A single isolated antibody or antibody fragment thereof binds to multiple variant sequences within an epitope of HIV-1 Tat protein displayed in multiple strains and subtypes of HIV-1. This "pan-epitope" antibody is useful in therapeutic and prophylactic compositions and treatments of HIV-1 infection, regardless of strain. This pan-epitope antibody is useful in assays for the detection of levels of HIV-1 based on a measurement of the amount of Tat protein in a biological sample.

Description of the Invention

SUMMARY OF THE INVENTION

In one aspect, the invention provides a single isolated antibody or fragment thereof, which binds to multiple HIV-1 Tat Epitope 1 variant sequences (hereafter referred to as a "pan-Epitope 1" antibody) and thereby binds to HIV-1 Tat protein from multiple strains and subtypes. In one embodiment, the single pan-Epitope 1 antibody binds to five or at least five variant sequences of HIV-1 Tat Epitope 1, which is specifically defined in the following detailed description of the invention.

In another embodiment, the single pan-Epitope 1 antibody binds to at least two variant sequences of HIV-1 Tat Epitope 1. In yet another embodiment, the single pan-Epitope 1 antibody or fragment binds at least one of the variant Tat Epitope 1 sequences (a) through (d) as defined below and at least one of the variant sequences (e) through (h) as defined below. In another embodiment, the single pan-Epitope 1 antibody binds to at least three, or at least four, of the variant HIV-1 Tat Epitope 1 sequences.

In another embodiment, the single pan-Epitope 1 antibody binds to at least six, of these sequences. In another embodiment, the single pan-Epitope 1 antibody binds to at least seven, or at least eight, of the variant HIV-1 Tat Epitope 1 sequences. In another embodiment, the single pan-Epitope 1 antibody binds to nine or more variant HIV-1 Tat Epitope 1 sequences. In another embodiment, a single pan-Epitope 1 antibody is reactive with greater than 95% of the known variants of the HIV-1 Tat protein (both B and non-B clades).

In another aspect, the invention provides a pharmaceutical composition comprising one single pan-Epitope 1 antibody as above defined. In another embodiment, the composition contains multiple different pan-Epitope 1 antibodies as above-defined. In still a further embodiment, the composition contains an additional antibody to HIV-1. Such a composition is intended to minimize chronic viremia which leads to AIDS. Such a composition is useful for chronically infected, symptomatic or asympomatic patients, or for patients on other anti-retroviral treatments.

In still a further aspect, the invention provides a diagnostic assay reagent comprising a single pan-Epitope 1 antibody or fragment as above-defined and a detectable label or label system.

In another aspect, the invention provides a kit for use in performing a sandwich assay comprising one or more pan-Epitope 1 antibodies or fragments, one or more additional antibody to HIV-1 Tat which binds to an epitope on HIV-1 Tat other than Epitope 1, and optionally one or more detectable labels or label systems for identifying binding of the antibodies.

In another aspect, the invention provides a kit for use in performing an assay comprising one or more pan-Epitope 1 antibodies or fragments and one or more detectable labels or label systems for identifying binding of the pan-Epitope 1 antibody to the Tat. Either kit of the invention also includes coated solid supports, miscellaneous substrates and apparatus for evoking or detecting the signals provided by the labels, as well as conventional apparatus for taking blood samples, appropriate vials and other diagnostic assay components.

In still a further aspect, the invention provides a method of inhibiting replication of HIV-1 or reducing the viral levels of HIV-1 in an infected human subject by administering to said subject a pharmaceutical composition as defined herein. In one embodiment the method involves administering the compositions of this invention to maintain lower viral levels of HIV-1 in a chronically infected subject.

In another aspect, the invention provides the use of a pan-Epitope 1 antibody in the preparation of a medicament for inhibiting replication of HIV-1 in a human subject. In one embodiment, this use employs a pan-Epitope 1 antibody that binds five or more different Epitope 1 variant sequences. In another aspect the invention provides the use of a pan-Epitope 1 antibody or antibody fragment and an anti-Epitope 2 antibody or antibody fragment in the preparation of a medicament for inhibiting replication of HIV-1 in a human subject.

In a further aspect, the invention provides a method of making a single isolated pan-Epitope 1 antibody or fragment thereof.

In still another aspect, the invention provides a diagnostic assay to measure levels of HIV-1 Tat in a subject. In one embodiment, the assay is a competition assay employing a pan-Epitope 1 antibody of this invention. In a further embodiment, the pan-Epitope 1 antibody is one that binds at least five of the Tat Epitope 1 variant sequences, i.e., pan-Epitope 1 antibody #5.

