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US20030091987A1 - Materials and methods for detecting, preventing, and treating retroviral infection - Google Patents

Materials and methods for detecting, preventing, and treating retroviral infection Download PDF

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US20030091987A1
US20030091987A1 US10/080,772 US8077202A US2003091987A1 US 20030091987 A1 US20030091987 A1 US 20030091987A1 US 8077202 A US8077202 A US 8077202A US 2003091987 A1 US2003091987 A1 US 2003091987A1
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Prior art keywords
fiv
protein
hiv
fragment
human
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Janet Yamamoto
Jennifer Janelle
Barbara Torres
Maki Arai
Taishi Tanabe
Ruiyu Pu
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University of Florida Research Foundation Inc
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Assigned to FLORIDA, UNIVERSITY OF reassignment FLORIDA, UNIVERSITY OF ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YAMAMOTO, JANET K., PU, RUIYU, ARAI, MAKI, TANABE, TAISHI, TORRES, BARBARA AUREA, JANELLE, JENNIFER WHITE
Assigned to UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC. reassignment UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF FLORIDA
Publication of US20030091987A1 publication Critical patent/US20030091987A1/en
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF FLORIDA
Priority to US12/407,730 priority patent/US8182820B2/en
Priority to US13/476,835 priority patent/US20120294891A1/en
Priority to US14/511,864 priority patent/US11154610B2/en
Priority to US17/444,242 priority patent/US20210386851A1/en
Abandoned legal-status Critical Current

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Definitions

  • FeLV feline leukemia virus
  • FeSV feline sarcoma virus
  • RD-114 endogenous type C oncoronavirus
  • FeSFV feline syncytia-forming virus
  • FeLV is the most significant pathogen, causing diverse symptoms including lymphoreticular and myeloid neoplasms, anemias, immune-mediated disorders, and an immunodeficiency syndrome that is similar to human acquired immune deficiency syndrome (AIDS).
  • AIDS human acquired immune deficiency syndrome
  • FeLV-AIDS a particular replication-defective FeLV mutant, designated FeLV-AIDS, has been more particularly associated with immunosuppressive properties.
  • feline T-lymphotropic lentivirus now designated as feline immunodeficiency virus, FIV
  • FIV feline immunodeficiency virus
  • FIV infection of cats is now considered to be a better feline AIDS model than FeLV-FAIDS.
  • FIV virus subtypes can be classified according to immunotype based on the level of cross-neutralizing antibodies elicited by each strain (Murphy and Kingsbury, 1990). Recently, viruses have been classified into subtypes according to genotype based on nucleotide sequence homology.
  • FIV subtyping is based on genotype (Sodora et al., 1994; Rigby et al., 1993; and Louwagie et al., 1993), little is known about the correlation between the genotype and immunotype of subtypes. FIV viral isolates are currently classified into four FIV subtypes: A, B, C and D. (Kakinuma et al., 1995).
  • FIV strains are used herein: Strain (subtype) Abbreviation Petaluma (A) FIV Pet Dixon (A) FIV Dix UK8 (A) FIV UK8 Bangston (B) FIV Bang Aomori-1 (B) FIV Aom1 Aomori-2 (B) FIV Aom2 Shizuoka (D) FIV Shimine (A) FIV Pet Dixon (A) FIV Pet Dixon (A) FIV Dix UK8 (A) FIV UK8 Bangston (B) FIV Bang Aomori-1 (B) FIV Aom1 Aomori-2 (B) FIV Aom2 Shizuoka (D) FIV Shipha (subtype) Abbreviation Petaluma (A) FIV Pet Dixon (A) FIV Dix UK8 (A) FIV UK8 Bangston (B) FIV Bang Aomori-1 (B) FIV Aom1 Aomori-2 (B) FIV Aom2 Shizuoka (D) FIV Shimine (
  • the subject invention concerns materials and methods for detecting, preventing and treating retroviral infections in humans and other non-feline animals susceptible to infection by retrovirus. It has been discovered that FIV can be transmitted from cats to humans and that the FIV can infect human cells in vivo. Persons infected with FIV produce an immune response against the virus, including the production of antibodies to FIV. It has also been discovered that antibodies generated by a person infected with FIV cross-react with HIV antigens. Thus, the methods and compositions of the subject invention can be used to detect, prevent and treat FIV infection in humans and other non-feline animals that are susceptible to FIV infection. The present invention includes materials and methods for diagnosing whether a person is infected with FIV or HIV. The methods and compositions of the invention can also be used to prevent and treat infection by HIV in humans.
  • FIGS. 1 A- 1 D show FIV Western blot analysis of subjects #FH1 and #FH2.
  • FIV Shi (D) and FIV Bang (B) Western blots (FIGS. 1 A- 1 C) were reacted with sera from subjects #FH1, #FH2, and #FH5 (control individual with minimum cat exposure) for 20 hours.
  • Experimentally FIV-infected cat (Cat +) was used as the source of strongly reactive control serum and uninfected SPF cat (Cat ⁇ ) was used as the source of non-reactive control serum. Key bands are highlighted with an arrowhead on the left.
  • FIG. 1D Virus neutralizing antibodies to FIV and HIV were detected in cultures, a Western blot of human sera on FIV Shi .
  • FIGS. 2A and 2B show alignment of gag sequences of cat #FC1 and subject #FH1.
  • FIG. 2A shows alignment of gag nucleotide sequences.
  • FIG. 2B shows alignment of gag amino acid sequences. Gag sequences of the nine clones isolated from cat #FC 1 and subject #FH1 are shown in comparison to the consensus sequence of cat #FC1 (top sequence). Hyphens denote nucleotide or amino acids identical to the consensus sequence derived from cat #FC1 and those, which differ from the consensus, are presented with the appropriate nucleotide or amino acid symbols.
