title: Correlates of antiviral immune restoration in acute and chronic HIV type 1 infection: sustained viral suppression and normalization of T cell subsets.
abstract: Highly active antiretroviral therapy (HAART) has suppressed viral replication and facilitated normalization of T cell subsets, resulting in restoration of immunity against opportunistic pathogens. Induction of full immune restoration in chronically infected individuals, including HIV-specific helper T cell responses, is considered a priority, particularly if immunological control of HIV is to be achieved. Regimens containing dual protease inhibitors (PIs) have provided greater suppression of viremia than single-PI regimens. We therefore conducted a prospective analysis of factors associated with immune restoration after 3 years of therapy in two cohorts of acutely and chronically HIV-infected patients, comparing dual- versus single-PI regimens. Earlier and more durable returns of p24-specific proliferation were demonstrated in patients receiving dual-PI compared with single-PI regimens. Individuals with restored p24 responses had larger reductions in total HIV-specific cytotoxic T lymphocytes (CTLs) associated with stronger viral suppression, but Gag-specific CTLs remained higher, demonstrating that Gag-specific helper T cell responses were a critical component of functional immune restoration. On examination of clinical factors associated with immune restoration, we demonstrated that decreasing activation of CD8+ T cells (%CD8+ CD38+) and increasing proportions of CD4+ T cells were independently associated with restoration of p24 responses. Minimal immune activation, resulting from maximal suppression of viral replication, was required for long-term restoration and maintenance of Gag-specific T cell responses. This study uniquely demonstrates that dual-PI regimens are superior in achieving these levels of virological control and immune restoration in both chronic and acute infection, compared with single-PI or non-PI regimens.
authors.affiliation: Australian Red Cross Blood Service, Sydney, NSW 2000, Australia. wdyer@arcbs.redcross.org.au
authors.forename: Wayne B
authors.initials: WB
authors.lastname: Dyer
authors.forename: Harmjan
authors.initials: H
authors.lastname: Kuipers
authors.forename: Marcel W
authors.initials: MW
authors.lastname: Coolen
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Geczy
authors.forename: Janice
authors.initials: J
authors.lastname: Forrester
authors.forename: Cassy
authors.initials: C
authors.lastname: Workman
authors.forename: John S
authors.initials: JS
authors.lastname: Sullivan
mesh_terms: D000208:Acute Disease; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D002908:Chronic Disease; D015683:Gene Products, gag / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D020276:HIV Long-Term Survivors; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013997:Time Factors; D014766:Viremia / Q000188:drug therapy / Q000276:immunology / Q000821:virology
chemical_list: D019380:Anti-HIV Agents; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors