Antonio Pires

A Balanced Type 1/Type 2 Response Is Associated with Long-Term Nonprogressive Human Immunodeficiency Virus Type 1 Infection

ABSTRACT Previous reports have emphasized the requirements for strong type 1 cell-mediated responses in the control of human immunodeficiency virus type 1 (HIV-1). HIV-1 Gag p24-specific CD4 helper T-lymphocyte (HTL) responses have been shown to inversely correlate with viral burden in HIV-1-infected individuals. In this study, peripheral blood mononuclear cells from 70 individuals with chronic progressive HIV-1 infection (clinical progressors), 10 clinical nonprogressors, and 3 immunologically discordant progressors were assessed for HTL proliferation and type 1/type 2 cytokine production. Clinical progressors lacked functional HIV-1-specific HTLs with proliferative and cytokine-producing capacity. Clinical nonprogressors were found to respond to a wide range of HIV-1 antigens from different clades, producing both type 1 and type 2 cytokines. Immunologically discordant progressors responded strongly to clade B Gag p24 with a type 1 cytokine profile but not to other antigens. Thus, in contrast to clinical nonprogressors, neither progressors nor immunologically discordant progressors secreted interleukin-4 (IL-4) in response to HIV-1 antigens. Both clinical nonprogressors and immunologically discordant progressors responded broadly to B clade Gag p24-overlapping peptides. However, IL-4 production in the nonprogressors was restricted to a limited number of p24 peptides. No HIV-1-specific T-cell responses were seen in 20 seronegative controls. Additionally, we observed a rapid type 1 to type 2 shift in the response of one immunologically discordant progressor upon onset of clinical symptoms. These results suggest that a balanced type 1/type 2 profile correlates with successful long-term control of HIV-1.

Reconstitution of CD4+ T cell responses in HIV-1 infected individuals initiating highly active antiretroviral therapy (HAART) is associated with renewed interleukin-2 production and responsiveness

Reconstitution of functional CD4+ T cell responsiveness to in vitro stimuli is associated with continuous highly active antiretroviral therapy (HAART). Thirty‐six antiretroviral naive patients received HAART over 16 weeks. Antigen‐specific, mitogen and interleukin (IL)‐2 induced lymphocyte proliferative responses and specific IL‐2 and IL‐4 production were assessed at each time‐point, together with quantification of HIV‐1 RNA load and lymphocyte populations. Reconstitution of recall responses was limited largely to persistent antigens such as Herpes simplex virus and Candida, rather than to HIV‐1 or neo‐antigens. Recall antigens, mitogens and IL‐2‐induced renewed responses were associated with in‐vitro production of IL‐2, but not IL‐4. Differential responsiveness to low versus high concentration IL‐2 stimulus increases in a stepwise manner, suggesting normalization of IL‐2 receptor expression and improved functionality. These increases in in‐vitro proliferative responses thus probably reflect short lived effector clones, driven by ongoing antigenic stimulus associated with persisting long‐term organisms. In this context non‐responsiveness to HIV‐1 antigens suggests ongoing HIV‐1 specific clonal T cell anergy.

Immune responses and reconstitution in HIV-1 infected individuals: impact of anti-retroviral therapy, cytokines and therapeutic vaccination

Most patients with chronic HIV-1 infection lack functional CD4(+) and CD8(+) HIV-1-specific T cells with proliferative and cytolytic capacity, respectively. This is despite being able to produce intracellular cytokines in response to viral antigens. Protease inhibitor (PI)-based highly active anti-retroviral therapy (HAART) is unable to completely eradicate virus and fails to enable total restoration of immunity including induction of anti-HIV-1 responses. We have taken novel approaches towards the treatment of chronic HIV-1 disease with the aim of instigating long-term non-progressor status and depletion of virus reservoirs. HIV-1-specific CD4(+) and CD8(+) T cell responses were measured following the administration of cytokines, during therapeutic vaccination, and following treatment interruption (TI) or drug therapy change. Administration of cytokines, with or without therapeutic vaccination, in HAART treated patients, improved both CD4(+) and CD8(+) HIV-1-specific T cell responses even in late-stage disease. Virus-specific T cell responses were also seen during TI or when transient viraemia was apparent, and following therapy change from a PI- to a non-nucleoside-based HAART regimen. Reconstitution of HIV-1-specific immune responses was found to be transient and reversal to the previous anergic state was rapid. Viral reservoirs in the latently infected resting CD4(+) T cells, on follicular dendritic cells of germinal centers or even in infected thymic epithelium may be involved in clonal suppression and anergy. These may present major obstacles to the maintenance of HIV-1-specific responses and the eventual eradication of HIV-1.