DETAILED DESCRIPTION OF THE INVENTION

This invention addresses the need in the art for therapeutic and diagnostic reagents and compositions for use in treating and diagnosing HIV-1 infection of multiple strains and subtypes. One unique advantage of the pan-Epitope 1 compositions of this invention involves the formulation and application of therapies that are less complex, that use a smaller number of reagents, and yet are efficacious against a full range of HIV-1 strains and subtypes. Similarly, the present invention permits detection of multiple HIV-1 strains and subtypes with a single assay and minimum number of reagents, thereby obviating multiple separate tests and reagents for each strain or subtype of HIV-1 by which a subject may be infected.

HIV-1 Tat Epitope 1 and the Pan-Epitope 1 Antibody

As used herein, the term "variant HIV-1 Tat Epitope 1 sequences" refers to the sequences represented by the formula R.sub.1-Asp-Pro-X.sub.7-Leu-Y.sub.9-Pro-R.sub.2 SEQ ID NO: 5, wherein X.sub.7 is Arg, Lys, Ser or Asn; Y.sub.9 is Glu or Asp; R.sub.1 is absent, Val, Glu-Val, or Glu-Pro-Val; and R.sub.2 is absent or Trp-Z.sub.12-R.sub.3, wherein Z.sub.12 is absent, Lys, or Asn, and R.sub.3 is absent or is all or part of the sequence -His-Pro-Gly-Ser- SEQ ID NO: 27. According to one preferred embodiment, an Epitope 1 sequence contains variable amino acids at the X.sub.7 and Y.sub.9 positions and R.sub.1 as Val and R.sub.2 is absent, i.e., Val-Asp-Pro-X.sub.7-Leu-Y.sub.9-Pro SEQ ID NO: 28. According to another embodiment an Epitope 1 sequence contains the three variable positions, X.sub.7, Y.sub.9 and Z.sub.12 positions, an absent R.sub.1, and an R.sub.2 which is Trp-Z.sub.12-R.sub.3, wherein R.sub.3 is absent, e.g., Asp-Pro-X.sub.7-Leu-Y.sub.9-Pro-Trp-Z.sub.12 SEQ ID NO: 29. Given the above formula, the entire scope of variant Epitope 1 sequences may be sequences of between 7 and about 14 amino acids in length, either containing fragments of the above-identified SEQ ID NO: 5 or larger sequences encompassing the fragments or entirety of SEQ ID NO: 5. Thus there exist greater than the eight Epitope 1 variant sequences specified by the Examples below.

As another embodiment, other variant HIV-1 Tat Epitope 1 sequences include the sequences represented by the formula Glu-Val-Asp-Pro-X.sub.7-Leu-Y.sub.9-Pro SEQ ID NO: 30, Val-Asp-Pro-X.sub.7-Leu-Y.sub.9-Trp-Z.sub.12- SEQ ID NO: 31, and Val-Asp-Pro-X.sub.7-Leu-Y.sub.9-Trp-Z.sub.12-His-Pro-Gly-Ser- SEQ ID NO: 32, as well as other sequences falling within the above formula. In one embodiment, exemplified below, certain selected variant HIV-1 Epitope 1 sequences are represented by the following eight sequences -- see Original Patent.

Thus, in one embodiment, for example, a pan-Epitope 1 antibody binds to variants (a), (b), (c), (d), and (h). In another embodiment a pan-Epitope 1 antibody binds to different combinations of multiple variants of (a) through (h).

This definition of Epitope 1 also encompasses homologous or analogous modified epitope sequences, wherein the non-variable amino acids in the formula of SEQ ID NO: 5 (i.e., those not represented by a single letter and subscript) may be conservatively replaced individually by amino acid residues having similar characteristics. For example, the non-variable amino acid residues of SEQ ID NO: 5 may be replaced by other amino acid residues bearing the same charge and/or similar side chain lengths. Similarly the non-variable naturally-occurring amino acids in the SEQ ID NO: 5 may be replaced by unnatural amino acid residues, i.e., an amino acid having a modification in the chemical structure, e.g., a D-amino acid, an amino acid bearing a non-naturally occurring side chains an N-methylated amino acid, etc. See, the cited references relating to N-methylated amino acids, among others. See, e.g., L. Aurelio et al, 2002 Organic Letters, 4(21):3767-3769 and references cited therein.

Thus the present invention provides a "pan-Epitope 1 antibody", which term refers to a single, isolated antibody or fragment thereof that is capable of binding to multiple HIV-1 Epitope 1 amino acid sequences. Desirably, as demonstrated in the examples below, the pan-Epitope 1 antibody has a K.sub.D of 1.0.times.10.sup.-9 or less for all variant sequences to which it binds. One of skill in the art will readily understand that the dissociation constant K.sub.D is derived from the measures of association (k.sub.a) and dissociation (k.sub.d). All pan-Epitope 1 antibodies of this invention desirably have similar K.sub.D values.

As exemplified herein, one embodiment of a pan-Epitope 1 antibody is a single isolated antibody or fragment that is capable of binding to at least five variant HIV-1 Epitope 1 sequences. In a further embodiment, the pan-Epitope 1 antibody is a single isolated antibody or fragment that is capable of binding to five variant HIV-1 Epitope 1 sequences. In still a further embodiment, the pan-Epitope 1 antibody is a single isolated antibody or fragment that is capable of binding to the following five variant HIV-1 Epitope 1 amino acid sequences: VDPRLEPW-Z.sub.12-R.sub.3 (SEQ ID NO: 6); VDPKLEPW-Z.sub.12-R.sub.3 (SEQ ID NO: 7); VDPSLEPW-Z.sub.12-R.sub.3 (SEQ ID NO: 8); VDPNLEPW-Z.sub.12-R.sub.3 (SEQ ID NO: 9); and VDPNLDPW-Z.sub.12-R.sub.3 (SEQ ID NO: 10), wherein Z.sub.12 is Lys or Asn, and R.sub.3 is absent or all or part of the sequence -His-Pro-Gly-Ser- SEQ ID NO: 27. This exemplified IgG1 pan-Epitope 1 antibody that binds to five variants is shown in the assays below to have a K.sub.D of 1.0.times.10.sup.-9 or less for all five variant sequences.

Another embodiment of a pan-Epitope 1 antibody is a single, isolated antibody or fragment thereof that is capable of binding to at least two variant HIV-1 Epitope 1 sequences, such as two of the above-listed variant Epitope 1 sequences (a) through (h). Still another embodiment of a pan-Epitope 1 antibody is a single, isolated antibody or fragment thereof that is capable of binding to at least three variant HIV-1 Epitope 1 sequences. Another embodiment of a pan-Epitope 1 antibody is a single, isolated antibody or fragment thereof that is capable of binding to at least four variant HIV-1 Epitope 1 sequences. In another embodiment, the pan-Epitope 1 antibody of the invention which binds to from two to four different Epitope 1 variants is an antibody or fragment that binds to at least one variant HIV-1 Epitope 1 sequence having Glu in position Y.sub.9 and at least one variant HIV-1 Epitope 1 sequence having Asp in position Y.sub.9.

In another embodiment, a single, isolated antibody or fragment that is a pan-Epitope 1 antibody binds to at least six variant HIV-1 Epitope 1 sequences. An additional embodiment includes a single, isolated antibody or fragment thereof that is capable of binding to at least seven variant HIV-1 Epitope 1 sequences. That term also refers to a single, isolated antibody or fragment thereof that is capable of binding to at least eight variant HIV-1 Epitope 1 sequences. That term also refers to a single, isolated antibody or fragment thereof that is capable of binding to at least nine or more variant HIV-1 Epitope 1 sequences, when the additional variable positions of Z.sub.12 or any flanking amino acids are taken into account. In still further embodiments, as demonstrated in the examples below, the pan-Epitope 1 antibody has a K.sub.D of 1.0.times.10.sup.-9 or less for each variant sequence.

In one embodiment, as taught in detail in the Examples below, a single selected pan-Epitope 1 antibody binds from two up to eight of the variant HIV-1 Epitope 1 sequences represented by the aforementioned eight sequences (a) through (h).

Thus, one single isolated pan-Epitope 1 antibody or fragment binds at least two of the variant sequences (a) through (h). Another single isolated antibody or fragment of the invention binds to from two to four said different variant sequences. A specific embodiment of such a single isolated pan-Epitope 1 antibody or fragment binds at least one of said variant sequences (a) through (d) and at least one of said variant sequences (e) through (h). Still other single isolated pan-Epitope 1 antibody or fragment binds any five through all eight of the variant sequences (a) through (h). As exemplified below, the pan-Epitope 1 antibody generated from one specific clone binds 5 variants of Epitope 1 (a) through (d), and (h). This specific antibody is referred throughout this specification as pan-Epitope antibody #5.

However, as noted above, other examples of pan-Epitope 1 antibodies may bind other Epitope 1 sequences, containing the Z.sub.12 amino acid or homologous sequences represented by (a) through (h) above in which at least one non-variable amino acid is an unnatural amino acid.

Thus, a single pan-Epitope antibody or fragment of the present invention binds to HIV-1 Tat protein from multiple strains and subtypes. In one embodiment, a single pan-Epitope antibody or fragment binds to greater than 95% of the known HIV-1 strains and subtypes, including strains and subtypes from both B and non-B clades.

As used herein, the term "antibody" refers to an intact immunoglobulin having two light and two heavy chains. Thus a single isolated antibody or fragment may be a monoclonal antibody, a synthetic antibody, a recombinant antibody, a chimeric antibody, a humanized antibody, or a human antibody. The term "antibody fragment" refers to less than an intact antibody structure, including, without limitation, an isolated single antibody chain, an Fv construct, a Fab construct, an Fc construct, a light chain variable or complementarity determining region (CDR) sequence, etc.

Such pan-Epitope 1 antibodies or fragments are generated using sequential selection and screening techniques such as described in the Examples below or using other synthetic or recombinant techniques. As referred to above, the single isolated pan-Epitope 1 antibody or fragment of this invention may be prepared by a method involving serial and sequential selection and screening from libraries of antibodies or antibody fragments. For example, selections involve contacting each single chain human Fv library with a synthetic Epitope 1 peptide and/or recombinant Tat protein, and presenting variant Tat Epitope 1 sequences to the libraries. For example, a library of single chain antibody variable sequences (scFv) is selected for sequences that bind to a first Epitope 1 variant amino acid sequence, such as a biotinylated peptide containing the variant sequence. A mixture of scFv that bind to this first sequence is obtained and the scFv that do not bind are discarded from the library. The resulting selected scFv mixture is then again serially and sequentially contacted with as many different Epitope 1 sequences as desired and the non-binding scFv successively discarded, until a mixture of resulting scFv is obtained that bind multiple variants of Epitope 1, e.g., from two, three, four, five, six, seven or eight or more different sequences of Epitope 1. The resulting scFv that binds to the desired number of Epitope 1 variants is then manipulated and cloned to provide source of that selected scFv. For example, the scFV is manipulated to present it in the antibody or fragment form desired.

Thereafter each clone is screened to determine its reactivity to different HIV-1 Tat Epitope 1 variants of different HIV-1 strains and subtypes. The screen is expanded until an antibody or antibody fragment or construct is obtained which exhibits the required binding to the selected multiple variant sequences, e.g., two, three, four, five, six, seven or eight or more Epitope 1 variant sequences of SEQ ID NO: 5.

The pan-Epitope 1 antibody must contain variable regions from the scFv that are capable of mediating binding to the multiple Epitope 1 variants. However, the constant regions can be altered by now conventional means. For example, the variable region of each pan-Epitope 1 scFv may be inserted into a constant region backbone, such as a human IgG1 backbone. Such an antibody is described in Example 1 below. Thus the resulting pan-Epitope 1 antibody may be a chimeric antibody containing human light chain variable regions associated with heavy chains from human or non-human sources, e.g., monkeys, etc., or a humanized antibody, using human IgG antibody backbones, or an antibody fragment. Selection of a suitable antibody backbone and insertion of the pan-Epitope 1 scFv are within the skill of the art, provided with this specification and the conventional teachings of immunology.

Given the teachings of this specification, one of skill in the art may generate any the different pan-Epitope 1 antibodies described herein.

Pharmaceutical Compositions and Methods of the Invention

Thus, another aspect of this invention is a pharmaceutical composition useful for the treatment of HIV-1 that contains a pan-Epitope 1 antibody or fragment and a pharmaceutically acceptable carrier. Such a pharmaceutical composition may preferably contain a single pan-Epitope 1 antibody or fragment that binds eight X.sub.7/Y.sub.9 variants of the Epitope 1 formula. Another pharmaceutical composition may contain a single pan-Epitope 1 antibody or fragment that binds five or more of the X.sub.7/Y.sub.9 variants of the Epitope 1. Still another pharmaceutical composition may contain a single pan-Epitope 1 antibody or fragment that binds two through seven of the X.sub.7/Y.sub.9 variants of Epitope 1. Yet another composition can contain a single pan-Epitope 1 antibody or fragment that binds nine or more X.sub.7/Y.sub.9/Z.sub.12 variants of Epitope 1.