  • FIGS. 3 A- 3 C show HIV-1 Western blot analysis of subjects #FH1 and #FH2. Strongly reactive (++), weakly reactive (+), and non-reactive ( ⁇ ) control human sera from the Bio-Rad Novapath HIV-1 Immunoblot Kit and Cambridge Biotech HIV-1 Western Blot Kit were used as controls for respective HIV-1 Western blot strips. Serum from subject #FH5 with miminal exposure to cats, was used as additional negative control for Western blots from both companies. The durations of serum incubation are shown and FDA-approved recommended incubation periods are also designated with asterisk. Key bands are highlighted with an arrowhead on the left.
  • FIG. 4 shows gag nucleotide sequence comparison of cat #FC1, subject #FH1 and FIV strains. Gag sequences of cat #FC1 and subject #FH1 were compared to all FIV strains available in our laboratory. The consensus sequence of subject #FH1 is shown at the top. Nucleotides identical to the consensus sequence of subject #FH1 (top sequence) are designated as a dot and those which differ from the consensus are presented with the appropriate nucleotide symbols. Gaps in sequence are presented as hyphens.
  • FIGS. 5 A- 5 E show HIV-1 and FIV Western blot analysis of experimentally FIV-infected cats and pet cats.
  • SPF cats #H3J, #D55, #455, and #X3D were experimentally infected with FIV Pet (subtype A), FIV UK8 (subtype A), FIV Shi (subtype D), and FIV Bang (subtype A gag /B Env ), respectively.
  • FIV Bang has Gag sequence of FIV subtype A and Env sequence of FIV subtype B.
  • These serum were reacted with HIV-1 Western blots (FIGS. 5A and 5B) or FIV Western blots (FIGS. 5C, 5D, and 5 E).
  • Serum samples of these cats before FIV infection were negative by both FIV and HIV-I Western blot analyses (data not shown).
  • Serum from pet cats #FC1 and #FC2 were also tested for their reactivity to HIV-1 and FIV antigens.
  • Cat #C9V (7 months post-inoculation serum shown) is an SPF cat inoculated with FIV isolated from pet Cat #FC 1. All sera were incubated at serum dilution of 1:100. All procedures are identical to those described in FIGS. 1 and 3 unless stated otherwise. Key bands are highlighted with an arrowhead on the left.
  • FIG. 5A and 0.5 hour for Bio-Rad Novapath HIV-1 Immunoblot Kit (FIG. 5B) were performed with the cat sera. Serum incubation for FIV Western blots was 20 hours (FIGS. 5C, 5D, and 5 E).
  • FIGS. 6 A- 6 C show HIV-1 and HTLV-1 ⁇ 2 immunoblot analysis of FIV-infected and FIV-vaccinated cat sera.
  • Sera from FIV-infected cats and FIV-vaccinated cats were tested for cross-reactive antibodies to HIV-1 with BioRad Novapath HIV-1 UCD1 and Cambridge Biotech HIV-1 IIIB immunoblot kits (FIGS. 6A & 6B) and to HTLV-1 ⁇ 2 with Cambridge Biotech HTLV-1 ⁇ 2 immunoblot kit (FIG. 6C).
  • Selected cat sera with unique banding patterns are shown to demonstrate the presence of cross-reactive antibodies with various patterns of reactivity to HIV-1 proteins. Serum samples of these cats before FIV inoculation were negative by both HIV-1 and HTLV-1 ⁇ 2 immunoblot analyses (data not shown).
  • FIGS. 7A and 7B show temporal development of cross-reactive antibodies to HIV-1. FIV and HIV-1 immunoblots are shown using selected sera from: FIG. 7A, FIV-infected cats from different weeks post-inoculation (wk pi or pi); and FIG. 7B, FIV-vaccinated cats from different weeks post-vaccination (post-vaccination number. Sera were compared to their pre-inoculation or pre-vaccination sera (Pre).
  • FIG. 8 shows absorption of cat sera with viral antigens.
  • FIG. 8A Cat sera were absorbed against inactivated FIV-infected cells followed by competition on HIV-1 immunoblots by inactivated FIV. Absorptions were also performed with PBS, uninfected cat FeT-J cells, and uninfected human H9/HuT-78 cells.
  • FIG. 8B Sera were absorbed against PBS, uninfected cells lysate, or inactivated HIV-infected HuT-78 cells prior to incubation with HIV-1 immunoblot strips. Absorptions were performed for 2 hours at room temperature before development with anti-cat reagents.
  • FIG. 8A Cat sera were absorbed against inactivated FIV-infected cells followed by competition on HIV-1 immunoblots by inactivated FIV. Absorptions were also performed with PBS, uninfected cat FeT-J cells, and uninfected human H9/HuT-78 cells.
  • FIG. 8B Sera were absorbed against PBS,
  • FIV-vaccinated cat sera containing neutralizing antibodies to HIV-1 (Cat #C6G and #C9K) and sera from uninfected FeT-J cell immunized cats (Cats #C6E and #3G5) were tested at 1:100 dilution for reactivity to 5 ⁇ g/ml of either uninfected FeT-J cells, uninfected HuT-78 cells, or purified FlVpet. Vaccinated cat sera had reactivity to FIV surface Env gp95 (arrow head).
  • Serum from a cat immunized with uninfected FeT-J cells was absorbed against PBS, FeT-J, H9/HuT-78 cells, and FIV-infected Fet-J cells. Reactivities in serum from Cat #305 were readily absorbed against uninfected cat and human cells. Immunoglobulin levels of all absorbed sera were not significantly altered by infected-cell absorptions when compared to PBS and uninfected-cell absorbed sera. Seven % PAGE gels were used for developing immunoblots to increase resolution of high molecular weight proteins. Molecular weights (M) are presented in kDa.
