Recombinant Glycoprotein Vaccines for Human Immunodeficiency Virus-Infected Children and Their Effects on Viral Quasispecies

Abstract

In individuals infected with human immunodeficiency virus type 1 (HIV-1), specific immunity is associated with a more diverse viral repertoire and slower disease progression. Attempts to enhance antiviral immunity with therapeutic vaccination have shown that recombinant glycoprotein (RGP) vaccines are safe, well tolerated, and immunogenic, but the effect of RGP vaccines on the viral repertoire is unknown. We evaluated diversification of the viral envelope in 12 HIV-infected children who received placebo or RGP vaccines. At baseline, 11 of 12 patients had multiple viral variants. On follow-up 6 months later, children who had a strong vaccineassociated lymphoproliferative immune response showed less viral diversification than those in whom the immune response was weak or absent. These results suggest that the immune response elicited by RGP vaccines does not exert a significant selection pressure on the viral quasispecies and therefore may not be helpful in changing the course of the disease.Infection with human immunodeficiency virus type 1 (HIV-1) leads to eventual immune attrition and the onset of AIDS. The rate of disease progression, however, is variable and appears to be determined, in part, by the nature of the immune response against the virus. Long-term slow progressors, for example, typically exhibit a broad range of antiviral responses, particularly cell-mediated immunity. Such individuals also harbor diverse viral quasispecies, and several recent reports have shown that this high degree of viral diversity is a direct consequence of immune selection pressure. (4,8,14) Attempts to boost specific immunity with HIV-1 recombinant glycoprotein (RGP) vaccines have resulted in some HIVinfected individuals developing augmented humoral and cellular immune responses. (7,12,15) Whether these vaccineassociated immune responses correlate with any change in the repertoire of viral quasispecies remains unknown.The objectives of the current study were to characterize quasispecies diversity at baseline in a group of 12 asymptomatic HIV-1-infected children who received either placebo or RGP vaccines and to determine whether these vaccines generate an added immunologic selection pressure capable of driving viral evolution. The vaccines studied were all recombinant envelope proteins; therefore, we assayed changes in the diversity of the viral envelope-the region of the genome most likely to be affected by a vaccine-associated immune response.The number of patients evaluated was small; however, our results suggest that RGP vaccination in these children did not drive viral evolution. Indeed, there seemed to be an inverse relationship between vaccine-associated immune response and the degree of viral diversity. Although the study sample was small, these findings are provocative, and we believe that the results merit further study in a larger cohort of patients. These data highlight the importance of measuring viral diversity to evaluate the efficacy of therapeutic HIV vaccination. MATERIALS AND METHODSPatients and vaccines. A...

Molecular study of the quasispecies evolution of a typical pigeon paramyxovirus type 1 after serial passages in pigeons by contact

“…However, the influence of vaccination and/or co-infection, for example with immunosuppressive agents such as circovirus (Todd, 2000), on the nature of pPMV-1 quasispecies is also worth studying. Indeed, such an influence has been shown for other viruses Essajee et al , 2002), and such a hypothesis relating to an interaction between the quasispecies nature of pPMV-1, vaccination and coinfections, together with the fact that suspect cases are more systematically reported, might explain why more and more cases of pigeon paramyxovirosis are recorded in Europe (Commission of the European Community, 2000; Terregino et al , 2003) despite the strengthening of control measures.…”

Therapeutic vaccination against HIV: current progress and future possibilities

“…In addition, rgp160 was demonstrated to be less beneficial for CD4 + T-cell counts and HIV viral load measurements than zidovudine monotherapy in this patient group [83]. Other recombinant Env proteins have been shown to be safe and some immunogenic by standard laboratory parameters, although no candidate vaccine has significantly delayed disease progression in any patient group [84,85].…”

Therapeutic AIDS Vaccines

“…The only exception is a Swedish study of therapeutic immunization with gp160 in which deaths were delayed significantly when data was censored at two years (p=0.026), but at the conclusion of study the number of total fatalities was not different between treatment groups [10]. It has been thus concluded that recombinant HIV envelope vaccines in general may not be helpful in changing the clinical outcome [14].…”

“…For example, in a pediatric study when the gp160 (IIIB; MicroGeneSys) was compared with gp120 (SF-2; Chiron) and gp120 (MN; Genentech) there was no difference in the outcome from any tested vaccine [13]. In this and other envelope vaccine studies CD4 cell counts and viremia did not differ significantly among vaccine and control groups [7][8][9][10][11][12][13][14][15][16]. The only exception is a Swedish study of therapeutic immunization with gp160 in which deaths were delayed significantly when data was censored at two years (p=0.026), but at the conclusion of study the number of total fatalities was not different between treatment groups [10].…”