Additional embodiments of pharmaceutical compositions may contain two or more different pan-Epitope 1 antibodies of this invention, e.g., two or three antibodies that each bind multiple different variants. For example, one pan-Epitope 1 antibody in a composition may bind only Epitope 1 variants in which Y.sub.9 is Glu and the second Epitope 1 antibody in the composition binds only the variants in which Y.sub.9 is Asp. A variety of such combinations may be readily prepared by one of skill in the art given this disclosure.

Pharmaceutical compositions of this invention also may contain antibodies to other HIV-1 epitopes, such as the previously identified HIV-1 Tat Epitope 2. As used herein, the term "HIV-1 Tat Epitope 2" refers to the sequence -Lys-X.sub.42-Leu-Gly-Ile-Ser-Tyr-Gly-Arg-Lys- SEQ ID NO: 2, where X.sub.42 is Gly or Ala.

Thus, one pharmaceutical composition may contain a pan-Epitope 1 antibody of this invention in combination with an antibody the specifically binds an epitope sequence located within Epitope 2.

Still other antibodies to other proteins and immunogenic sites on the HIV-1 virus may be readily generated and combined in a suitable pharmaceutical composition of this invention. Alternatively, the compositions of this invention may be used in conjunction with, or sequentially with, other HIV-1 anti-viral therapies or pharmaceutical regimens.

As defined herein, the pharmaceutically acceptable carrier suitable for use in an immunogenic proteinaceous composition of the invention are well known to those of skill in the art. Such carriers include, without limitation, water, saline, buffered saline, phosphate buffer, alcoholic/aqueous solutions, emulsions or suspensions. Other conventionally employed diluents, adjuvants and excipients, may be added in accordance with conventional techniques. Such carriers can include ethanol, polyols, and suitable mixtures thereof, vegetable oils, and injectable organic esters. Buffers and pH adjusting agents may also be employed. Buffers include, without limitation, salts prepared from an organic acid or base. Representative buffers include, without limitation, organic acid salts, such as salts of citric acid, e.g., citrates, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, trimethanmine hydrochloride, or phosphate buffers. Parenteral carriers can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous carriers can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose and the like. Preservatives and other additives such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like may also be provided in the pharmaceutical carriers. The present invention is not limited by the selection of the carrier. The preparation of these pharmaceutically acceptable compositions, from the above-described components, having appropriate pH isotonicity, stability and other conventional characteristics is within the skill of the art. See, e.g., texts such as Remington: The Science and Practice of Pharmacy, 20th ed, Lippincott Williams & Wilkins, publ., 2000; and The Handbook of Pharmaceutical Excipients, 4.sup.th edit., eds. R. C. Rowe et al, APhA Publications, 2003.

Thus the invention provides for use of a pan-Epitope 1 antibody in the preparation of a medicament for inhibiting replication of HIV-1 in a human subject.

Such pharmaceutical compositions of this invention are useful in a method of inhibiting replication of HIV-1 in a human subject exposed to HIV-1. A suitable dose of a composition according to this invention is administered to a human subject in an amount effective to bind HIV-1 Tat protein released from infected cells. In one embodiment, the pharmaceutical compositions may be therapeutically administered to an HIV-1 infected human for treatment or control of viral infection. Such an infected human may be asymptomatic or symptomatic. The pan-Epitope 1 antibodies reduce chronic viral multiplication in infected subjects and minimize progression to AIDS. See, e.g., the in vitro results of an inhibition assay embodied in the previously-discussed FIG. 1 (see Original Patent).

The method operates by permitting the pan-Epitope 1 antibody to block the transfer of Tat from infected cells to other infected or uninfected cells. This action reduces the multiplicity of infection and blocks the burst of HIV-1 viral expansion, and thus lowers viral levels. In already infected patients, this method of reduction of viral levels can reduce chronic viremia and progression to AIDS. The method can involve chronically administering the composition. Among such patients suitable for treatment with this method are HIV-1 infected patients who are immunocompromised by disease and unable to mount a strong immune response. In later stages of HIV infection, the likelihood of generating effective titers of antibodies is less, due to the immune impairment associated with the disease. Also among such patients are HIV-1 infected pregnant women, neonates of infected mothers, and unimmunized patients with putative exposure (e.g., a human who has been inadvertently "stuck" with a needle used by an HIV-1 infected human).