  • FIGS. 9A and 9B show reactivity of FIV-vaccinated cat sera and PBMC to HIV p24 and gp160.
  • FIG. 9A Sera from cats immunized with dual-subtype FIV vaccine were tested by ELISA using recombinant HIV-1 BRU p24, HIV-1 IIIB gp160, and FIV p24. ELISA results at serum dilution of 1:300 are presented as mean difference between pre- and post-vaccination sera.
  • FIG. 9A Sera from cats immunized with dual-subtype FIV vaccine were tested by ELISA using recombinant HIV-1 BRU p24, HIV-1 IIIB gp160, and FIV p24.
  • ELISA results at serum dilution of 1:300 are presented as mean difference between pre- and post-vaccination sera.
  • FIG. 9A Sera from cats immunized with dual-subtype FIV vaccine were tested by ELISA using recombinant HIV-1 BRU p
  • PBMC from dual-subtype FIV vaccinated cats at 2 weeks post-5th vaccination were tested for interferon- ⁇ production in response to recombinant HIV-1 BRU p24, HIV-1 IIIB gp160, and FIV p24. All PBMC stimulated with SEA were positive for IFN ⁇ production (data not shown). The average of the triplicate samples are shown for IFN ⁇ production. Standard deviations of the average IFN ⁇ titer were less than 10% of the mean.
  • FIG. 10 shows sequence alignments for partial FIV gag sequence from subject #FH1 PBMC following Real-time PCR.
  • SEQ ID NO. 1 is a sense primer or amplification of FIV gag that can be used according to the present invention.
  • SEQ ID NO. 2 is a antisense primer or amplification of FIV gag that can be used according to the present invention.
  • the subject invention concerns materials and methods for detecting, preventing and treating infection by FIV in humans and other non-feline animals susceptible to infection by FIV.
  • the present invention is based on the surprising discovery that FIV can be transmitted from cats to humans and can infect human cells in vivo. Human subjects have been identified that are FIV positive and appear to have been infected through contact with their pet cats. Infection of humans by FIV has been demonstrated by confirmation of the presence of FUV nucleotide sequences in human cells using polymerase chain reaction (PCR) and by Western blot detection of FIV proteins expressed in human cells. Sequence analysis confirms that the subject is infected with FIV. Both of the human subjects infected with FIV identified thus far are currently clinically and immunologically asymptomatic. It has also been demonstrated that antibodies to FIV cross-react with HIV proteins. In addition, antibodies from FIV vaccinated animals can neutralize HIV-1 virus.
  • the subject invention also concerns materials and methods for preventing and treating infection by HIV in humans.
  • One aspect of the subject invention concerns methods for detecting FIV infection of human cells.
  • One method of the present invention comprises detecting the presence of antibodies that bind to an FIV protein or peptide, or nucleotide sequences of FIV.
  • FIV diagnostic tests of the invention include ELISA, Western blot, and PCR tests. Current commercially available HIV antibody tests cross react with FIV proteins and, therefore, can give “false positive” results in subjects which are not infected with HIV but which are infected with FIV. Thus, FIV diagnostic tests for humans are needed in facilities doing HIV testing, such as hospitals and blood banks, in order to screen false positives and indeterminant results obtained from current HIV tests.
  • Methods for FUV detection include PCR assaying for proviral FIV nucleotide sequences, RT-PCR assaying for FIV RNA nucleotide sequences, oligonucleotide probe assays (including Real-time PCR), and antibody-based assays.
  • Antibody-based assays include, for example, methods to detect the presence of antibodies to FUV, such as ELISA and Western blots, and methods to detect the presence and/or expression of FIV proteins in human biological samples.
  • a biological sample from a human that is being assayed for the presence of antibodies to HIV or HIV sequences is assayed for the presence of antibodies to FIV or FIV sequences.
  • the present invention concerns materials and methods for inducing an immune response to FIV in a human or non-feline animal that is susceptible to infection by FIV.
  • the present invention also concerns materials and methods for inducing an immune response to HIV in a human.
  • an amount of an FIV immunogen effective to induce an immune response is administered to the human or animal.
  • FIV immunogens that can be used include, for example, synthetic FIV peptide, natural or recombinant FIV protein or a fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or a fragment thereof and an HIV protein (such as NeF protein) or a fragment thereof, inactivated or attenuated whole FIV viral isolate, FIV viral fragment, inactivated cells infected with FUV, and compositions comprising FIV and HIV proteins or fragments thereof.
  • synthetic FIV peptide natural or recombinant FIV protein or a fragment thereof
  • polynucleotide comprising a sequence that encodes an FIV protein or fragment thereof polynucleotide comprising a sequence that encodes an FIV protein or a fragment thereof and an HIV protein (such as NeF protein) or a fragment thereof, inactivated or attenuated whole FIV viral isolate, FIV viral fragment, in
  • the present invention also concerns materials and methods for preventing FIV infection in humans and other animals. Specifically contemplated are methods and vaccine compositions which can be administered to human subjects and other susceptible host animals which will prevent infection by FIV. In one embodiment, an amount of an FIV immunogen effective to induce an immune response is administered to the human or animal.
  • FIV immunogens that can be used include, for example, synthetic FIV peptide, natural or recombinant FIV protein or a fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or a fragment thereof and an HIV protein (such as NeF protein) or a fragment thereof, inactivated or attenuated whole FIV viral isolate, FIV viral fragment, inactivated cells infected with FIV, and compositions comprising FIV and HIV proteins or fragments thereof.
  • the FIV immunogen comprises an epitope of an FIV protein, such as core gag protein or envelope protein, that is evolutionarily conserved between FIV and HIV.
  • the subject invention also concerns materials and methods for treating persons and other animals that are infected with FIV.
  • an effective amount of a composition which can induce an immune response against FIV is administered to a person or animal in need of such treatment.
