS drug screen of many new compounds which are active against the AIDS virus in tissue culture experiments. These compounds include both synthetic drugs and natural products. Several of these are in the initial phases of development.

• Determination of the first crystal structure of retroviral protease and its successful use to predict the structure of the HIV protease and substrate using supercomputer methodology. HIV protease is an enzyme whose action is required in the processing of HIV proteins and production of infectious virions. NCI scientists have identified several inhibitors of the HIV protease including KNI-272 which has exhibited potent anti-HIV activity and favorable pharmacokinetics in test animals. Following the completion of ongoing pharmacology and toxicology, NCI scientists plan to implement clinical trials of KNI-272.

• Growth hormone (GH) and insulin-like growth factor (IGF)-1 are critical for normal T cell development within the thymus. GH-deficient dwarf mice have marked thymic hypoplasia and deficiency in T progenitor cells. Treatment of these mice with GH leads to T cell reconstitution within the thymus. In the severe combined immunodeficiency (SCID) mouse model reconstituted with human peripheral blood cells, GH and IGF-1 lead to increased numbers of lymph node and thymic CD4 cells and may promote immunoreconstitution by enhancing overall thymic function. Clinical trials combining GH and/or IGF-1 with AZT and ddI are underway in adults and children with severe HIV infection. Measurement of GH and/or IGF-1 induced changes in CD4+ cell number and function and immunologic parameters is an integral part of this study.

• The CD4 AIDS virus receptor on the surface of human T-cells has been found to be physically associated with a proto-oncogene known as p56lck, the protein product of which is a tyrosine-specific kinase. The efficacy of daily intramuscular injections of recombinant CD4 in preventing progression of simian AIDS in rhesus monkeys has been demonstrated. This protein may be useful as a therapeutic agent for the treatment of human AIDS.

• HIV-infected cells may release biologically active Tat, the protein product of the tat gene, which can be taken up by cells in close proximity and induce cell proliferation, viral transactivation and perhaps other toxic effects. In particular, scientists have learned that the tat gene can trigger the AIDS virus to replicate at an increased rate. Thus, manipulation of the tat gene could lead to control of the growth of the virus.

• Individuals infected with HIV may be asymptomatic for years before progressing to overt AIDS. Since monocytes possess surface CD4 molecules, they can bind and act as a reservoir for HIV in infected individuals. Latently infected monocytoid THP-1 cells and freshly isolated adherent monocytes from asymptomatic seropositive individuals did not show detectable viral expression until they are co-cultured with activated T cells from HIV-negative normal donors. Cell-cell contact is required and seems to induce factor(s) in monocytes capable of overcoming latency. Thus, monocytes in AIDS patients can harbor latent HIV inducible by T cells during an immune response. HIV produced by such monocytes infects T cells leading to viral-induced pathology. In addition to monocytes, NIAID scientists determined that follicular dendritic cells (FDC) also serve as reservoirs for latent HIV infection, sequestering HIV for eventual transmission to CD4+ cells.

• The magnitude of CNS disease is often more prominent and the latency period which precedes HIV-related encephalopathy shorter in children than in adults, suggesting that fetal or developing brain cells (in particular, glial cells) may release cytokines capable of activating expression of latent HIV. To address the pathogenesis of neurologic disorders in HIV-1 infected children, NCI scientists have developed an in vitro model using a normal fetal olfactory neuroblast cell line, to investigate the potential contributions of direct viral infection and virally-induced cytokines in glial (and perhaps other accessory) cells to neurodevelopmental impairment.

• NCI epidemiologists have played a major role in uncovering the emergence of a new peak of tuberculosis (TB)-associated death in young individuals (ages 20-49) that appears linked to AIDS.

• Recent studies of vaginally-delivered multiple birth cohorts in HIV-infected women demonstrate that HIV transmission is greatest for the first-born infant, suggesting that some component of HIV transmission occurs at the time of the delivery in the cervix or vagina.

• Immunoepidemiologic studies have found that humoral immunity (i.e. antibody) directed against the HIV envelope glycoprotein gp120 in the mother protects against the risk for maternal-fetal transmission. Now, the protective contributions of cellular immunity have also been uncovered, using the T helper lymphocyte test. This HIV-specific T-cell immunity appears to occur very early in HIV infection and has been found in approximately 50 to 60 percent of seronegative individuals in high-risk populations (homosexual men, IVDUs, HIV-exposed health care workers), many of whom have not yet seroconverted after two years' follow-up, suggesting that T-cells are capable of mediating immune protection. In addition, NCI scientists have now found that neutralizinag antibody to the envelope protein, gp41, confers protection agaisnt maternal-fetal transmission.

• Sequential studies have now defined critical peptides that elicit distinct T-cell and B-cell (especially neutralizing antibody) responses and identified those peptides recognized by multiple histocompatibility antigens. NCI scientists have now developed two new prototype synthetic vaccines consisting of broadly- recognized histocompatibility determinants of T helper cells (so-called "cluster peptides") and a combined site constructed to elicit both cytotoxic T lymphocytes (CTL) and neutralizing antibody.

• NCI scientist have constructed novel vaccines comprised of various recombinant and live vectors (attenuated vaccinia, avipox, and Salmonella typhimurium) carrying HIV-1, HIV-2 and SIV antigenic proteins or protein units. These constructs are now being tested in rhesus macaques for their efficacy as initial immunogens, followed by "boosters" using purified native or viral antigens, in eliciting protective immune responses. In particular, the potential of an orally-administered recombinant Salmonella-based vaccine incorporating HIV-2 gag and env genes to confer protection from HIV-2 infection is under investigation in both mice and primates. Early results indicate that the recombinant Salmonella-viral antigen constructs are able to induce MHC class I-restricted CD8+ CTL that are directed against both Gag and Env proteins in both animal models. Other recombinant constructs coupling vaccinia virus vectors to various HIV antigens have also been shown to induce virus-specific cellular and humoral responses in primates, thus suggesting that vaccinia vectors may also be promising delivery systems for an HIV vaccine.

• Eukaryotic recombinant expression vector systems, in particular the baculovirus-insect cell and metallothione promoter vector systems, HIV, simian immunodeficiency virus (SIV), and proviral molecular clones of bovine immunodeficiency virus (BIV), are being used to engineer novel noninfectious pseudovirons. These virus-like particles are designed to contain Gag proteins, Gag-Pol-Env, or Gag and a combination of T- and/or B-cell reactive virus Env epitopes (e.g., primary neutralizing and/or fusion domains) or immunomodulators (e.g., IL-2).

• The bovine immunodeficiency-like virus (BIV) is a unique member of the lentivirus subfamily of retroviruses. Chronic infection in specific pathogen-free rabbits (Oryctolagus cuniculus) has been established with a natural isolate or progeny of an infectious molecular clone of BIV. The infection results in a rapid and sustained BIV-specific humoral response suggesting that infection is targeted to cells of the immune system.

• NCI investigators have put the poly Tat activation region (TAR) which binds to the viral regulatory protein, Tat, into the HIV promoter, thereby inhibiting viral replication. Since binding of Tat to TAR is necessary for RNA expression and viral replication, the polymeric TAR (poly TAR) provides a molecular decoy which inhibits viral replication. Cultures containing the protected cells show a gradual decline in virus production that reaches 90% in two months. Six months after infection the protected cell cultures express little detectable virus and are resistant to reinfection. Poly TAR appears to be an effective antiviral gene that may have eventual clinical application as a gene therapy modality.

• A glycoprotein growth factor known as Oncostatin M, derived from activated T-cells, is a potent growth stimulator for AIDS-KS cells. This growth factor is distinct from other important cytokines in AIDS-KS, namely IL-6 and the HIV Tat protein, but binds to the active subunit of the IL-6 receptor. Oncostatin M appears to cause AIDS-KS cell proliferation both directly and in part by enhancing the expression of IL-6 by vascular endothelial cells, and further induces morphologic changes in AIDS-KS cells, namely to the spindle configuration of smooth muscle cells.

• The striking production of autostimulatory and angiogenic growth factors by KS cells suggest that these factors should be an important target for therapy. In the past year, Phase I clinical trials were begun on a new inhibitor of angiogenesis, Fumagillin, and its synthetic analog, TNP-470.

• NCI scientists have found a non-cytotoxic bacterial product, a sulfated polysaccharide-peptidoglycan compound (SP-PG) which inhibits the growth and vascular responses, in particular the induction of angiogenesis and hyperpermeability, of AIDS-KS spindle cells in vitro and in a nude mouse model.

• Profound cellular immunodeficiency plays a central role in lymphomagenesis, as evidenced by the striking relationship between the depletion of CD4 lymphocytes and the development of NHL, particularly when the CD4 count falls below 50/mm3. NCI investigators are expanding the clinical data and laboratory correlates generated from the continuing follow-up of the original AZT-treated AIDS cohort (8 of the 55 of whom developed NHL a median of two years after AZT institution) and similar observations in 61 ddI- treated AIDS patients. In the AZT-treated cohort, there is roughly a 30 percent chance of developing NHL within three years. The most important risk factor determinant for both the AZT- and ddI-treated cohort/s is a CD4 count below the critical level of 50/mm3.

• The remarkable occurrence of high-grade B-cell, non-Hodgkin's lymphomas (NHL) has recently emerged as a major sequela of HIV infection, especially in patients who survive other consequences of AIDS in a protracted state of profound immunosuppression. NHLs develop in approximately 10 percent of AIDS patients treated with dideoxynucleosides. NCI investigators have developed a "lymphoma subpanel" comprised of two AIDS lymphoma cell lines including an EBV+ Burkitt's lymphoma, and eight non-AIDS lymphoma cell lines for screening potential therapeutic compounds.

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