Methods of identifying HIV patients sensitive to therapy with GP120 V3 glycan-directed antibodies

1. A method of reducing the HIV-1 viral load in a human subject in need thereof, the method comprising:

a) Identifying a human subject who is infected with HIV-1 clade B;

b) Identifying in a biological sample from the subject via polynucleotide or polypeptide sequencing an HIV-1 gp120 comprising the following amino acid residues: N332glycan, D325, and one or more amino acid residues selected from the group consisting of T63, L179, T320, and H330, wherein the amino acid positions are with reference to SEQ ID NO: 4, wherein the biological sample is selected from blood, peripheral blood mononuclear cells (PBMCs), serum, plasma, semen or lymph nodes; and

c) Administering to the subject an effective amount of an antibody or antigen-binding fragment thereof that comprises a VH region comprising a VH-CDR1, a VH-CDR2, and a VH-CDR3; and a VL region comprising a VL-CDR1, a VL-CDR2, and a VL-CDR3, wherein the VH region and the VL region bind to an epitope of the HIV-1 gp120 within the third variable loop (V3); wherein the VH-CDR1, the VH-CDR2, the VH-CDR3 the VL-CDR1, the VL-CDR2, and the VH-CDR3 comprise the sequences set forth, respectively, in:

i. SEQ ID NOs.: 7, 8, 9, 10, 11 and 12;

ii. SEQ ID NOs.: 7, 13, 9, 10, 11 and 12;

iii. SEQ ID NOs.: 14, 15, 16, 17, 11 and 18;

iv. SEQ ID NOs.: 14, 19, 20, 17, 11 and 18;

V. SEQ ID NOs.: 21, 22, 23, 24, 25 and 26;

vi. SEQ ID NOs.: 21, 22, 27, 24, 25 and 26;

vii. SEQ ID NOs.: 28, 29, 30, 31, 32 and 33; or

viii. SEQ ID NOs.: 34, 35, 36, 37, 25 and 38.

2. The method of claim 1 , comprising identifying a subject infected with a population of HIV-1 expressing a gp120 comprising the following amino acid residues:

i. N332glycan, D325 and T63;

ii. N332glycan, D325 and L179;

iii. N332glycan, D325 and T320;

iv. N332glycan, D325 and H330;

V. N332glycan, D325, T63 and L179;

vi. N332glycan, D325, T63 and T320;

vii. N332glycan, D325, T63 and H330;

viii. N332glycan, D325, L179 and T320;

ix. N332glycan, D325, L179 and H330;

X. N332glycan, D325, T320 and H330;

xi. N332glycan, D325, T63, T320 and H330;

xii. N332glycan, D325, T63, L179 and T320;

xiii. N332glycan, D325, T63, L179 and H330;

xiv. N332glycan, D325, L179, T320 and H330; or

XV. N332glycan, D325, T63, L179, T320 and H330.

3. The method of claim 1 , comprising identifying a subject infected with a population of HIV-1 expressing a gp120 comprising the following amino acid residues:

i. N332glycan, D325 and T63;

ii. N332glycan, D325 and L179;

iii. N332glycan, D325 and T320; or

iv. N332glycan, D325 and H330.

4. The method of claim 1 , comprising identifying a subject infected with a population of HIV-1 expressing a gp120 comprising the following amino acid residues:

i. N332glycan, D325, T63 and L179;

ii. N332glycan, D325, T63 and T320;

iii. N332glycan, D325, T63 and H330;

iv. N332glycan, D325, L179 and T320;

V. N332glycan, D325, L179 and H330; or

vi. N332glycan, D325, T320 and H330.

5. The method of claim 1 , comprising identifying a subject infected with a population of HIV-1 expressing a gp120 comprising the following amino acid residues:

i. N332glycan, D325, L179, T320 and H330;

ii. N332glycan, D325, T63, T320 and H330;

iii. N332glycan, D325, T63, L179 and T320; or

iv. N332glycan, D325, T63, L179 and H330.

6. The method of claim 1 , comprising identifying a subject infected with a population of HIV-1 expressing a gp120 comprising the following amino acid residues:

i. N332glycan, D325, T63 and H330;

ii. N332glycan, D325, T320 and H330;

iii. N332glycan, D325, L179, T320 and H330; or

iv. N332glycan, D325, T63, L179, T320 and H330.

7. The method of claim 1 , wherein at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%, of the HIV-1 species in the population of HIV-1 comprise the recited amino acid residues.

8. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises VH and VL regions from an antibody selected from the group consisting of GS-9722 (elipovimab), GS-9721, PGT-121, PGT-121.66, PGT-121.414, PGT-124, PGT-134, GS-2872, 10-1074, 10-1074-J, PGT-122 and PGT-123.

9. The method of claim 1 , wherein the antibody comprises an Fc region comprising the following amino acids at the indicated positions (EU index numbering):

i. Tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (YTE); or

ii. Leucine at position 428 and serine at position 434 (LS).

10. The method of claim 1 , wherein the antibody comprises an Fc region comprising the following amino acids at the indicated positions (EU index numbering):

i. Aspartate at position 239 and glutamate at position 332 (DE);

ii. Aspartate at position 239, glutamate at position 332 and leucine at position 330 (DEL);

iii. Aspartate at position 239, glutamate at position 332, alanine at position 236 (DEA); or

iv. Aspartate at position 239, glutamate at position 332, alanine at position 236 and leucine at position 330 (DEAL).

11. The method of claim 1 , comprising administering an antigen binding fragment.

12. The method of claim 11 , wherein the antigen binding fragment is selected from the group consisting of scFv, Fab, Fab2, Fab′, F(ab′)2, Fv, and a diabody.

13. The method of claim 1 , wherein the antibody is a multi-specific antibody.

14. The method of claim 1 , wherein the human subject is acutely infected with HIV-1.

15. The method of claim 14 , wherein the antibody is administered to a human subject having an HIV-1 infection of Fiebig stage IV or earlier.

16. The method of claim 14 , wherein the antibody is administered to a human subject who has not seroconverted.

17. The method of claim 1 , wherein the antibody is administered to a human subject having an HIV-1 infection of Fiebig stage V or Fiebig stage VI.

18. The method of claim 1 , wherein the human subject is chronically infected with HIV-1.

19. The method of claim 1 , further comprising administering to the subject one or more additional therapeutic agents for treating an HIV-1 infection.

20. The method of claim 1 , wherein the subject is not receiving antiretroviral therapy (ART) or ART is discontinued prior to administration of the antibody.

21. The method of claim 1 , wherein ART is discontinued after one or more administrations of the antibody or antigen-binding fragment thereof.

22. The method of claim 1 , further comprising administering one or more antiretroviral therapy (ART) agents to the subject.

23. The method of claim 1 , further comprising administering to the subject a TLR agonist.

24. The method of claim 23 , wherein the TLR agonist is a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist or a TLR9 agonist.

25. The method of claim 24 , wherein the TLR7 agonist is selected from the group consisting of vesatolimod, imiquimod, and resiquimod.

26. The method of claim 1 , comprising multiple administrations of the antibody or antigen-binding fragment thereof, optionally with a TLR agonist, at predetermined intervals.

27. The method of claim 1 , wherein, after one or more administrations of the antibody or antigen-binding fragment thereof, the subject does not exhibit symptoms of HIV-1 or AIDS in the absence of anti-retroviral treatment (ART) for at least 6 months, at least 1 year, at least 2 years, at least 3 years, or more.

28. The method of claim 1 , wherein, after one or more administrations of the antibody, the subject has a viral load copies/ml blood of less than 500, less than 400, less than 300, less than 200, less than 100, less than 50, in the absence of anti-retroviral treatment (ART) for at least 6 months, at least 1 year, at least 2 years, at least 3 years, or more.

29. The method of claim 1 , comprising identifying a population of HIV-1 RNA in a serum or plasma sample.

30. The method of claim 1 , further comprising the step of obtaining one or more biological samples from the subject.

31. The method of claim 30 , wherein two or more biological samples are obtained from the subject.

32. The method of claim 31 , wherein the two or more biological samples are obtained from the same tissue or fluid at two or more different time points.

33. The method of claim 31 , wherein the two or more biological samples are obtained from different tissues or fluids, or from different anatomical locations.

34. The method of claim 1 , wherein the VH region and the VL region comprise amino acid sequences that are at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%, identical to the VH region and the VL region amino acid sequences set forth, respectively, in:

SEQ ID NOs.: 400 and 401;

SEQ ID NOs.: 402 and 403;

SEQ ID NOs.: 402 and 404;

SEQ ID NOs.: 464 and 465;

SEQ ID NOs.: 405 and 406;

SEQ ID NOs.: 466 and 467;

SEQ ID NOs.: 407 and 408;

SEQ ID NOs.: 409 and 410;

SEQ ID NOs.: 411 and 412;

SEQ ID NOs.: 413 and 414; or

SEQ ID NOs.: 415 and 416.