  • one or more antiretroviral drugs can be administered to the person or animal.
  • Antiretroviral drugs which can be used in the present invention include, but are not limited to, nucleoside analogs, such as azidothymidine (AZT) and lamivudine (3TC), non-nucleoside inhibitors ofretroviral reverse transcriptase, and retroviral protease inhibitors.
  • a person or animal can be treated using one or more antibody that cross-reacts with both FIV and HIV antigens.
  • a cocktail of one or more antibody that is specific to an FIV antigen and one or more antibody that is specific to an HIV antigen can be administered.
  • a person or non-feline animal can be treated using an FIV immunogen that induces an immune response against FIV.
  • FIV immunogens that can be used include, for example, synthetic FIV peptide, natural or recombinant FIV protein or a fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or a fragment thereof and an HIV protein (such as NeF protein) or a fragment thereof, inactivated or attenuated whole FIV viral isolate, FIV viral fragment, inactivated cells infected with FIV, and composition comprising FIV and HIV proteins or fragments thereof.
  • synthetic FIV peptide natural or recombinant FIV protein or a fragment thereof
  • polynucleotide comprising a sequence that encodes an FIV protein or a fragment thereof polynucleotide comprising a sequence that encodes an FIV protein or a fragment thereof and an HIV protein (such
  • antiretroviral drugs can be used in combination with FUV immunogen treatment or antibody therapy, or both, described above.
  • Other animals which can be treated according to methods of present invention include dogs, horses, and captive non-domesticated animals such as those found in zoos and circuses, including tigers and lions.
  • the subject invention also concerns materials and methods for preventing HIV infection in humans that are not infected with HIV.
  • an FIV immunogen is administered to a person.
  • the FIV immunogen induces an immune response against one or more subtypes of FIV.
  • FIV immunogens that can be used include, for example, synthetic FIV peptide, natural or recombinant FIV protein or a fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or a fragment thereof and an HIV protein (such as NeF protein) or a fragment thereof, inactivated or attenuated whole FIV viral isolate, FIV viral fragment, inactivated cells infected with FIV, and composition comprising FIV and HIV proteins or fragments thereof.
  • a person or animal can be administered an FIV immunogen and then subsequently receive a secondary administration of an HIV immunogen.
  • the FIV immunogen elicits an immune response against more than one FIV subtype.
  • HIV immunogens can include core gag protein (p24) and envelope protein (gp100/gp120).
  • the FIV immunogen comprises an epitope of an FIV protein, such as core gag protein or envelope protein, that is evolutionarily conserved between FIV and HIV.
  • the invention also concerns materials and methods for treating persons that are already infected with HIV.
  • an FIV immunogen is administered to a person.
  • the FIV immunogen induces an immune response against one or more subtypes of FIV.
  • FIV immunogens that can be used include, for example, synthetic FIV peptide, natural or recombinant FIV protein or a fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or a fragment thereof and an HIV protein (such as NeF protein) or a fragment thereof, inactivated or attenuated whole FIV viral isolate, FIV viral fragment, inactivated cells infected with FIV, and composition comprising FIV and HIV proteins or fragments thereof.
  • a person or animal can be administered an FIV immunogen and then subsequently receive a secondary administration of an HIV immunogen.
  • the FIV immunogen elicits an immune response against more than one FIV subtype.
  • HIV immunogens can include core gag protein (p24) and envelope protein (gp100/gp120).
  • a person or animal infected with HIV can be treated using one or more antibody that cross-reacts with both an FIV protein or antigen and an HIV protein or antigen.
  • a cocktail of one or more antibody that is specific to an FIV antigen and one or more antibody that is specific to an HIV antigen can be administered.
  • antiretroviral drugs can be used in combination with FIV immunogen treatment or antibody therapy, or both, described above.
  • Antiretroviral drugs for treating HIV are known in the art and include nucleoside analogs such as azidothymidine (AZT) and lamivudine (3TC), non-nucleoside inhibitors ofretroviral reverse transcriptase, and retroviral protease inhibitors.
  • compositions of the invention when administered to a human or other animals susceptible to FIV infection, can induce protective humoral and/or cellular immune responses against infection by FIV.
  • the composition can induce immune responses against multiple strains of FIV. More preferably, the compositions of the invention can induce immune responses against homologous and heterologous strains of FIV.
  • compositions can be, for example, composed of synthetic FIV peptide, natural or recombinant FIV protein or a fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or fragment thereof, polynucleotide comprising a sequence that encodes an FIV protein or a fragment thereof and an HIV protein (such as NeF protein) or a fragment thereof, inactivated or attenuated whole FIV viral isolate, FIV viral fragment, inactivated cells infected with FIV, and composition comprising FIV and HIV proteins or fragments thereof, or a combination of any of the above.
  • the vaccine composition of the subject invention comprises peptides, proteins or strains of FIV from two different FIV subtypes.
  • FIV subtype A and FIV subtype D are represented in the composition.
  • the composition comprises peptides, proteins or viral isolates from three FIV strains, each strain from a different FIV subtype. More preferably, at least one FIV strain from each of FIV subtype A, subtype B and subtype D is included in the vaccine composition.
  • Compositions directed to multiple subtypes of FIV are described in U.S. Pat. No. 5,846,825.
  • compositions of the subject invention also encompass recombinant viral vector-based FUV constructs that may comprise, for example, FIV env, gag/pro, or env-gag/pro.
  • Any suitable viral vector that can be used to prepare recombinant vector/FIV constructs is contemplated for use with the subject invention.
  • viral vectors derived from adenovirus, avipox, feline herpesvirus, vaccinia, canarypox, entomopox, swinepox and others known in the art can be used with the compositions and methods of the present invention.
