The Thai Phase III HIV Type 1 Vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120

1 Department of Retrovirology, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS) , Bangkok, Thailand .
AIDS research and human retroviruses (Impact Factor: 2.33). 10/2012; 28(11). DOI: 10.1089/aid.2012.0103
Source: PubMed


Abstract The Thai Phase III clinical trial (RV144) showed modest efficacy in preventing HIV-1 acquisition. Plasma collected from HIV-1-uninfected trial participants completing all injections with ALVAC-HIV (vCP1521) prime and AIDSVAX B/E boost were tested for antibody responses against HIV-1 gp120 envelope (Env). Peptide microarray analysis from six HIV-1 subtypes and group M consensus showed that vaccination induced antibody responses to the second variable (V2) loop of gp120 of multiple subtypes. We further evaluated V2 responses by ELISA and surface plasmon resonance using cyclic (Cyc) and linear V2 loop peptides. Thirty-one of 32 vaccine recipients tested (97%) had antibody responses against Cyc V2 at 2 weeks postimmunization with a reciprocal geometric mean titer (GMT) of 1100 (range: 200-3200). The frequency of detecting plasma V2 antibodies declined to 19% at 28 weeks post-last injection (GMT: 110, range: 100-200). Antibody responses targeted the mid-region of the V2 loop that contains conserved epitopes and has the amino acid sequence KQKVHALFYKLDIVPI (HXB2 Numbering sequence 169-184). Valine at position 172 was critical for antibody binding. The frequency of V3 responses at 2 weeks postimmunization was modest (18/32, 56%) with a GMT of 185 (range: 100-800). In contrast, naturally infected HIV-1 individuals had a lower frequency of antibody responses to V2 (10/20, 50%; p=0.003) and a higher frequency of responses to V3 (19/20, 95%), with GMTs of 400 (range: 100-3200) and 3570 (range: 200-12,800), respectively. RV144 vaccination induced antibodies that targeted a region of the V2 loop that contains conserved epitopes. Early HIV-1 transmission events involve V2 loop interactions, raising the possibility that anti-V2 antibodies in RV144 may have contributed to viral inhibition.

Download full-text


Available from: Jerome Hahn Kim, Jan 31, 2014
51 Reads
  • Source
    • "Additional analyses showed that plasma Abs from RV144 vaccinees reactive in a microarray to a linear V3 peptide from CRF01_AE were also an inverse correlate of infection risk, but only in vaccine recipients who had lower levels of Env-specific plasma IgA and aggregate neutralizing Ab activity (Gottardo et al., 2013), and V3-specific Abs from RV144 vaccinees were shown to capture infectious virions, including the vaccine strain CM244 (Liu et al., 2013). These and previous data (Karasavvas et al., 2012) generated the hypothesis that IgG Abs to epitopes in both the V2 and V3 regions of gp120 are part of a complex interplay of immune responses that contributed to the reduced rate of infection in RV144 participants, and suggested that further delineation of additional elements of the V3 Ab response might reveal important information about the factors involved in blocking HIV infection. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the role of V3-specific IgG antibodies (Abs) in the RV144 clinical HIV vaccine trial, which reduced HIV-1 infection by 31.2%, the anti-V3 Ab response was assessed. Vaccinees' V3 Abs were highly cross-reactive with cyclic V3 peptides (cV3s) from diverse virus subtypes. Sieve analysis of CRF01_AE breakthrough viruses from 43 vaccine- and 66 placebo-recipients demonstrated an estimated vaccine efficacy of 85% against viruses with amino acids mismatching the vaccine at V3 site 317 (p=0.004) and 52% against viruses matching the vaccine at V3 site 307 (p=0.004). This analysis was supported by data showing vaccinees' plasma Abs were less reactive with I(307) replaced with residues found more often in vaccinees' breakthrough viruses. Simultaneously, viruses with mutations at F(317) were less infectious, possibly due to the contribution of F(317) to optimal formation of the V3 hydrophobic core. These data suggest that RV144-induced V3-specific Abs imposed immune pressure on infecting viruses and inform efforts to design an HIV vaccine.
    11/2014; 1(1):37-45. DOI:10.1016/j.ebiom.2014.10.022
  • Source
    • "Again, this experiment showed maximal α4β7 binding for a number of diverse peptides spanning different lengths (Figure 9). The peptide with the strongest activity toward α4β7 (starting with sequence LRD) is also the same peptide that was previously shown to strongly react with antibodies elicited by vaccinees in the immune-correlates analysis of the RV144 trial (Figure 9) [2], [10]. In the analysis, Karasavvas et al. used ELISA to test antibody responses of RV144 participants to linear biotinylated V2 loop peptides. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The peptide segment of the second variable loop of HIV-1 spanning positions 166-181 harbors two functionally important sites. The first, spanning positions 179-181, engages the human α4β7 integrin receptor which is involved in T-cell gut-homing and may play a role in human immunodeficiency virus (HIV)-host cell interactions. The second, at positions 166-178, is a major target of anti-V2 antibodies elicited by the ALVAC/AIDSVAX vaccine used in the RV144 clinical trial. Notably, these two sites are directly adjacent, but do not overlap. Here, we report the identity of a second determinant of α4β7 binding located at positions 170-172 of the V2 loop. This segment - tripeptide QRV170-172- is located within the second site, yet functionally affects the first site. The absence of this segment abrogates α4β7 binding in peptides bearing the same sequence from position 173-185 as the V2 loops of the RV144 vaccines. However, peptides exhibiting V2 loop sequences from heterologous HIV-1 strains that include this QRV170-172 motif bind the α4β7 receptor on cells. Therefore, the peptide segment at positions 166-178 of the V2 loop of HIV-1 viruses appears to harbor a cryptic determinant of α4β7 binding. Prior studies show that the anti-V2 antibody response elicited by the RV144 vaccine, along with immune pressure inferred from a sieve analysis, is directed to this same region of the V2 loop. Accordingly, the anti-V2 antibodies that apparently reduced the risk of infection in the RV144 trial may have functioned by blocking α4β7-mediated HIV-host cell interactions via this cryptic determinant.
    PLoS ONE 09/2014; 9(9):e108446. DOI:10.1371/journal.pone.0108446 · 3.23 Impact Factor
  • Source
    • "Interestingly, these two vaccines when given individually failed to induce significant immunity in humans [5] [6]. Subsequent studies of the RV144 trial data indicated that antibody-dependent cell-mediated cytotoxicity (ADCC) [7] and antibodies directed towards the V1/V2 region of env may contributed to the protective immunity observed [8] [9] [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We have established that the efficacy of a heterologous poxvirus vectored HIV vaccine, fowlpox virus (FPV)-HIV gag/pol prime followed by attenuated vaccinia virus (VV)-HIV gag/pol booster immunisation, is strongly influenced by the cytokine milieu at the priming vaccination site, with endogenous IL-13 detrimental to the quality of the HIV specific CD8+ T cell response induced. We have now developed a novel HIV vaccine that co-expresses a C-terminal deletion mutant of the mouse IL-4, deleted for the essential tyrosine (Y119) required for signalling. In our vaccine system, the mutant IL-4C118 can bind to IL-4 type I and II receptors with high affinity, and transiently prevent the signalling of both IL-4 and IL-13 at the vaccination site. When this IL-4C118 adjuvanted vaccine was used in an intranasal rFPV/intramuscular rVV prime-boost immunisation strategy, greatly enhanced mucosal/systemic HIV specific CD8+ T cells with higher functional avidity, expressing IFN-γ, TNF-α and IL-2 and greater protective efficacy were detected. Surprisingly, the IL-4C118 adjuvanted vaccines also induced robust long-lived HIV gag-specific serum antibody responses, specifically IgG1 and IgG2a. The p55-gag IgG2a responses induced were of a higher magnitude relative to the IL-13Rα2 adjuvant vaccine. More interestingly, our recently tested IL-13Rα2 adjuvanted vaccine which only inhibited IL-13 activity, even though induced excellent high avidity HIV-specific CD8+ T cells, had a detrimental impact on the induction of gag-specific IgG2a antibody immunity. Our observations suggest that (i) IL-4 cell-signalling in the absence of IL-13 retarded gag-specific antibody isotype class switching, or (ii) IL-13Rα2 signalling was involved in inducing good gag-specific B cell immunity. Thus, we believe our novel IL-4R antagonist adjuvant strategy offers great promise not only for HIV-1 vaccines, but also against a range of chronic infections where sustained high quality mucosal and systemic T and B cell immunity are required for protection.
    Vaccine 08/2014; 32(43). DOI:10.1016/j.vaccine.2014.08.023 · 3.62 Impact Factor
Show more