RESUMEN
Cytotoxic T lymphocytes (CTL) play a critical role in controlling human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) infections. However, in spite of developing a strong CTL response most HIV-1-infected patients eventually progress to AIDS. Amino acid changes in CTL epitope have been previously described and may permit HIV to escape from CTL immune responses. The importance of CTL selection pressure in controlling the course of viral evolution in HIV-infected patient remains debatable. For over a 10-year period, we longitudinally followed a patient for bulk unstimulated effector (eCTL) and stimulated memory CTL responses (mCTL) against the viral proteins Gag, Pol, and Nef. The patient showed a strong CTL response against Nef in unstimulated peripheral blood mononuclear cells with a peak during Month 40 of the follow-up. The mCTL response was also higher against Nef than Gag and Pol. PCR amplification and nucleotide sequencing of the plasma viral variants showed a viral variant with the epitope deletion that was detected early during the follow-up and essentially replaced the wild-type virus during the peak eCTL response. These studies support the importance of Nef epitope deletion as a mechanism for HIV-1 escape from CTL immune pressure.
Asunto(s)
Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Productos del Gen nef/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Eliminación de Secuencia/genética , Linfocitos T Citotóxicos/inmunología , Secuencia de Aminoácidos , Recuento de Linfocito CD4 , Epítopos de Linfocito T/química , Estudios de Seguimiento , Productos del Gen nef/química , Productos del Gen nef/genética , Variación Genética/genética , Antígenos VIH/genética , Antígenos VIH/inmunología , Infecciones por VIH/virología , VIH-1/genética , Humanos , Datos de Secuencia Molecular , Filogenia , ARN Viral/sangre , Carga Viral , Productos del Gen nef del Virus de la Inmunodeficiencia HumanaRESUMEN
The safety and the immunogenicity of a recombinant canarypox live vector expressing the human immunodeficiency virus type 1 (HIV-1) gp160 gene from the MN isolate, ALVAC-HIV (vCP125), followed by booster injections of a soluble recombinant hybrid envelope glycoprotein MN/LAI (rgp160), were evaluated in vaccinia-immune, healthy adults at low risk for acquiring HIV-1 infection. Volunteers (n = 20) received vCP125 (10(6) TCID50) at 0 and 1 month, followed randomly by rgp160 formulated in alum or in Freund's incomplete adjuvant (FIA) at 3 and 6 months. Local and systemic reactions were mild or moderate and resolved within the first 72 hr after immunization. No significant biological changes in routine tests were observed in any volunteer. Two injections of vCP125 did not elicit antibodies. Neutralizing antibodies (NA) against the HIV-1 MN isolate were detected in 65 and 90% of the subjects after the first and the second rgp 160 booster injections, respectively. Six months after the last boost, only 55% were still positive. Seven of 14 sera with the highest NA titers against MN weakly cross-neutralized the HIV-1 SF2 isolate; none had NA against the HIV-1 LAI or against a North American primary isolate. Specific lymphocyte T cell proliferation to rgp 160 was detected in 25% of the subjects after vCP125 and in all subjects after the first booster injection and 12 months after the first injection. An envelope-specific cytotoxic lymphocyte activity was found in 39% of the volunteers and characterized for some of them as CD3+, CD8+, MHC class I restricted. The adjuvant formulation did not influence significantly the immune responses.(ABSTRACT TRUNCATED AT 250 WORDS)