  • Recombinant polynucleotide vectors that encode and express FIV components can be constructed using standard genetic engineering techniques known in the art.
  • the various compositions described herein can be used separately and in combination with each other.
  • primary immunizations of a person or other animal may utilize recombinant vector-based FIV constructs, having single or multiple subtype components, followed by secondary boosts with vaccine compositions comprising synthetic FIV peptides and/or recombinant FIV proteins.
  • Other immunization protocols with the vaccine compositions of the invention are apparent to persons skilled in the art and are contemplated within the scope of the present invention.
  • Natural, recombinant or synthetic polypeptides of FIV viral proteins, and peptide fragments thereof, can also be used as compositions according to the subject methods.
  • FIV polypeptides derived from multiple FIV subtypes are combined in a vaccine composition and are used to vaccinate a human or other susceptible animal in need of such treatment.
  • polypeptides based on the FIV envelope glycoprotein from at least two prototype FIV strains from different subtypes can be combined in the vaccine.
  • the polypeptides may be homologous to one strain or may comprise “hybrid” or “chimeric” polypeptides whose amino acid sequence is derived from joining or linking polypeptides from at least two distinct FIV subtypes.
  • FIV polypeptides can be synthesized using solid-phase synthesis methods (Merrifield, 1963). FIV polypeptides can also be produced using recombinant DNA techniques wherein a polynucleotide molecule encoding an FIV protein or peptide is expressed in a host cell, such as bacteria, yeast, or mammalian cell lines, and the expressed protein purified using standard techniques of the art.
  • the FIV vaccine compositions described herein are administered to a human or other animal susceptible to FIV infection in an effective amount and in a manner capable of inducing protective immunity against subsequent challenge or infection of the human or animal by FIV.
  • the vaccines are typically administered parenterally, by injection, for example, either subcutaneously, intraperitoneally, or intramuscularly.
  • Other modes of vaccine administration contemplated by the invention include oral or nasal administration.
  • the vaccines are administered to a subject at least two times, with an interval of one or more weeks between each administration.
  • other regimens for the initial and booster administrations of the vaccine are contemplated, and may depend on the judgment of the practitioner and the particular host animal being treated.
  • the vaccine compositions of the subject invention can be prepared by procedures well known in the art.
  • the vaccines are typically prepared as injectables, e.g., liquid solutions or suspensions.
  • the vaccines are administered in a manner that is compatible with dosage formulation, and in such amount as will be therapeutically effective and immunogenic in the recipient.
  • the optimal dosages and administration patterns for a particular vaccine formulation can be readily determined by a person skilled in the art.
  • Virus for use in a vaccine formulation may be inactivated or attenuated using methods known in the art. For example, whole virus and infected cells can be inactivated or attenuated by exposure to paraformaldehyde, formalin, phenol, UV light, elevated temperature and the like.
  • a biological sample such as blood, serum, saliva and the like, is obtained from a person and assayed for the presence of antibodies that can bind specifically to FIV or an FIV antigen.
  • the sample can be assayed for antibodies that bind with all subtypes or strains of FIV or antigens thereof, as well as for antibodies that are specific to a particular subtype or strain of FIV or antigen thereof so as to facilitate diagnosis of the FIV subtype or strain infecting the subject.
  • the sample can optionally be assayed for the presence of antibodies that bind to HIV or an HIV antigen.
  • Assay techniques e.g., ELISA and Western blotting, for detecting antibodies to FIV and HIV are known in the art.
  • a biological sample is assayed for the presence of FIV-specific nucleotide sequences and/or proteins.
  • Standard PCR and nucleotide hybridization techniques can be used to amplify and detect the presence of FIV-specific nucleotide sequences in a sample.
  • RT-PCR can be used to detect FIV RNA sequences.
  • FIV oligonucleotide primers and probes for use in such techniques and which are substantially complementary with a portion of the FIV genomic sequence or FIV RNA sequences can be readily prepared based on known FIV sequences.
  • PCR Polymerase chain reaction
  • oligonucleotide primer annealing to the DNA template
  • primer extension by a DNA polymerase
  • the oligonucleotide primers used in PCR are designed to anneal to opposite strands of the DNA, and are positioned so that the DNA polymerase-catalyzed extension product of one primer can serve as the template strand for the other primer.
  • PCR amplification process results in the exponential increase of discrete DNA fragments whose length is defined by the 5′ ends of the oligonucleotide primers.
  • Nucleotide hybridization methods are disclosed, for example, in U.S. Pat. No. 4,358,535.
  • the subject invention also concerns antibodies that cross-react with both FIV and HIV antigens.
  • Antibodies can be prepared and isolated using standard methods known in the art. For example, a suitable animal can be immunized with with an FIV immunogen via one or more intramuscular or subcutaneous injections, optionally with an adjuvant, over a period of time. Immunized animals can be periodically bled and antibodies isolated from the antisera. The anti FIV antibodies can then be screened for cross-reactivity with FIV.
  • Antibodies of the present invention can be polyclonal or monoclonal. Monoclonal antibodies can be prepared according to the methods of Kohler and Milstein (1976).
  • the antibody can be “humanized” to minimize immune reactions against the antibody by the human system.
  • Techniques for humanizing antibodies are well known in the art and are described in U.S. Pat. Nos. 5,807,715, 5,693,762, 5,585,089, 5,530,101, and Morrison et al. (1984).
  • the subject invention also concerns compositions comprising at least one FIV protein and/or antigen or fragment thereof and at least one HIV protein and/or antigen or fragment thereof.
  • the composition comprises epitopes of FIV and HIV proteins that are evolutionarily conserved between the viruses.
  • the composition comprises core gag protein and/or viral envelope protein.
  • the subject invention also concerns polynucleotide molecules that encode at least one FIV protein or fragment thereof and at least one HIV protein (such as NeF) or fragment thereof.
  • the subject invention also concerns materials and methods for preventing infection in humans and other animals by lentivirus such as CAEV and SIV.
  • PBMC Primary PBMC were cocultured with mitogen-stimulated PBMC from either a FUV-seronegative individual or an SPF cat.
  • the mitogens used were Staphylococcal enterotoxin A (SEA, 0.5 ⁇ g/ml) or concanavalin A (Con A, 1 ⁇ g/ml).
  • SEA Staphylococcal enterotoxin A
  • Con A concanavalin A
  • RNA and genomic DNA were extracted from the cultured PBMCs by guanidine isothiocyanate-phenol procedure using TRIZOL Reagent (GIBCO BRL, Rockville, Md.) and QIAamp DNA blood Mini kit (QIAGEN, Valencia, Calif.), respectively.
  • RT reverse transcriptase activity present in cultured fluids were measured by a RT assay (Yamamoto et al., 1988b).
  • Viral RNA was extracted from plasma using QIAamp Viral RNA Mini kit (QIAGEN, Valencia, Calif.). After DNase treatment, RNA was reverse transcribed to cDNA with AMV RT and random hexamer primers.
  • cDNA from cell associated RNA
  • cDNA from plasma RNA in 62.5 ⁇ l of plasma
  • genomic DNA from 1 ⁇ 10 5 cells were used for PCR analysis. Nested PCR for FIV gag was performed using primer sets as previously described (Hohdatsu et al. 1998).
  • FIV whole gag genes were amplified by single PCR with sense primer GAGF (5′-CAACAAGGTAGGAGAGATTCTACA-3′) (SEQ ID NO:1) and antisense primer, GAGR (5′-TAAAATTGTTATATCTGCTCCTGT-′3) (SEQ ID NO:2). Primers used for detection of HIV-1 were previously described (Ou et al., 1988). Amplification products of the expected size were cloned into the pCR 2.1 TOPO cloning vector (Invitrogen, Carlsbad, Calif.) and sequenced (ICBR core lab, UF). Sequences of FIV strains and other retroviruses were obtained from NCBI/GenBank and analyzed by CRYSTAL W program and Basic Local Alignment Search Tool (BLAST).
  • BLAST Basic Local Alignment Search Tool
  • RT-PCR without nesting
  • FIV gag primers determined the presence of a 1500 bp band indicating detection of FIV gag RNA (FIGS. 2 A-B).
  • the control culture consisting of cells from SPF cat or FIV-seronegative individual were negative by the same assays. Thus, the entire gag gene was found to reside in PBMC from the #FH1 subject. Culture fluids were negative for FIV by RT assay.
  • RNA gag sequence was derived from PBMC
  • serum from #FH1 was retested using FDA-approved HIV-1 Westem blot assays (FIGS. 3 A-C).
  • the previous HIV-1 Western blot test performed by licensed diagnostic laboratories used the Western blot kit from Cambridge (HIV-1 IIIB , subtype B).
  • Western blot strips from Bio-Rad Laboratories use HIV-1 UCD1 (subtype B) as the source of viral proteins. Serum from #FH1 reacted to both sets of strips at p24 and weakly at p55, but unlike FIV Western blot results, no minor core and RT reactions were observed.
  • FIV serology and positive FIV gag nested RT-PCR of the subject #FH1 Upon determination of positive FIV serology and positive FIV gag nested RT-PCR of the subject #FH1, the source of the FIV infection was investigated. FIV was isolated and sequenced from the FIV-seropositive pet cat #FC1. FIV from cat #FC1 was readily isolated from PBMC by coculturing with Con-A-stimulated PBMC from an SPF cat, and the culture fluids were positive for FIV by RT assay. The cocultured cells were positive for FIV gag by both proviral PCR and RT-PCR. Control cultures consisting of cells from a SPF cat were negative by the same assays. Nested RT-PCR of plasma from Cat #FC1 also tested positive for FIV RNA gag.
  • Gag/gag sequences from Cat #FC1 had 83.1-94.2% nucleotide and 87.4-98.2% amino acid homology to subtype B FIV isolates (FIV Aomori-1 , FIV Aomori-2 FIV Sendai-2 , FIV Yokohama , FIV TM2 ) but were clearly different from the FIV strains ( ⁇ 85.2% nucleotide and ⁇ 88.6% amino acid homology) which were being produced in our laboratory (FIG. 4, amino acid sequences shown). Thus, the sequences derived from subject #FH1 and her cat, were not due to contamination from laboratory strains of FIV.
  • subject #FH2 Since subject #FH2 has previously worked with HIV-1, she was tested for HIV-1 infection by PCR and HIV-1 antibodies by commercial HIV-1 Western blot analysis upon request by the subject. Based on standard HIV-1 Western blot analyses using Cambridge Biotech (20-hour serum incubation) and Bio-Rad Laboratories (30-minute serum incubation) tests, this subject was negative for HIV-I antibodies. This finding was also confirmed by a licensed diagnostic laboratory. However, upon longer incubation period (20 hours) on Bio-Rad Western blot strip, faint antibody reactivity to p24 was observed repeatedly using serum collected from subject #FH2 on two different days in 2001 but slightly stronger reactivity to p24 was detected in serum collected after 1993.
  • HIV-1 Western blot analyses were performed on sera from SPF cats experimentally infected for prolonged period of time with four FIV strains currently being produced in our laboratory (FIGS. 5A and 5B). Sera from pet cats #FC1 and #FC2 were also tested along with sera from a SPF cat and a SPF cat (#C9V) infected with FIVFCl isolated from pet Cat #FC1.
  • FIV FC1 core sequence which has 99.3% amino acid homology to FIV sequence isolated from subject #FH1, can readily induce cross-reactive antibodies to HIV-1.
  • sera from cat #FC2 and cats infected with FIV Shi (cat #455) and FIV Bang (cat #X3D) were non-reactive to HIV-1 proteins on both HIV-1 Western blots. All FIV-infected laboratory cats and cat #FC1 were strongly positive for FIV antibodies (FIGS. 5C and 5D). Although the numbers of serum samples are small, it is interesting to note that not all long-term FIV-infected cats produced anti-FIV antibodies that cross-reacted with HIV-1 p24 and p32.
  • Vaccinated and Infected Animals Specific-pathogen-free cats were obtained from the investigator's SPF breeding colony or purchased from Liberty Research (Waverly, N.Y.) and Cedar River Laboratories (Mason City, Iowa). All SPF cats tested negative for toxoplasma, feline leukemia virus, and FIV before experimental infection. These cats were immunized at 2-6 weeks intervals with FIV Pet and FIV Shi vaccines at combined or single dose of 250-500 ⁇ g for whole virus vaccine and 2.5-5 ⁇ 10 6 cells for inactivated infected-cell vaccines and sera collected at 2-4 weeks post vaccination (Pu et al., 2001). SPF cats were inoculated intravenously with 10-100 median cat infectious doses (CID 50 ) of either in vitro-derived or in vivo-derived inoculum as previously described (Pu et al., 2001).
  • CID 50 median cat infectious doses
  • Immunoblot, ELISA, and VN Antibody Analyses Commercial HIV-1 (BioRad, Hercules, Calif.; Cambridge Biotech, Rockville, Md.) and HTLV-I and II (Cambridge Biotech) immunoblot strips were performed at 1:100 serum dilution using the methods described in the kits except for the anti-cat reagents and for the absorption/competition studies.
  • Alkaline-phosphatase conjugated goat anti-cat IgG (Chemicon, Temecula, Calif.) at 0.3 ⁇ g/ml and biotinlylated anti-cat IgG (Vector, Burlingame, Calif.) at 0.4 ⁇ g/ml were used in place of the anti-human reagents for testing feline serum.
  • ELISA assays were developed using commercial recombinant HIV-1 gp160 (Chemicon), HUV-1BRU p24 (Biodesign, Kennebunk, Me.), and FIV p24 (Fort Dodge, Fort Dodge, Iowa) using a method as previously described (Yamamoto et al., 1993) with the following modifications.
  • HIV-1 p24 and gp160 were coated on the plate at 300 and 150 ng/well, respectively. FIV 24 was coated at 50 ng/well. All samples for ELISA were performed in triplicates.
  • the HIV VN antibody assay will be identical to the FIV VN antibody assay with the exception of SEA-stimulated human PBMC as indicator cells and HIV-1LAV (20 TCID 50 ) or HIV-1 UCD1 (0.1-50 TCID 50 ) as inocula (Pu et al., 2001; Yamamoto et al., 1993).
  • FIV-infected FIV Shi -infected FeT-J and FIV Bang -infected FeT-J cell combination
  • HIV-infected HIV-1 ucdinfected HuT-78 and HIV-1 LAV infected H9 cell combination
  • uninfected FeT-J alone or HuT-78/H9 combination
  • IgG levels of the cell-absorbed and unabsorbed mock sera were determined by commercial feline IgG radial-immunodiffusion assay (Bethyl Laboratory, Montgomery, Tex.).
  • Virus-specific cellular immune responses of PBMC from vaccinated cats were determined by measuring the amount of interferon- ⁇ produced in response to 10 ⁇ g/ml of recombinant FIV p24, HIV-1 BRU p24, and HIV-1 IIIB gp160 using the method previously described (Pu et al., 1999).
  • cells stimulated with uninfected cell lysate (20 ⁇ g/ml), SEA (0.2 ⁇ g/ml, positive control), media diluent (negative control), and purified whole FIV Pet and FIV Shi (20 ⁇ g/ml) were also included as additional controls.
  • Antibodies to FIV were developed in specific pathogen free (SPF) cats by either active infection with FIV strains or immunization with inactivated FIV vaccines.
  • Sera from 41 FIV-infected cats at different time post-FIV inoculation were evaluated on BioRad HIV-1 UCD1 and Cambridge Biotech HV-1 IIIB immunoblots (Table 1, FIG. 6A).
  • 18 of 41 (44%) infected cats had antibodies to HIV-1 core capsid p24, matrix p18, Gag p55, intergrase p32, transmembrane envelope gp41, surface envelope gp120 or precursor envelope gp160 (Table 1, FIG. 6A) with greatest reactivity to p24.
  • HIV-1 IIIB and HIV-1 UCD1 are subtype B isolates that were produced in human H9 and HuT-78 cells, respectively.
  • HUV-1 IIIB and HUV-1 UCD1 has 97% amino acid sequence homology at p24 and 85% amino acid sequence homology at Env.
  • the specificity of the cross-reactivity appears to differ based on the HIV-1 strain at polymerases and Env.
  • Six FIV-infected and six FIV-vaccinated cats that reacted to HIV-1 immunoblot were tested against HTLV-I/II using Cambridge HTLV-I/II Western Blot Kit. Three vaccinated and two infected cats had cross-reactive antibodies to HTLV-I/II core p24 (FIG. 6C).
  • One of the infected cat also had antibodies weakly reactive to HTLV Tax p38, while the other infected cat also had antibodies weakly reactive to HTLV precursor Gag p53 and Gag intermediate p42.
  • lentiviruses As previously reported for lentiviruses (Olmsted et al, 1989a; Matsuo et al. 1992; Goudsmit et al., 1986), core sequences appear to be evolutionarily conserved even between retrovirus families (Egberink et al., 1991).
  • FIV antibodies from infected cats that were negative for HIV-1 cross-reactivity were negative throughout 6-120 wk pi (data not shown).
