Ional unit of Env, as expressed on the surface of infectious

Ional unit of Env, as expressed on the surface of infectious virions, is a trimer of non-covalently-associated extracellular subunit (gp120) and transmembrane subunit (gp41). Due to the tremendous genetic diversity of the HIV Env, the antibodies elicited by a successful vaccine will have to neutralize a wide range of circulating HIV-1 isolates [2]. Such antibodies are referred to as broadly neutralizing antibodies (bNAbs). Although eliciting such responses by vaccination has not yet been achieved, numerous studies have investigated the development and characteristics of broadly neutralizing antibodies produced during natural HIV-1 infection in humans. Such studies provided novel information on the epitopes targeted by these cross-clade neutralizing activities, and the factors associated withtheir development. Several studies of infected subjects in early and chronic HIV-1 infection have demonstrated that broadly neutralizing antibody responses develop in approximately 15 of infected individuals [1,12?8], and become detectable within 2 to 3 years post infection [14,16,19]. In contrast, autologous neutralizing antibody responses develop weeks to months after infection in virtually all infected subjects, but although potent, are largely strain-specific and rapidly escaped by the virus [8,20?3]. Systematic analyses of the epitope Title Loaded From File specificities of broadly neutralizing antibody responses in HIV+ sera have demonstrated that a limited number of specificities are responsible for the serum cross-neutralizing activity in any given individual [13,15,24?9]. Monoclonal antibodies (MAbs) with broad neutralizing activities have been isolated from chronically-infected HIV+ subjects and have been shown to target structurally-conserved epitopes of Env: the CD4 binding site (CD4-BS) [30?4], conserved elements of the V2 loop and associated carbohydrates [35,36] and conserved elements of the V3 loop and associated carbohydrates [37,38] on gp120. In addition, a few broadly neutralizing MAbs target the membrane proximal external region of the gp41 subunit [39,40]. In a previous study we sought to determine the timing of the development of the broadly neutralizing antibody response to ?HIV-1 clade B in a cohort of anti-retroviral naive subjects that have been monitored longitudinally from a few months to up to 7 years post infection [14]. Our findings indicated that broadlyCo-Evolving bNAbs during HIV-Infectionneutralizing antibody responses emerged gradually, and became detectable at approximately 2.5 years of infection. Subsequently, these responses increased both in potency 1407003 and breadth. Others have also Title Loaded From File reported on a similar time-dependent development of cross-neutralizing antibody responses during HIV-1 infection [16,19,41]. Epitope mapping studies of the polyclonal IgG responses in plasmas from the cohort we examined indicated that the earliest cross-neutralizing antibody responses targeted either the CD4-BS on gp120 or epitopes not present on monomeric gp120 [14]. Since neutralizing activities against the gp41 subunit of Env were not detectable in the plasmas, we assumed that these later neutralizing activities targeted epitopes present on the oligomeric Env, but not present on monomeric gp120. We also reported that in certain plasmas a small number of epitope specificities contributed to the overall cross-neutralizing activity of a plasma sample. For example, anti-CD4-BS antibodies were responsible for neutralizing a certain number of viruses, and antib.Ional unit of Env, as expressed on the surface of infectious virions, is a trimer of non-covalently-associated extracellular subunit (gp120) and transmembrane subunit (gp41). Due to the tremendous genetic diversity of the HIV Env, the antibodies elicited by a successful vaccine will have to neutralize a wide range of circulating HIV-1 isolates [2]. Such antibodies are referred to as broadly neutralizing antibodies (bNAbs). Although eliciting such responses by vaccination has not yet been achieved, numerous studies have investigated the development and characteristics of broadly neutralizing antibodies produced during natural HIV-1 infection in humans. Such studies provided novel information on the epitopes targeted by these cross-clade neutralizing activities, and the factors associated withtheir development. Several studies of infected subjects in early and chronic HIV-1 infection have demonstrated that broadly neutralizing antibody responses develop in approximately 15 of infected individuals [1,12?8], and become detectable within 2 to 3 years post infection [14,16,19]. In contrast, autologous neutralizing antibody responses develop weeks to months after infection in virtually all infected subjects, but although potent, are largely strain-specific and rapidly escaped by the virus [8,20?3]. Systematic analyses of the epitope specificities of broadly neutralizing antibody responses in HIV+ sera have demonstrated that a limited number of specificities are responsible for the serum cross-neutralizing activity in any given individual [13,15,24?9]. Monoclonal antibodies (MAbs) with broad neutralizing activities have been isolated from chronically-infected HIV+ subjects and have been shown to target structurally-conserved epitopes of Env: the CD4 binding site (CD4-BS) [30?4], conserved elements of the V2 loop and associated carbohydrates [35,36] and conserved elements of the V3 loop and associated carbohydrates [37,38] on gp120. In addition, a few broadly neutralizing MAbs target the membrane proximal external region of the gp41 subunit [39,40]. In a previous study we sought to determine the timing of the development of the broadly neutralizing antibody response to ?HIV-1 clade B in a cohort of anti-retroviral naive subjects that have been monitored longitudinally from a few months to up to 7 years post infection [14]. Our findings indicated that broadlyCo-Evolving bNAbs during HIV-Infectionneutralizing antibody responses emerged gradually, and became detectable at approximately 2.5 years of infection. Subsequently, these responses increased both in potency 1407003 and breadth. Others have also reported on a similar time-dependent development of cross-neutralizing antibody responses during HIV-1 infection [16,19,41]. Epitope mapping studies of the polyclonal IgG responses in plasmas from the cohort we examined indicated that the earliest cross-neutralizing antibody responses targeted either the CD4-BS on gp120 or epitopes not present on monomeric gp120 [14]. Since neutralizing activities against the gp41 subunit of Env were not detectable in the plasmas, we assumed that these later neutralizing activities targeted epitopes present on the oligomeric Env, but not present on monomeric gp120. We also reported that in certain plasmas a small number of epitope specificities contributed to the overall cross-neutralizing activity of a plasma sample. For example, anti-CD4-BS antibodies were responsible for neutralizing a certain number of viruses, and antib.

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