Human immunodeficiency virus therapies utilizing N332-glycan-dependent antibodies and a reservoir activator

1. A method for inhibiting viral replication, reducing proviral DNA, or reducing viral load comprising administering to a subject infected with human immunodeficiency virus type 1 (HIV-1) a first regimen comprising one or more doses of an N332 glycan-dependent antibody and a reservoir activator until a proviral DNA level in a tissue of the subject is below about 1,000 DNA copies/10 6 cells, and, at least two months after completion of the first regimen, administering a second regimen comprising one or more doses of the N332 glycan-dependent antibody with or without a reservoir activator, wherein said N332 glycan-dependent antibody is selected from the group consisting of:

(a) an antibody comprising:

(i) a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; or

(ii) a heavy chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain having at least 97% sequence identity to the sequence of SEQ ID NO: 8;

(b) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 10, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 11, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 14;

(c) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22;

(d) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 137, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 138, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 139, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 140, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 142, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 143;

(e) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 25, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 26, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 27, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 30;

(f) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 35, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 36, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 37, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 38;

(g) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 41, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 43, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 44, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 46;

(h) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 49, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 50, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 51, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 52, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 53, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 54;

(i) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 57, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 58, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 59, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 60, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 61, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 62;

(j) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 145, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 146, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 147, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 148, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 149, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 150;

(k) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 153, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 154, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 155, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 156, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 157, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 158;

(l) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 73, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 74, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 75, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 76, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 77, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 78;

(m) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 81, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 82, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 83, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 84, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 85, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 86;

(n) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 97, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 98, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 99, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 100, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 101, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 102;

(o) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 169, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 170, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 171, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 172, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 173, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 174;

(p) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 177, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 178, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 179, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 182; and

(q) an antibody comprising

a heavy chain complementarity determining region (CDR-H) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 315, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 316, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 317, and a light chain complementarity determining region (CDR-L) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 318, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 319, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 320.

2. The method of claim 1 , wherein said N332 glycan-dependent antibody is PGT121.

3. The method of claim 1 , wherein said reservoir activator is a histone deacetylase (HDAC) inhibitor selected from romidepsin, vorinostat, and panobinostat.

4. The method of claim 1 , wherein said method further comprises administering at least a second antibody and a third antibody; wherein:

(a) said N332 glycan-dependent antibody is PGT121, said second antibody is 3BNC117, and said third antibody is CAP256-VRC26,

(b) said N332 glycan-dependent antibody is PGT121, said second antibody is VRC07-523, and said third antibody is CAP256-VRC26, or

(c) said N332 glycan-dependent antibody is PGT121, said second antibody is 3BNC117, and said third antibody is VRC07-523.

5. The method of claim 1 , wherein said N332 glycan-dependent antibody is 10-1074.

6. The method of claim 1 , wherein said reservoir activator is an immunologic activator selected from a cytokine and a TLR agonist.

7. The method of claim 1 , wherein said subject is a human.

8. The method of claim 1 , wherein the N332 glycan-dependent antibody and the reservoir activator is administered to said subject in the first regimen until said proviral DNA level in the tissue is below about 100 DNA copies/10 6 cells.

9. The method of claim 1 , wherein said tissue is lymph node tissue, gastrointestinal tissue, and/or peripheral blood.

10. The method of claim 1 , wherein said subject has a plasma viral load of less than 3,500 RNA copies/ml.

11. The method of claim 10 , wherein said subject has a plasma viral load of less than 2,000 RNA copies/ml.

12. The method of claim 1 , wherein said subject has an undetectable plasma viral load for at least 2 months following administration of said N332 glycan-dependent antibody and said reservoir activator.

13. The method of claim 12 , wherein said subject has an undetectable plasma viral load for at least 6 months following administration of said N332 glycan-dependent antibody and said reservoir activator.

14. The method of claim 1 , wherein said N332 glycan-dependent antibody is administered intravenously, intramuscularly, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, by gavage, in cremes, or in lipid compositions.

15. The method of claim 1 , wherein said N332 glycan-dependent antibody is administered at a concentration of about 0.01 mg/kg to about 20 mg/kg.

16. The method of claim 1 , wherein said method comprises administering a single dose of said N332 glycan-dependent antibody.

17. The method of claim 1 , wherein said second regimen is administered at least about 6 months after said first regimen.

18. The method of claim 1 , further comprising administering one or more of an antiretroviral therapy (ART); an HIV1-specific, broadly neutralizing antibody (bnAb); a CD4 binding site (CD4bs)-specific antibody; a V2 glycan-dependent antibody; or an immunomodulator.

19. The method of claim 18 , wherein the immunomodulator is AS-101, bropirimine, acemannan, CL246,738, EL10, FP-21399, gamma interferon, granulocyte macrophage colony stimulating factor, HIV core particle immunostimulant, IL-2, immune globulin intravenous, IMREG-1, IMREG-2, imuthiol diethyl dithio carbamate, alpha-2 interferon, methionine-enkephalin, MTP-PE muramyl-tripeptide, granulocyte colony stimulating factor, beta-propiolactone inactive HIV-1, CD4, a rCD4-IgG hybrid, SK&F 106528 Soluble T4, thymopentin, tumor necrosis factor, or infliximab.

20. The method of claim 18 , wherein the ART is efavirenz, emtricitabine, and tenofovir disoproxil fumarate; emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate; lamivudine and zidovudine; emtricitabine (FTC); lamivudine (3TC); abacavir and lamivudine; zalcitabine, dideoxycytidine (ddC); zidovudine (ZDV) or azidothymidine (AZT); abacavir, zidovudine, and lamivudine; tenofovir disoproxil fumarate and emtricitabine; enteric coated didanosine (ddl EC); didanosine (ddl) or dideoxyinosine; tenofovir disoproxil fumarate (TDF); stavudine (d4T); abacavir sulfate (ABC); rilpivirine; etravirine; delavirdine (DLV); efavirenz (EFV); nevirapine (NVP); amprenavir (APV); tipranavir (TPV); indinavir (IDV); saquinavir; saquinavir mesylate (SQV); lopinavir and ritonavir (LPV/RTV); Fosamprenavir Calcium (FOS-APV); ritonavir (RTV); Darunavir; atazanavir sulfate (ATV); nelfinavir mesylate (NFV); enfuvirtide (T-20); maraviroc; raltegravir (RAL); or dolutegravir.

21. The method of claim 18 , wherein said CD4bs-specific antibody is 3BNC117 or VRC07-523.

22. The method of claim 18 , wherein said V2 glycan-dependent antibody is CAP256-VRC26.

23. The method of claim 18 , wherein the antiretroviral therapy (ART) or the immunomodulator is administered prior to, concurrently with, or subsequent to administration of said N332 glycan-dependent antibody.

24. The method of claim 1 , wherein said N332 glycan-dependent antibody is PGT121 and said reservoir activator is a TLR agonist.

25. The method of claim 1 , wherein said reservoir activator is a TLR agonist.

26. The method of claim 1 , wherein said reservoir activator is a cytokine.

27. The method of claim 1 , wherein said N332 glycan-dependent antibody is PGT122, PGT123, PGT124, PGT125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT132, PGT133, PGT134, PGT135, PGT136, PGT137, PGT138, PGT139, or 10-1074.

28. The method of claim 5 , wherein said reservoir activator is a TLR agonist.

29. The method of claim 27 , wherein said reservoir activator is a TLR agonist.

30. The method of claim 2 , wherein said subject is a human.

31. The method of claim 5 , wherein said subject is a human.

32. The method of claim 27 , wherein said subject is a human.

33. The method of claim 1 , wherein said reservoir activator is a histone deacetylase (HDAC) inhibitor.

34. The method of claim 1 , wherein the antibody comprises

the CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and the CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.

35. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 15 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 16.

36. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 23 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 24.

37. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 143 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 144.

38. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 31 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 32.

39. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 39 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 40.

40. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has to the amino acid sequence of SEQ ID NO: 47 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 48.

41. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 55 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 56.

42. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has to the amino acid sequence of SEQ ID NO: 63 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 64.

43. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 151 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 152.

44. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 159 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 160.

45. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 79 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 80.

46. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 87 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 88.

47. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 103 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 104.

48. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 175 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 176.

49. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 183 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 184.

50. The method of claim 1 , wherein

the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 321 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 322.

51. The method of claim 34 , wherein said reservoir activator is a TLR agonist.

52. The method of claim 35 , wherein said reservoir activator is a TLR agonist.

53. The method of claim 36 , wherein said reservoir activator is a TLR agonist.

54. The method of claim 37 , wherein said reservoir activator is a TLR agonist.

55. The method of claim 38 , wherein said reservoir activator is a TLR agonist.

56. The method of claim 39 , wherein said reservoir activator is a TLR agonist.

57. The method of claim 40 , wherein said reservoir activator is a TLR agonist.

58. The method of claim 41 , wherein said reservoir activator is a TLR agonist.

59. The method of claim 42 , wherein said reservoir activator is a TLR agonist.

60. The method of claim 43 , wherein said reservoir activator is a TLR agonist.

61. The method of claim 44 , wherein said reservoir activator is a TLR agonist.

62. The method of claim 45 , wherein said reservoir activator is a TLR agonist.

63. The method of claim 46 , wherein said reservoir activator is a TLR agonist.

64. The method of claim 47 , wherein said reservoir activator is a TLR agonist.

65. The method of claim 48 , wherein said reservoir activator is a TLR agonist.

66. The method of claim 49 , wherein said reservoir activator is a TLR agonist.

67. The method of claim 50 , wherein said reservoir activator is a TLR agonist.

68. The method of claim 1 , wherein the heavy chain variable domain of the antibody has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7 and the light chain variable domain of the antibody has at least 97% sequence identity to the sequence of SEQ ID NO: 8.

69. The method of claim 68 , wherein the CDR-H2 of the antibody comprises a serine to asparagine substitution at position 60 of SEQ ID NO: 7.

70. The method of claim 1 , wherein the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 7 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 8.

71. The method of claim 1 , wherein the heavy chain variable domain of the antibody has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7 and the light chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 8.

72. The method of claim 1 , wherein the heavy chain variable domain of the antibody has the amino acid sequence of SEQ ID NO: 7 and the light chain variable domain of the antibody has at least 97% sequence identity to the amino acid sequence of SEQ ID NO: 8.

73. The method of claim 1 , further comprising measuring the proviral DNA level in the tissue of the subject during or after the first regimen.