  • the temporal development of the cross-reactive antibodies to HIV-1 in FIV vaccine sera was next determined (FIG. 7B).
  • the cross-reactive antibodies developed as early as second vaccination and persisted for a prolonged period of time. Similar to anti-p24 antibodies in the infected cat sera, the antibodies reactive to FIV p24 developed much earlier than those cross-reactive with HIV-1 p24 (FIGS. 7A and 7B).
  • the cross-reactive anti-p24 antibodies in the vaccinated cat sera were detected after the development of cross-reactive antibodies to Env (gp120, gp 160) and polymerase (p66).
  • Env gp120, gp 160
  • polymerase p66
  • selected sera from FIV-vaccinated and FIV-infected cats were preabsorbed extensively with either uninfected feline FeT-J cells or FIV-infected FeT-J cells.
  • the dual-subtype vaccine viruses were produced in FeT-J cells or a cell line from FeT-J lineage (FL-4 cells) (Pu et al., 2001).
  • Controls included pooled serum from two HIV-1 positive individuals, serum from an HIV-negative individual, and sera from SPF cats immunized with uninfected FeT-J cells (Cat #3G5) or Fet-J lysates (Cat #C6E). Both proviral PCR levels and RT activity were used to detect HIV-1 levels in the antibody-treated cultures.
  • One (Cat #C6G) of six vaccine sera tested positive for VN antibodies to HIV-1 LAV (50 VN titer) and to HIV-1 UCD1 (10 VN titer).
  • FIV-specific antibodies react to recombinant HIV-1 p24 protein, it is conceivable that this protein has epitopes for stimulating the necessary cellular immune components such as cytokines needed to develop these cross-reactive antibodies.
  • the ability of FIV/EIV-1 evolutionarily conserved epitopes to generate cellular immunity was evaluated.
  • PBMC from dual-subtype FIV vaccinated cats produced high levels of interferon- ⁇ (IFN ⁇ ) production upon stimulation with inactivated whole FIV antigens (Pu et al., 2001; Pu et al. 1999).
  • IFN ⁇ is a TH1 cytokine that is also essential in the production of IgG (Abbas et al., 2000).
  • Partial FIV gag were isolated from cocultures of #FH1 PBMC with either human PBMC (134) or feline PBMC (A9) using Real-time PCR followed by regular PCR. Positive PCR products after Real-time PCR were used as samples for regular PCR. All the primers and probe for Real-time PCR and regular PCR were described in Norway et al. (2001). After regular PCR, amplification products of the expected size were isolated from agarose gel and cloned into the pCR 2.1 TOPO cloning vector according to the manufacturer's instructions (Invitrogen, Carlsbad, Calif.) and sequenced (ICBR core lab, UF) (FIG. 10). These results confirm the presence of FIV sequences in the #FH1 subject's cells. The conditions under which the assay was performed minimized any possibility of cross-contamination.
  • Vaccines compositions of the present invention comprising FIV proteins and peptides, recombinant viral vector-based FIV constructs, attenuated or inactivated FIV viral isolates, and the like, having antigenic or immunogenic properties, can be prepared by procedures well known in the art.
  • such vaccines can be prepared as injectables, e.g., liquid solutions or suspensions. Solid forms for solution in, or suspension in, a liquid prior to injection also can be prepared.
  • the preparation also can be emulsified.
  • the active antigenic ingredient or ingredients can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient.
  • the vaccine can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or adjuvants such as aluminum hydroxide or muramyl dipeptide or variations thereof.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or adjuvants such as aluminum hydroxide or muramyl dipeptide or variations thereof.
  • cholera toxin subunit B or other agents which stimulate antibody production at mucosal sites can be used.
  • coupling to larger molecules such as KLH or tetanus toxoid sometimes enhances immunogenicity.
  • the vaccines are conventionally administered parenterally, by injection, for example, either subcutaneously or intramuscularly.
  • Additional formulations which are suitable for other modes of administration include suppositories and, in some cases, oral formulations.
  • traditional binders and carriers include, for example, polyalkalene glycols or triglycerides.
  • Suppositories can be formed from mixtures containing the active ingredient in the range of about 0.5% to about 10%, preferably about 1 to about 2%.
  • Oral formulations can include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. These compositions can take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain from about 10% to about 95% of active ingredient, preferably from about 25% to about 70%.
  • compositions can be formulated into the vaccine as neutral or salt forms.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the peptide) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • the vaccines are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective and immunogenic.
  • the quantity to be administered can depend on the subject to be treated and the degree of protection desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and can be peculiar to each individual. However, suitable dosage ranges are of the order of about several hundred micrograms active ingredient per individual. Suitable regimes for initial administration and booster shots are also variable, but are typified by an initial administration followed in one or two week intervals by a subsequent injection or other administration.
  • a serum was considered antibody positive for specific HIV protein if it was positive on either HIV-1 IIIB or HIV-1 UCD1 immunoblot analysis.
  • a serum was considered positive for either gp120 or gp160 if it was positive on both HIV-1 IIIB and HIV-1 UCD1 immunoblot analyses.

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US10/080,772 US20030091987A1 (en) 2001-02-22 2002-02-22 Materials and methods for detecting, preventing, and treating retroviral infection
US12/407,730 US8182820B2 (en) 2001-02-22 2009-03-19 Method for inducing cross-reactive immune responses to the human immunodeficiency virus (HIV) in a host by administering feline immunodeficiency virus (FIV) capsid (CA) or reverse transcriptase (RT) immunogens
US13/476,835 US20120294891A1 (en) 2001-02-22 2012-05-21 Materials and methods for detecting, preventing, and treating retroviral infection
US14/511,864 US11154610B2 (en) 2001-02-22 2014-10-10 Immunogenic compositions comprising FIV and HIV gag antigens
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