These pan-Epitope 1 antibody compositions are administered as passive immunotherapy to inhibit viral multiplication and lower the viral load. The exogenous antibodies which react with greater than 95%, or greater than 99%, of known Tat proteins from HIV-1 provide in the patient an immediate interdiction of the transfer of Tat from virally infected cells to other infected or uninfected cells. According to this method, the patient may be chronically treated with the antibody composition for a long treatment regimen.

Another unique aspect of the present invention is provided by an alternative method of inhibiting HIV-1 replication, which involves administering both the pan-Epitope 1 antibody and an Epitope 2 antibody to an infected patient. It is anticipated that such a method may employ administering a combination of pan-Epitope 1 antibody and an Epitope 2 antibody as a single composition. Alternatively, each antibody may be administered as a separate composition, in conjunction or sequentially to the patient. Surprisingly the combination of the two antibodies or antibody fragments produces a synergistic result. This result indicates that when administered used together, dosages of the antibodies that are lower than the dosages used when each antibody is administered separately are useful to achieve the desired therapeutic result, i.e., a reduction in viremia.

The synergy between these two reagents is exemplified in an inhibition assay. When used in an in vitro inhibition assay format for the inhibition of HIV-1 Tat levels in HIV-1 infected cell culture, the pan-Epitope 1 antibody and the Epitope 2 antibody, used alone as a pharmaceutical composition, produce parallel virus-inhibiting results. See, e.g., FIG. 2 (see Original Patent). However, unexpectedly the two antibodies, administered together, provide a more potent inhibition of virus levels than the relatively equivalent inhibition provided when either anti-Tat antibody is used alone. See, the results of the assay described for FIG. 2. Such synergistic activity of the pan-Epitope 1 antibody with an Epitope 2 antibody was not expected.

In each of the above-described methods, these compositions of the present invention are administered by an appropriate route, e.g., by the subcutaneous, oral, mucosal, intravenous, intraperitoneal, intramuscular, nasal, or inhalation routes. The presently preferred route of administration is subcutaneous, intravenous or intramuscular.

The amount of the pan-Epitope 1 antibody of the invention, with or without other anti-HIV-1 antibodies present in each dose, is selected with regard to consideration of the patient's age, weight, sex, general physical condition and the like. The amount of antibody required to produce an exogenous effect in the patient without significant adverse side effects varies depending upon the pharmaceutical composition employed. In infected patients, generally, each dose will comprise between about 5 to 400 mg/mL injection of the pan-Epitope 1 antibody in a sterile solution. Another dosage is about 200 mg of the antibody. Still another dosage is about 100 mg of the antibody. Still another embodiment is a dosage of about 50 mg of the antibody. A further embodiment is a dosage of about 10 mg of the antibody. When used together, dosages of the pan-Epitope 1 antibody and an Epitope 2 antibody, in one embodiment, are the same as above. In another embodiment, due to the synergy between the two antibodies, a combination dosage is lower than additive single dosages of each antibody alone.

The frequency of chronic administration may range from daily dosages to once or twice a week to once a month, and may depend upon the half-life of the antibody (e.g., about 7-21 days). However, the duration of chronic treatment for such infected patients is anticipated to be an indefinite, but prolonged period. Other dosage ranges may also be contemplated by one of skill in the art, particularly where administration of the antibody composition is in conjunction or sequential with other anti-viral treatments.

The compositions of the present invention can be employed in chronic treatments for subjects at risk of acute infection due to needle sticks or maternal infection. The antibody compositions of the present invention can also be employed in chronic treatments for infected patients, or patients with advanced HIV.
 

Claim 1 of 9 Claims

1. A single isolated antibody or antibody fragment which binds five variant sequences, wherein each variant sequence is represented by the formula R.sub.1-Asp-Pro-X.sub.7-Leu-Y.sub.9-Pro-R.sub.2 (SEQ ID NO: 5), wherein X.sub.7 is Arg, Lys, Ser or Asn; wherein Y.sub.9 is Glu or Asp; wherein R.sub.1 is Val; wherein R.sub.2 is absent; and wherein said single isolated antibody or antibody fragment binds to HIV-1 Tat protein from at least five HIV-1 strains and subtypes.
 

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