Hiv-encoded chemoattractant

Abstract

The combination of HIV proteins Tat and Nef is chemotactic for CD4+ cells. Utilizing the capacity of Tat and Nef to modulate CD4+ cell trafficking and infiltration, the invention provides various treatment modes for individuals infected with HIV. The invention further provides treatment modes for other localized diseases by controlling CD4+ cell trafficking and infiltration. In particular, the invention provides methodology for promoting CD4+ cell chemotaxis to a localized site of infection as a means of augmenting the efficacy of extant chemotherapeutic methods. The invention further provides methodology for diverting CD4+ cell infiltration from a localized site where the presence of CD4+ cells is detrimental to the clinical outcome, by providing a composition comprising Tat and Nef at a distinct site, such as blood, within the individual where the accumulation of CD4+ cells is less detrimental.

What is claimed is:  
     
         1 . A pharmaceutical composition comprising Tat and Nef, or a functional fragment or derivative thereof, in an effective amount to promote localized accumulation of CD4+ cells, and a chemotherapeutic agent.  
     
     
         2 . The pharmaceutical composition of    claim 1   , further comprising a pharmacologically acceptable diluent, carrier, stabilizer, or excipient.  
     
     
         3 . The pharmaceutical composition of    claim 1   , wherein said chemotherapeutic i agent is an antibiotic.  
     
     
         4 . The pharmaceutical composition of    claim 1   , wherein said chemotherapeutic agent is a compound effective at inhibiting HIV replication.  
     
     
         5 . The pharmaceutical composition of    claim 4   , wherein said chemotherapeutic agent is a component of highly active anti-retroviral therapy (HAART).  
     
     
         6 . The pharmaceutical composition of    claim 4   , wherein said pharmaceutical composition further comprises interleukin-2 (IL-2) and IL-6.  
     
     
         7 . The pharmaceutical composition of    claim 6   , wherein said pharmaceutical composition further comprises tumor necrosis factor-α (TNF-α).  
     
     
         8 . A composition comprising Tat and Nef, or a functional fragment of derivative thereof, in an effective amount to promote localized accumulation of CD4+ cells, and a compound that stimulates the differentiation of CD4+ Th0 cells into either Th1 cells or Th2 cells.  
     
     
         9 . The composition of    claim 8   , wherein said compound stimulates differentiation of CD4+ Th0 cells into Th1 cells, and is selected from the group consisting of IL-12 and an antibody that is capable of binding IL-4.  
     
     
         10 . The composition of    claim 8   , wherein said compound stimulates differentiation of CD4+ Th0 cells into Th2 cells, and is selected from the group consisting of IL-4 and an antibody that is capable of binding interferon γ.  
     
     
         11 . The composition of    claim 8   , further comprising an antigen and an adjuvant.  
     
     
         12 . A method of treating a disease, comprising administering a pharmaceutical composition and a chemotherapeutic compound to an individual in need thereof, wherein said pharmaceutical composition comprises Tat and Nef, or a functionally active fragment or derivative thereof, in an effective amount to promote localized accumulation of CD4+ cells, and wherein said chemotherapeutic compound is administered in an amount effective to treat said disease.  
     
     
         13 . The method of    claim 12   , wherein said pharmaceutical composition and said chemotherapeutic composition are co-administered.  
     
     
         14 . The method of    claim 12   , wherein said disease is selected from the group consisting of bacterial infection, parasitic infection, and viral infection.  
     
     
         15 . The method of    claim 12   , wherein said administration is by non-systemic injection, inhalation, oral, or topical application.  
     
     
         16 . A method of treating a disease, comprising administering a pharmaceutical composition to an individual in need thereof, wherein said pharmaceutical composition comprises Tat and Nef, or a functionally active fragment or derivative thereof, in an effective amount to promote localized accumulation of CD4+ cells, and wherein a localized, detrimental infiltration of CD4+ cells has occurred in association with a disease state, and wherein said administration is at a site distinct form said localized, detrimental infiltration of CD4+ cells.  
     
     
         17 . The method of    claim 16   , wherein said disease is an inflammatory disease, and said administration is by injection at a site distinct from said localized CD4+ cell infiltration.  
     
     
         18 . The method of    claim 16   , wherein said disease is selected from the group consisting of psoriasis, inflammatory bowl disease, and asthma.  
     
     
         19 . A method of obtaining CD4+ cells, comprising (a) administration of a composition comprising Tat and Nef, or a functionally active fragment or derivative thereof, to a tissue in an amount effective to promote the exfilitration of CD4+ cells from said tissue, and (b) obtaining said CD4+ cells.  
     
     
         20 . A method of treating HIV infection, comprising systemically administering a composition comprising Tat and Nef in an amount effective to inhibit CD4+ cell extravasation, and a neutralizing antibody capable of binding gp120.  
     
     
         21 . The method of    claim 20   , wherein said composition further comprising a chemotherapeutic agent that is a component of HAART.  
     
     
         22 . A method of treating HIV infection, comprising systemically administering a composition comprising Tat and Nef in an amount effective to promote chemotaxis of CD4+ cells into the circulation, and a neutralizing antibody capable of binding gp120.  
     
     
         23 . The method of    claim 22   , wherein said composition further comprising a chemotherapeutic agent that is a component of HAART.