Initiation of antiretroviral therapy during recent HIV-1 infection results in lower residual viral reservoirs

Summary: To measure proviral HIV-1 DNA in patients treated with effective antiretroviral therapy (ART) during recent and chronic HIV-1 infection, and in long-term non-progressors (LTNP). We quantified HIV-1 DNA in peripheral blood samples from 39 HIV-1-infected subjects; 26 patients initiated non-nucleoside reverse transcriptase inhibitor (NNRTI) based ART at two different stages of infection: 16 during recent infection (RI) (HIV-1 exposure >60 days <1 year), and 10 during chronic infection (CI) (infected >2 years). The results were compared with those seen in 13 LTNP (infected >8 years, therapy naïve, and controlled viremia). Thirty-six weeks after initiation of ART, HIV-1-proviral DNA levels decreased from baseline in the RI group (P < 0.005) to levels comparable to LTNP. HIV-1 DNA also declined in the CI group (P = 0.053) but it remained significantly higher than in RI (P < 0.002) and LTNP (P < 0.02). However, plasma HIV-1 RNA levels become undetectable in 80% of CI patients 12 weeks post initiation of ART, compared to 41.2% in the RI group. All patients reached undetectable viremia by week 36 of therapy. These data indicate that initiation of NNRTI based ART during recent HIV-1 infection reduces HIV-1 DNA to levels comparable to those seen in LTNP, which is not apparent if therapy is started during chronic infection, and suggests an association between timing of initiation of ART and decay of the HIV-1 reservoir.

Thymic Output during Initial Highly Active Antiretroviral Therapy (HAART) and during HAART Supplementation with Interleukin 2 and/or with HIV Type 1 Immunogen (Remune)

The thymic output of patients receiving highly active antiretroviral therapy (HAART) was assessed by sjTREC (signal joint T cell receptor rearrangement excision circle) analysis to determine the thymic contribution to CD4(+) T cell reconstitution during initial therapy and during interleukin 2 (IL-2) and/or Remune supplementation of HAART. Levels of sjTRECs were observed to decline dramatically after the first 4 weeks of HAART and then increased without significant associated changes in CD4(+) T cell counts. HAART supplementation with IL-2 was observed to lead to rapid increases in CD4(+) T cells that were accompanied by sjTREC decreases. No notable changes in CD4(+) T cell counts and sjTRECs were seen in patients receiving HAART supplemented with Remune alone. The results indicate CD4(+) T cell maintenance during initial treatment of HIV-1 with HAART and early CD4(+) T cell reconstitution of patients receiving IL-2 with HAART is largely due to thymus-independent mechanisms, with the thymus making a limited contribution.

Treatment of primary HIV-1 infection with nonnucleoside reverse transcriptase inhibitor-based therapy is effective and well tolerated

Objectives Highly active antiretroviral therapy (HAART) has been advocated for the management of primary HIV‐1 infection. We investigated the use of a nonnucleoside reverse transcriptase inhibitor (NNRTI)‐based regimen in this setting.

Thymic activity in late‐stage HIV‐1 infected individuals receiving highly active antiretroviral therapy: potential effect of steroid therapy

Objective Our objective was to monitor the effect of steroid therapy on the thymic output and function of late‐stage HIV‐1‐infected patients undergoing highly active antiretroviral therapy (HAART).