Compositions and methods for determining whether a subject would benefit from co-receptor inhibitor therapy

摘要

The present invention provides methods and compositions for determining whether a subject would benefit from co-receptor inhibitor therapy. In certain aspects, the methods can be used to determine whether a subject infected with a dual-mixed tropic population of HIV would benefit from CCCR5-inhibitor therapy or CXCR4-inhibitor therapy, the methods comprising determining whether the HIV population is a homogeneous or heterogeneous population of HIV, wherein the nature of the homogenous or heterogenous population of HIV indicates whether the patient would benefit from co-receptor inhibitor therapy.

主权项

1. A method for determining whether a subject infected with a dual-mixed tropic population of human immunodeficiency viruses (HIV) would benefit from CXCR4-inhibitor or CCR5-inhibitor therapy, comprising:
a. determining whether the population is a homogeneous dual-mixed tropic or heterogeneous population by contacting a viral particle with a cell; wherein the viral particle or the cell comprises an indicator gene, the expression of which is dependent upon the entry of the viral particle into the cell; and wherein if the population is a homogeneous dual-mixed tropic population, step b but not step c or d of the method is performed, and wherein if the population is a heterogeneous population, step c and d but not step b of the method are performed; b. determining that the subject would benefit from CCR5-inhibitor therapy if the homogeneous dual-mixed tropic population is Dual_R tropic, determining that the subject would benefit from CXCR4-inhibitor therapy if the homogeneous dual-mixed tropic population is Dual_X tropic, and determining that the subject would not benefit from either CCR5-inhibitor or CXCR4-inhibitor therapy if the homogeneous dual-mixed tropic population is neither Dual_R tropic nor Dual_X tropic, wherein the population is Dual_R tropic if the population has at least 10-fold greater ability to enter cells expressing the CCR5 co-receptor relative to the population's ability to enter cells co-expressing CXCR4, and wherein the population is Dual_X tropic if the population has at least 10-fold greater ability to enter cells expressing the CXCR4 co-receptor relative to the population's ability to enter cells co-expressing CCR5, and treating the subject with an effective amount of a CCR5 inhibitor if the homogeneous dual-mixed tropic population is Dual_R tropic, treating the subject with an effective amount of a CXCR4 inhibitor if the homogeneous dual-mixed tropic population is Dual_X tropic, and treating the subject with an effective amount of an inhibitor other than a CCR5 inhibitor or a CXCR4 inhibitor if the homogeneous dual-mixed tropic population is neither Dual_R tropic nor Dual_X tropic; c. determining the relative proportions of CCR5-tropic, CXCR4-tropic, Dual_R tropic, Dual_X tropic, or dual tropic HIV of the heterogeneous population, wherein the HIV is Dual_R tropic if the HIV has at least 10-fold greater ability to enter cells expressing the CCR5 co-receptor relative to the HIV's ability to enter cells co-expressing CXCR4, and wherein the HIV is Dual_X tropic if the HIV has at least 10-fold greater ability to enter cells expressing the CXCR4 co-receptor relative to the HIV's ability to enter cells co-expressing CCR5; and d. determining whether the subject would benefit from CXCR4-inhibitor or CCR5-inhibitor therapy, comprising:
i. determining that the subject would benefit from CCR5-inhibitor therapy if the heterogeneous population contains CCR5-tropic and/or Dual_R tropic and CXCR4-tropic and/or Dual_X tropic HIV and comprises substantially more CCR5-tropic and/or Dual_R tropic HIV than CXCR4-tropic and/or Dual_X tropic HIV, and treating the subject with an effective amount of a CCR5 inhibitor;ii. determining that the subject would not benefit from either CCR5-inhibitor or CXCR4 inhibitor therapy if the heterogeneous population contains CCR5-tropic and/or Dual_R tropic and CXCR4-tropic and/or Dual_X tropic HIV and comprises comparable amounts of CCR5-tropic and/or Dual_R tropic and CXCR4-tropic and/or Dual_X tropic HIV, and treating the subject with an effective amount of an inhibitor other than a CCR5 inhibitor or CXCR4 inhibitor;iii. determining that the subject would benefit from CXCR4-inhibitor therapy if the heterogeneous population contains CCR5-tropic and/or Dual_R tropic and CXCR4-tropic and/or Dual_X tropic HIV and comprises substantially more CXCR4-tropic and/or Dual_X tropic HIV than CCR5-tropic and/or Dual_R tropic HIV, and treating the subject with an effective amount of a CXCR4 inhibitor;iv. determining that the subject would benefit from CCR5-inhibitor therapy if the heterogeneous population contains CCR5-tropic and/or Dual_R tropic and dual-tropic HIV and comprises substantially more CCR5-tropic and/or Dual_R tropic HIV than dual-tropic HIV, and treating the subject with an effective amount of a CCR5 inhibitor;v. determining that the subject would not benefit from CCR5-inhibitor therapy if the heterogeneous population contains CCR5-tropic and/or Dual_R tropic and dual-tropic HIV and comprises relatively comparable amounts of CCR5-tropic and/or Dual_R tropic HIV and dual-tropic HIV or comprises substantially more dual-tropic HIV than CCR5-tropic and/or Dual_R tropic HIV, and treating the subject with an effective amount of an inhibitor other than a CCR5 inhibitor;vi. determining that the subject would benefit from CXCR4-inhibitor therapy if the heterogeneous population contains CXCR4-tropic and/or Dual_X tropic and dual-tropic HIV and comprises substantially more CXCR4-tropic and/or Dual_X tropic HIV than dual-tropic HIV, and treating the subject with an effective amount of a CXCR4 inhibitor;vii. determining that the subject would not benefit from either CXCR4-inhibitor or CCR-5 inhibitor therapy if the heterogeneous population contains CXCR4-tropic and/or Dual_X tropic and dual-tropic HIV and comprises relatively comparable amounts of CXCR4-tropic and/or Dual_X tropic HIV and dual-tropic HIV or comprises substantially more dual-tropic HIV than CXCR4-tropic and/or Dual_X tropic HIV, and treating the subject with an effective amount of an inhibitor other than a CCR5 inhibitor or CXCR4 inhibitor;viii. determining that the subject would benefit from CCR5-inhibitor therapy if the heterogeneous population contains CCR5-tropic and/or Dual_R tropic, CXCR4-tropic and/or Dual_X tropic, and dual-tropic HIV and comprises substantially more CCR5-tropic and/or Dual_R tropic HIV than CXCR4-tropic and/or Dual_X tropic and dual-tropic HIV, and treating the subject with an effective amount of a CCR5 inhibitor;ix. determining that the subject would not benefit from either CCR5-inhibitor or CXCR4-inhibitor therapy if the heterogeneous population contains CCR5-tropic and/or Dual_R tropic, CXCR4-tropic and/or Dual_X tropic, and dual-tropic HIV and comprises relatively comparable amounts of CCR5-tropic and/or Dual_R tropic HIV and CXCR4-tropic and/or Dual_X tropic and dual-tropic HIV, and treating the subject with an effective amount of an inhibitor other than a CCR5 inhibitor or CXCR4 inhibitor; orx. determining that the subject would benefit from CXCR4-inhibitor therapy if the heterogeneous population contains CCR5-tropic and/or Dual_R tropic, CXCR4-tropic and/or Dual_X tropic, and dual-tropic HIV and comprises substantially more CXCR4-tropic and/or Dual_X tropic HIV than CCR5-tropic and/or Dual_R tropic and dual-tropic HIV, and treating the subject with an effective amount of a CXCR4 inhibitor.